CN117769441A - Compositions and methods for improved treatment of X-linked myotubulomyopathy - Google Patents

Compositions and methods for improved treatment of X-linked myotubulomyopathy Download PDF

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CN117769441A
CN117769441A CN202280051606.0A CN202280051606A CN117769441A CN 117769441 A CN117769441 A CN 117769441A CN 202280051606 A CN202280051606 A CN 202280051606A CN 117769441 A CN117769441 A CN 117769441A
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patient
administered
viral vector
cholestasis
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W·米勒
N·巴克特尔
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Astras Gene Therapy
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Astras Gene Therapy
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Priority claimed from PCT/US2022/030716 external-priority patent/WO2022251208A1/en
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Abstract

The present invention provides methods for treating co-morbid cholestatic liver dysfunction (e.g., bile stasis and hyperbilirubinemia) associated with neuromuscular disorders. In certain embodiments, the invention provides methods for assessing the readiness of a subject suffering from X-linked myotubulomyopathy (xltm) for combination therapy with an anti-cholestasis agent.

Description

Compositions and methods for improved treatment of X-linked myotubulomyopathy
Sequence listing
The present application contains a sequence listing, which has been electronically filed in ASCII format and incorporated by reference herein in its entirety. The ASCII copy was created at 2022, 5 months and 24 days, named "51037-057wo3_sequence_listing_5_24_22_st25" and was 69,743 bytes in size.
Technical Field
The present invention relates to a method for treating cholestatic liver dysfunction in a patient, such as a human patient, in connection with the current treatment of neuromuscular disorders.
Background
X-linked myomicrotubule myopathy (XLM) is a fatal skeletal muscle monogenic disease caused by loss of function mutations in myotubulin 1 (MTM 1). One of about every 50,000 newborn boys suffers from xltm, which generally exhibits marked hypotonia and respiratory failure. In extremely rare cases, women will suffer from severe forms of XLMTM. Survival beyond the postnatal period requires intensive support, including respiratory support at birth (i.e., mechanical ventilation) for 85% -90% of patients, ventilator dependence for 24 hours for nearly 50% of patients, and tracheostomies for about 60% of patients. Until recently, only supportive treatment options were available, such as using a ventilator or feeding tube. Recently, gene therapies involving the delivery of MTM1 have been developed for the treatment of xltm. However, there is a need in the art for improved methods of administering gene therapy to patients suffering from xltm.
Disclosure of Invention
The present disclosure provides methods for treating X-linked myotubulomyopathy (xltm) in a human patient in need thereof. In some embodiments, a therapeutically effective amount of a viral vector containing a transgene encoding myotubulin 1 (MTM 1) and an anti-cholestasis agent are administered to a patient.
In one aspect, the present disclosure provides a method of treating xltm in a human patient in need thereof, the method comprising administering to the patient (i) a therapeutically effective amount of a transgene encoding MTM1 and (ii) an anti-cholestasis agent, wherein the anti-cholestasis agent is administered to the patient in one or more doses beginning within about six weeks (e.g., about six weeks prior to administration or about six weeks after administration) of the transgene to the patient.
In a second aspect, the present disclosure provides a method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm, the method comprising administering to the patient (i) a therapeutically effective amount of a viral vector comprising a transgene encoding MTM1 and (ii) an anti-cholestasis agent, wherein the anti-cholestasis agent is administered to the patient in one or more doses that begin within about six weeks (e.g., about six weeks prior to administration or about six weeks after administration) of the viral vector to the patient.
In another aspect, the present disclosure provides a method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm, the method comprising administering to the patient (i) a therapeutically effective amount of a viral vector comprising a transgene encoding MTM1 and (ii) an anti-cholestasis agent, wherein the anti-cholestasis agent is administered to the patient in one or more doses that begin within about six weeks (e.g., about six weeks prior to administration or about six weeks after administration) of the viral vector to the patient.
In some embodiments, the anti-cholestasis agent is administered to the patient at one or more doses beginning within about five weeks (e.g., about five weeks before or about five weeks after administration) of the transgene to the patient, optionally wherein the anti-cholestasis agent is administered to the patient at one or more doses beginning within about four weeks (e.g., about four weeks before or about four weeks after administration) of the transgene to the patient, within about three weeks (e.g., about three weeks before or about three weeks after administration), within about two weeks (e.g., about two weeks before or about two weeks after administration), or within about one week (e.g., about one week before or about two weeks after administration), about six days before or about six days after administration, about five days before or about five days after administration, about four days before or about three days after administration, about two days before or about one day before or about two days after administration).
In some embodiments, the anti-cholestasis agent is administered to the patient in one or more doses beginning on the same day as the transgene is administered to the patient.
In another aspect, the present disclosure provides a method of treating xltm in a human patient in need thereof and who has previously been administered an anti-cholestasis agent, the method comprising administering to the patient a therapeutically effective amount of a transgene encoding MTM 1.
In another aspect, the present disclosure provides a method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm and previously administered an anti-cholestasis agent, the method comprising administering to the patient a therapeutically effective amount of a viral vector comprising a transgene encoding MTM 1.
In another aspect, the present disclosure provides a method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm and previously administered an anti-cholestasis agent, the method comprising administering to the patient a therapeutically effective amount of a viral vector comprising a transgene encoding MTM 1.
In some embodiments of any of the above aspects, the method further comprises monitoring the patient for development of cholestasis or hyperbilirubinemia.
In some embodiments of any of the above aspects, the patient's development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof is monitored by assessing a parameter of a blood sample obtained from the patient, wherein finding that the parameter is above a reference level identifies the patient as suffering from cholestasis, hyperbilirubinemia, or one or more symptoms thereof.
In some embodiments, the parameter comprises the level of serum bile acid in the blood sample. In some embodiments, the serum bile acid is cholic acid, chenodeoxycholic acid, deoxycholic acid, or ursodeoxycholic acid.
In some embodiments, the parameter comprises one or more results of a liver function test.
In some embodiments of any of the above aspects, the parameter comprises the level of aspartate aminotransferase or alanine aminotransferase in the blood sample.
In another aspect, the present disclosure provides a method of treating an xltm in a human patient in need thereof, the method comprising: (a) administering to the patient a transgene encoding MTM1, (b) monitoring the patient for development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, (c) administering to the patient an anti-cholestasis agent.
In another aspect, the present disclosure provides a method of treating an xltm in a human patient in need thereof, the method comprising: (a) At less than about 3x 10 14 An amount of vg/kg (e.g., less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 1014vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less, (b) monitoring the patient for development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, (c) administering an anti-cholestasis agent to the patient.
In another aspect, the present disclosure provides a method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm, the method comprising: (a) At less than about 3x10 14 An amount of vg/kg (e.g., less than about 3x10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less, (b) monitoring the patient for development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, (c) administering an anti-cholestasis agent to the patient.
In another aspect, the present disclosure provides a method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm, the method comprising: a) At less than about 3x10 14 An amount of vg/kg (e.g., less than about 3x10 14 vg/kg、2.9x 10 14 vg/kg、2.8x10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less), (b) monitoring the progression of cholestasis, hyperbilirubinemia, or one or more symptoms thereof in the patient, and if the patient exhibits bileStasis, hyperbilirubinemia, or one or more symptoms thereof, (c) administering an anti-cholestasis agent to the patient.
In another aspect, the present disclosure provides a method of treating an xltm in a human patient in need thereof, the method comprising: (a) administering to the patient a transgene encoding MTM1, (b) determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and (c) administering to the patient an anti-cholestasis agent.
In another aspect, the present disclosure provides a method of treating an xltm in a human patient in need thereof, the method comprising: (a) At less than about 3x10 14 An amount of vg/kg (e.g., less than about 3x10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less, (b) determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and (c) administering an anti-cholestasis agent to the patient.
In another aspect, the present disclosure provides a method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm, the method comprising: (a) At less than about 3x10 14 An amount of vg/kg (e.g., less than about 3x10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less, (b) determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and (c) administering an anti-cholestasis agent to the patient.
In another aspect, the present disclosure provides a method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm, the method comprising: (a) At less than about 3x10 14 An amount of vg/kg (e.g., less than about 3x10 14 vg/kg、2.9x 10 14 vg/kg、2.8x10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less, (b) determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and (c) administering an anti-cholestasis agent to the patient.
In another aspect, the present disclosure provides a method of treating XLMTM in a human patient in need thereof aged five or less (e.g., 5 years or less, 4 years or less, 3 years or less, 2 years or less, 1 year or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less), the method comprising: (a) administering to the patient a therapeutically effective amount of a transgene encoding MTM1, (b) monitoring the patient for development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, (c) administering to the patient an anti-cholestasis agent.
In another aspect, the present disclosure provides a method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm, the method comprising: (a) administering to the patient a therapeutically effective amount of a viral vector comprising a transgene encoding MTM1, (b) monitoring the patient for development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, (c) administering to the patient an anti-cholestasis agent.
In another aspect, the present disclosure provides a method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm, the method comprising: (a) administering to the patient a therapeutically effective amount of a viral vector comprising a transgene encoding MTM1, (b) monitoring the patient for development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, (c) administering to the patient an anti-cholestasis agent.
In another aspect, the present disclosure provides a method of treating XLMTM in a human patient in need thereof aged five or less (e.g., 5 years or less, 4 years or less, 3 years or less, 2 years or less, 1 year or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less), the method comprising: (a) administering to the patient a therapeutically effective amount of a transgene encoding MTM1, (b) determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and (c) administering to the patient an anti-cholestasis agent.
In another aspect, the present disclosure provides a method of treating XLMTM in a human patient in need thereof aged five or less (e.g., 5 years or less, 4 years or less, 3 years or less, 2 years or less, 1 year or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less), the method comprising: (a) administering to the patient a therapeutically effective amount of a transgene encoding MTM1, (b) determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and (c) administering to the patient an anti-cholestasis agent.
In another aspect, the present disclosure provides a method of treating or preventing cholestasis or hyperbilirubinemia in a human patient suffering from xltm and having previously been administered a transgene encoding MTM1, the method comprising administering an anti-cholestasis agent to the patient.
In another aspect, the present disclosure provides a method of treating or preventing cholestasis or hyperbilirubinemia in a human patient having an xltm and having previously been administered a viral vector comprising a transgene encoding MTM1 in an amount of less than about 3x 10 14 vg/kg (e.g., less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less), comprising administering an anti-cholestasis agent to a patient.
In another aspect, the present disclosure provides a method of treating or preventing cholestasis or hyperbilirubinemia in a human patient having xltm, a transgene encoding MTM1 that has been previously administered, and five years or less (e.g., 5 years old or less, 4 years old or less, 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgene is administered, the method comprising administering an anti-cholestasis agent to the patient.
In some embodiments of any of the above aspects, the transgene encoding MTM1 is administered to the patient by transduction with a viral vector containing the transgene encoding MTM 1.
In some embodiments of any of the above aspects, the patient is five years old or less (e.g., 5 years old or less, 4 years old or less, 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
In some embodiments of any of the above aspects, the patient is four years old or less (e.g., 4 years old or less, 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered, optionally wherein the patient is three years old or less (e.g., 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, or 1 month or less, e.g., 1 month or less), 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less), one year old or less (e.g., 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) or six months or less (e.g., 6 months or less, 3 months or less, 2 months or less, 1 year old or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less (e.g., 6 months or less), 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less).
In some embodiments of any of the above aspects, the patient is about 1 month to about 5 years old (e.g., about 1 month to about 5 years old, about 2 months to about 5 years old, about 3 months to about 5 years old, about 4 months to about 5 years old, about 5 months to about 5 years old, about 6 months to about 5 years old, about 1 year to about 5 years old, about 2 years to about 5 years old, about 3 years to about 5 years old, or about 4 years to about 5 years old) at the time of administration of the transgenic or viral vector.
In some embodiments of any of the above aspects, the viral vector is present in an amount of less than about 3x10 14 An amount of vg/kg (e.g., less than about 3x10 14 vg/kg、2.9x 10 14 vg/kg、2.8x10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to a patient.
In some embodiments of any of the above aspects, the viral vector is present at less than about 2.5x10 14 An amount of vg/kg (e.g., less than about 2.5x10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less), optionally wherein the viral vector is administered to the patient in an amount of less than about 2x 10 14 vg/kg (e.g., less than about 2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less), less than about 1.5x10 14 vg/kg (e.g., less than about 1.5x10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less), less than about 1.4x10 14 vg/kg (e.g., less than about 1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less) is administered to the patient.
In some embodiments of any of the above aspects, the viral vector is present at about 3x10 13 vg/kg to about 2.3X10 14 The amount of vg/kg is administered to the patient, optionally wherein the viral vector is administered at about 8x 10 13 vg/kg to about 1.8x10 14 vg/kg, about 1X 10 14 vg/kg to about 1.6x10 14 vg/kg, about 1.1X10 14 vg/kg to about 1.5x10 14 vg/kg or about 1.2x10 14 vg/kg to about 1.4x10 14 The amount of vg/kg is administered to the patient. For example, the viral vector may be about 3x10 13 vg/kg、3.1x 10 13 vg/kg、3.2x 10 13 vg/kg、3.3x 10 13 vg/kg、3.4x 10 13 vg/kg、3.5x 10 13 vg/kg、3.6x 10 13 vg/kg、3.7x 10 13 vg/kg、3.8x10 13 vg/kg、3.9x 10 13 vg/kg、4x 10 13 vg/kg、4.1x 10 13 vg/kg、4.2x 10 13 vg/kg、4.3x 10 13 vg/kg、4.4x 10 13 vg/kg、4.5x 10 13 vg/kg、4.6x 10 13 vg/kg、4.7x 10 13 vg/kg、4.8x 10 13 vg/kg、4.9x 10 13 vg/kg、5x 10 13 vg/kg、5.1x 10 13 vg/kg、5.2x 10 13 vg/kg、5.3x 10 13 vg/kg、5.4x 10 13 vg/kg、5.5x 10 13 vg/kg、5.6x 10 13 vg/kg、5.7x 10 13 vg/kg、5.8x 10 13 vg/kg、5.9x 10 13 vg/kg、6x 10 13 vg/kg、6.1x 10 13 vg/kg、6.2x 10 13 vg/kg、6.3x 10 13 vg/kg、6.4x 10 13 vg/kg、6.5x 10 13 vg/kg、6.6x 10 13 vg/kg、6.7x 10 13 vg/kg、6.8x 10 13 vg/kg、6.9x 10 13 vg/kg、7x 10 13 vg/kg、7.1x 10 13 vg/kg、7.2x 10 13 vg/kg、7.3x 10 13 vg/kg、7.4x 10 13 vg/kg、7.5x 10 13 vg/kg、7.6x 10 13 vg/kg、7.7x 10 13 vg/kg、7.8x 10 13 vg/kg、7.9x 10 13 vg/kg、8x 10 13 vg/kg、8.1x 10 13 vg/kg、8.2x 10 13 vg/kg、8.3x 10 13 vg/kg、8.4x 10 13 vg/kg、8.5x 10 13 vg/kg、8.6x 10 13 vg/kg、8.7x 10 13 vg/kg、8.8x 10 13 vg/kg、8.9x 10 13 vg/kg、9x 10 13 vg/kg、9.1x 10 13 vg/kg、9.2x 10 13 vg/kg、9.3x 10 13 vg/kg、9.4x 10 13 vg/kg、9.5x 10 13 vg/kg、9.6x 10 13 vg/kg、9.7x 10 13 vg/kg、9.8x 10 13 vg/kg、9.9x 10 13 vg/kg、1x 10 14 vg/kg、1.1x 10 14 vg/kg、1.2x 10 14 vg/kg、1.3x 10 14 vg/kg、1.4x 10 14 vg/kg、1.5x 10 14 vg/kg、1.6x 10 14 vg/kg、1.7x 10 14 vg/kg、1.8x 10 14 vg/kg、1.9x 10 14 vg/kg、2x 10 14 vg/kg、2.1x 10 14 vg/kg、2.2x 10 14 vg/kg or 2.3X10 14 The amount of vg/kg is administered to the patient.
In some embodiments of any of the above aspects, the viral vector is present at about 1.3x10 14 The amount of vg/kg is administered to the patient.
In some embodiments of any of the above aspects, the transgene or viral vector is administered to the patient in a single dose comprising the amount.
In some embodiments of any of the above aspects, the transgene or viral vector is administered to the patient in two or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) doses that together comprise the amount.
In some embodiments of any of the above aspects, the transgene or viral vector is administered to the patient in two or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) doses each individually comprising the amount.
In some embodiments of any of the above aspects, two or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) doses are separated from one another by one or more years (e.g., one year or more, zero six months or more a year, two years or more, three years or more, four years or more, or five years or more).
In some embodiments of any of the above aspects, the two or more doses are administered to the patient within about 12 months (e.g., about 12 months, about 11 months, about 10 months, about 9 months, about 8 months, about 7 months, about 6 months, about 5 months, about 4 months, about 3 months, about 2 months, or about 1 month) of each other.
In some embodiments of any of the above aspects, the viral vector is selected from the group consisting of adeno-associated virus (AAV), adenovirus, lentivirus, retrovirus, poxvirus, baculovirus, herpes simplex virus, vaccinia virus, and synthetic virus.
In some embodiments, the viral vector is AAV. In some embodiments, the AAV is AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh10, or AAVrh74 serotype.
In some embodiments, the viral vector is a pseudotyped AAV. In some embodiments, the pseudotyped AAV is AAV2/8 or AAV2/9, optionally wherein the pseudotyped AAV is AAV2/8.
In some embodiments, the transgene encoding MTM1 is operably linked to a muscle-specific promoter. In some embodiments, the muscle-specific promoter is a desmin promoter, a muscle creatine kinase promoter, a myosin light chain promoter, a myosin heavy chain promoter, a cardiac troponin C promoter, a troponin I promoter, a myoD gene family promoter, an actin alpha promoter, an actin beta promoter, an actin gamma promoter, or a promoter within intron 1 of pair-like homology domain 3 in the eye. In some embodiments, the muscle-specific promoter is a desmin promoter.
In some embodiments of any of the above aspects, the viral vector is birnesyl (resamirigene bilparvovec).
In some embodiments of any of the above aspects, the viral vector is administered to the patient by intravenous, intramuscular, intradermal, or subcutaneous administration.
In some embodiments of any one of the above aspects, the anti-cholestasis agent is selected from the group consisting of: bile acids, farnesol X Receptor (FXR) ligands, fibroblast growth factor 19 (FGF-19) mimics, takeda-G protein receptor 5 (TGR 5) agonists, peroxisome proliferator-activated receptor (PPAR) agonists, PPAR-alpha agonists, PPAR-delta agonists, dual PPAR-alpha and PPAR-delta agonists, apical sodium-dependent bile acid transporter (ASBT) inhibitors, immunomodulatory drugs, anti-fibrotic therapies, and nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitors.
In some embodiments, (i) the FXR ligand is obeticholic acid (cilofaci), cilofaci (cilofacitor), te Luo Fasuo (tropidexior), tretinoin (tretinoin), or EDP-305; (ii) FGF-19 mimetic is Aldafermin; (iii) the TGR5 agonist is INT-777 or INT-767; (iv) The PPAR agonist is bezafibrate (bezafibrate), seladelpar (seladelpar) or elabefeno (elafilaro); (v) the PPAR-alpha agonist is fenofibrate (fenofibrate); (vi) the PPAR-delta agonist is seladelpha; (vii) The dual PPAR-alpha and PPAR-delta agonists are elafeenox (elafebriranor); (viii) ASBT inhibitors are oxepibat (odevixibat), maraxibat (maraxibat), or linexibat (linexibat); (ix) The immunomodulatory drug is rituximab (rituximab), abatacept (abatacept), utezomib (ustekinumab), infliximab (infliximab), baratinib (baricitinib) or FFP-104; (x) The anti-fibrosis therapy is vitamin D receptor agonist or Xin Tuozhu monoclonal antibody (simtuzumab); and/or the (xi) NOX inhibitor is celecoxib (setanaxib).
In some embodiments, the bile acid is ursodeoxycholic acid (e.g., xiong Erchun), norursodeoxycholic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, the bile acid is bear diol.
In some embodiments of any of the above aspects, the bile acid is administered to the patient in a single dose. In some embodiments, the bile acid is administered to the patient in multiple doses.
In some embodiments, the bile acid is administered to the patient in an amount of about 5 mg/kg/dose to about 20 mg/kg/dose, optionally wherein the bile acid is administered to the patient in an amount of about 6 mg/kg/dose to about 19 mg/kg/dose, about 7 mg/kg/dose to about 18 mg/kg/dose, about 8 mg/kg/dose to about 17 mg/kg/dose, about 10 mg/kg/dose to about 15 mg/kg/dose, or about 12 mg/kg/dose to about 13 mg/kg/dose. For example, bile acid is administered to a patient in an amount of about 5 mg/kg/dose, 6 mg/kg/dose, 7 mg/kg/dose, 8 mg/kg/dose, 9 mg/kg/dose, 10 mg/kg/dose, 11 mg/kg/dose, 12 mg/kg/dose, 13 mg/kg/dose, 14 mg/kg/dose, 15 mg/kg/dose, 16 mg/kg/dose, 17 mg/kg/dose, 18 mg/kg/dose, 19 mg/kg/dose, or 20 mg/kg/dose.
In some embodiments, the bile acid is administered to the patient in an amount of about 5 mg/kg/dose to about 11 mg/kg/dose, optionally wherein the bile acid is administered to the patient in an amount of about 6 mg/kg/dose to about 10 mg/kg/dose or about 7 mg/kg/dose to about 9 mg/kg/dose. For example, bile acid is administered to a patient in an amount of about 5 mg/kg/dose, 6 mg/kg/dose, 7 mg/kg/dose, 8 mg/kg/dose, 9 mg/kg/dose, 10 mg/kg/dose, or 11 mg/kg/dose.
In some embodiments, the bile acid is administered to the patient in one or more (e.g., one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) doses per day, per week, or per month.
In some embodiments, the bile acid is administered to the patient in one or more (e.g., one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) doses per day, optionally wherein the bile acid is administered to the patient in one dose per day, two doses per day, three doses per day, four doses per day, or five doses per day.
In some embodiments, the bile acid is administered to the patient at one dose per day.
In some embodiments, the bile acid is administered to the patient in an amount of about 5 mg/kg/day to about 40 mg/kg/day, optionally wherein (i) the bile acid is administered to the patient in an amount of about 6 mg/kg/day to about 39 mg/kg/day, about 8 mg/kg/day to about 37 mg/kg/day, about 13 mg/kg/day to about 32 mg/kg/day, or about 20 mg/kg/day to about 25 mg/kg/day, or (ii) the bile acid is administered to the patient in an amount of about 17 mg/kg/day to about 23 mg/kg/day, about 18 mg/kg/day to about 22 mg/kg/day, or about 19 mg/kg/day to about 21 mg/kg/day. For example, bile acid is administered to a patient in an amount of about 5 mg/kg/day, 6 mg/kg/day, 7 mg/kg/day, 8 mg/kg/day, 9 mg/kg/day, 10 mg/kg/day, 11 mg/kg/day, 12 mg/kg/day, 13 mg/kg/day, 14 mg/kg/day, 15 mg/kg/day, 16 mg/kg/day, 17 mg/kg/day, 18 mg/kg/day, 19 mg/kg/day, 20 mg/kg/day, 25 mg/kg/day, 30 mg/kg/day, 35 mg/kg/day, or 40 mg/kg/day. In some embodiments, bile acid is administered to the patient in an amount of 20 mg/kg/day.
In some embodiments, the bile acid is administered to the patient by a unit dosage form comprising 250mg bile acid. In some embodiments of any of the above aspects, the bile acid is administered to the patient by a unit dosage form comprising 500mg bile acid.
In some embodiments of any of the above aspects, the bile is administered to the patient by enteral administration.
In some embodiments of any of the above aspects, the patient has no history of cholestasis or hyperbilirubinemia. In some embodiments, the patient does not have any history of potential liver disease.
In some embodiments of any of the above aspects, the patient is born at or above 35 weeks of gestational age and is or has been at the time of administration of the transgenic or viral vector at a sufficient month of age (e.g., adjusted sufficient month of age) to about 5 years (e.g., 1 day to about 5 years, 2 days to about 5 years, 3 days to about 5 years, 4 days to about 5 years, 5 days to about 5 years, 6 days to about 5 years, 7 days to about 5 years, 8 days to about 5 years, 9 days to about 5 years, 10 days to about 5 years, 11 days to about 5 years, 12 days to about 5 years, 13 days to about 5 years, 14 days to about 5 years, 15 days to about 5 years, 16 days to about 5 years, 17 days to about 5 years, 18 days to about 5 years, 19 days to about 5 years, 20 days to about 5 years, 25 days to about 5 years, one month to about 5 years, two months to about 5 years, 3 months to about 5 years, 4 days to about 5 years, 12 days to about 5 years, 13 days to about 5 years, 18 days to about 5 years, and about 5 years to about 1 month to about 5 years).
In some embodiments of any of the above aspects, the patient is male.
In some embodiments of any of the above aspects, the patient requires mechanical ventilation support, optionally wherein the mechanical ventilation support comprises invasive mechanical ventilation support and non-invasive mechanical ventilation support.
In some embodiments of any of the above aspects, the patient exhibits a change in the number of hours of mechanical ventilatory support over time relative to baseline after administration of the transgene or viral vector to the patient, optionally wherein the patient exhibits a change in the number of hours of mechanical ventilatory support over time relative to baseline about 24 weeks after administration of the transgene or viral vector to the patient, optionally wherein the patient exhibits a change in the number of hours of mechanical ventilatory support over time relative to baseline about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
In some embodiments of any of the above aspects, the patient achieves functional independence for at least 30 seconds after administration of the transgene or viral vector to the patient, optionally wherein the patient achieves functional independence for about 24 weeks after administration of the transgene or viral vector to the patient, optionally wherein the patient exhibits functional independence for at least 30 seconds about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
In some embodiments of any of the above aspects, the patient exhibits a reduction in the desired mechanical ventilator support to about 16 hours or less per day after administration of the transgene or viral vector to the patient, optionally wherein the patient exhibits a reduction in the desired mechanical ventilator support about 24 weeks after administration of the viral vector to the patient, optionally wherein the patient exhibits a reduction in the desired mechanical ventilator support about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
In some embodiments of any of the above aspects, the patient exhibits a change from baseline in the philadelphia child hospital neuromuscular disorder infant test (CHOP end) after administration of the transgene or viral vector to the patient, optionally wherein the patient exhibits a change from baseline in CHOP end about 24 weeks after administration of the transgene or viral vector to the patient, optionally wherein the patient exhibits a change from baseline in CHOP end about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
In some embodiments of any of the above aspects, the patient exhibits a change in (MIP) from baseline after administration of the transgene or viral vector to the patient, optionally wherein the patient exhibits a change in MIP from baseline about 24 weeks after administration of the viral vector to the patient, optionally wherein the patient exhibits a change in MIP from baseline about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
In some embodiments of any of the above aspects, the patient exhibits a change from baseline in a quantitative analysis of myo-tubulin expression in a muscle biopsy after administration of the transgene or viral vector to the patient, optionally wherein the patient exhibits a change from baseline in a quantitative analysis of myo-tubulin expression in a muscle biopsy about 24 weeks after administration of the transgene or viral vector to the patient, optionally wherein the patient exhibits a change from baseline in a quantitative analysis of myo-tubulin expression in a muscle biopsy about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient. In some embodiments, the quantitative analysis of myotubulin expression in the muscle biopsy is continued for at least 48 weeks (e.g., 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, or 2 years) from baseline after administration of the viral vector to the patient.
In some embodiments of any of the above aspects, the patient exhibits a reduction in stiffness and/or joint contracture after administration of the viral vector to the patient, optionally wherein the patient exhibits a reduction in stiffness and/or joint contracture about 24 weeks after administration of the viral vector to the patient, optionally wherein the patient exhibits a reduction in stiffness and/or joint contracture about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
In some embodiments of any of the above aspects, the patient exhibits diaphragmatic and/or respiratory muscle progression after administration of the viral vector to the patient, optionally wherein the patient exhibits diaphragmatic and/or respiratory muscle progression about 24 weeks after administration of the viral vector to the patient, optionally wherein the patient exhibits diaphragmatic and/or respiratory muscle progression about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
In some embodiments of any of the above aspects, the patient is identified by finding that the patient exhibits a molecular weight of greater than 14 mu mol/L (e.g., greater than 14 μmol/L, 15 μmol/L, 16 μmol/L, 17 μmol/L, 18 μmol/L, 19 μmol/L, 20 μmol/L, 21 μmol/L, 22 μmol/L, 23 μmol/L, 24 μmol/L, 25 μmol/L, 26 μmol/L, 27 μmol/L, 28 μmol/L, 29 μmol/L, 30 μmol/L, 31 μmol/L, 32 μmol/L, 33 μmol/L, 34 μmol/L, 35 μmol/L, 36 μmol/L, 37 μmol/L, 38 μmol/L, 39 μmol/L, 40 μmol/L, 41 μmol/L, 42 μmol/L, 43 μmol/L, and 44. Mu. Mol/L, 45. Mu. Mol/L, 46. Mu. Mol/L, 47. Mu. Mol/L, 48. Mu. Mol/L, 49. Mu. Mol/L, 50. Mu. Mol/L, 51. Mu. Mol/L, 52. Mu. Mol/L, 53. Mu. Mol/L, 54. Mu. Mol/L, 55. Mu. Mol/L, 56. Mu. Mol/L, 57. Mu. Mol/L, 58. Mu. Mol/L, 59. Mu. Mol/L, 60. Mu. Mol/L, 61. Mu. Mol/L, 62. Mu. Mol/L, 63. Mu. Mol/L, 64. Mu. Mol/L, 65. Mu. Mol/L, 66. Mu. Mol/L, 67. Mu. Mol/L, 68. Mu. Mol/L, 69. Mu. Mol/L, 70. Mu. Mol/L, 71. Mu. Mol/L, 72. Mu. Mol/L, serum total bile acid levels of 73 μmol/L, 74 μmol/L, 75 μmol/L, 76 μmol/L, 77 μmol/L, 78 μmol/L, 79 μmol/L, 80 μmol/L, 81 μmol/L, 82 μmol/L, 83 μmol/L, 84 μmol/L, 85 μmol/L, 86 μmol/L, 87 μmol/L, 88 μmol/L, 89 μmol/L, 90 μmol/L, 91 μmol/L, 92 μmol/L, 93 μmol/L, 94 μmol/L, 95 μmol/L, 96 μmol/L, 97 μmol/L, 98 μmol/L, 99 μmol/L or 100 μmol/L) determine that the patient exhibits cholestasis or one or more symptoms thereof.
In some embodiments of any of the above aspects, the patient is determined to exhibit cholestasis or one or more symptoms thereof by finding that the patient exhibits an increase or decrease in one or more parameters in the blood test relative to a reference level.
In some embodiments of any of the above aspects, the blood test is a liver function test.
In some embodiments of any of the above aspects, the one or more parameters include the level of γ -glutamyl transferase, alkaline phosphatase, aspartate aminotransferase, and/or alanine aminotransferase.
In some embodiments of any of the above aspects, the method comprises administering to the subject a therapeutic agent that exhibits a bilirubin assay of greater than 1mg/dL (e.g., greater than 1mg/dL, 1.1mg/dL, 1.2mg/dL, 1.3mg/dL, 1.4mg/dL, 1.5mg/dL, 1.6mg/dL, 1.7mg/dL, 1.8mg/dL, 1.9mg/dL, 2mg/dL, 2.1mg/dL, 2.2mg/dL, 2.3mg/dL, 2.4mg/dL, 2.5mg/dL, 2.6mg/dL, 2.7mg/dL, 2.8mg/dL, 2.9mg/dL, 3mg/dL, 3.1mg/dL, 3.2mg/dL, 3.3 mg/dL, 3.4mg/dL, 3.5mg/dL a bilirubin level of 3.6mg/dL, 3.7mg/dL, 3.8mg/dL, 3.9mg/dL, 4mg/dL, 4.1mg/dL, 4.2mg/dL, 4.3mg/dL, 4.4mg/dL, 4.5mg/dL, 4.6mg/dL, 4.7mg/dL, 4.8mg/dL, 4.9mg/dL, 5mg/dL, 10mg/dL, 15mg/dL, 20mg/dL, 30mg/dL, 40mg/dL, 50mg/dL, 60mg/dL, 70mg/dL, 80mg/dL, 90mg/dL or 100 mg/dL), the patient is determined to exhibit hyperbilirubinemia or one or more symptoms thereof.
In some embodiments of any of the above aspects, after administration of the viral vector to the patient, the patient exhibits greater than 1mg/dL (e.g., greater than 1mg/dL, 1.1mg/dL, 1.2mg/dL, 1.3mg/dL, 1.4mg/dL, 1.5mg/dL, 1.6mg/dL, 1.7mg/dL, 1.8mg/dL, 1.9mg/dL, 2mg/dL, 2.1mg/dL, 2.2mg/dL, 2.3mg/dL, 2.4mg/dL, 2.5mg/dL, 2.6mg/dL, 2.7mg/dL, 2.8mg/dL, 2.9mg/dL, 3mg/dL, 3.1mg/dL, 3.4mg/dL, 3.5mg/dL, 3.6mg/dL, 3.8mg/dL, 3.9mg/dL, 3.1.9 mg/dL, 4mg/dL, 4.5mg/dL, 4.1.1.6 mg/dL, 3.7mg/dL, 2.3.3 mg/dL, 4mg/dL, 4.8mg/dL, 4.1.8 mg/dL, 4mg/dL, 4.1.5 mg/dL, 4mg/dL, 4.1.1.4 mg/dL, 4mg/dL, 4.1.1.1.5 mg/dL, 4mg/dL, 4.1.1 mg/dL, 4mg/dL, 4.1.1.9 mg/dL, 4mg/dL, 4.1.1.1.9 mg/dL, 1.9mg/dL, 1.1, 1.3mg/dL, 1.3mg and about, 1 mg/mg and about.
In some embodiments of any of the above aspects, the bilirubin level comprises a direct bilirubin level or a total bilirubin level.
In some embodiments of any of the above aspects, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof by finding that the patient exhibits an increase in a parameter in a blood test relative to a reference level.
In some embodiments of any of the above aspects, the parameter comprises the level of serum bile acid.
In some embodiments of any of the above aspects, the serum bile acid is cholic acid, chenodeoxycholic acid, deoxycholic acid, or ursodeoxycholic acid.
In some embodiments of any of the above aspects, the blood test is a liver function test.
In some embodiments of any of the above aspects, the parameter comprises the level of aspartate aminotransferase or alanine aminotransferase.
In one aspect, the present disclosure provides a kit comprising a transgene encoding MTM1 and a package insert, wherein the package insert directs a user of the kit to administer the transgene to a patient having xltm according to the method of any one of the above aspects.
In one aspect, the present disclosure provides a kit comprising a viral vector comprising a transgene encoding MTM1 and a package insert, wherein the package insert directs a user of the kit to administer the viral vector to a patient having xltm according to the method of any one of the above aspects.
In one aspect, the present disclosure provides a kit comprising an anti-cholestasis agent and a package insert, wherein the package insert directs a user of the kit to administer the anti-cholestasis agent to a patient to treat or prevent cholestasis or hyperbilirubinemia according to the method of any of the above aspects.
Drawings
FIG. 1 is a schematic diagram of an exemplary pseudotyped adeno-associated virus (AAV) 2/8 (AAV 2/8) viral vector (e.g., birelearnyl) for expressing a human myotubulin 1 (hMTM 1) gene. From left to right, the shaded arrows and rectangles represent nucleic acid sequences encoding: human desmin (hDes) promoter operably linked to β -globulin intron (SEQ ID NO: 3), hMTM1 gene (SEQ ID NO: 4), β -globulin polyadenylation signal (Beta-globin_pA) and flanking AAV2 Inverted Terminal Repeat (ITR). Abbreviations: AAV2_itr, adeno-associated virus 2 inverted terminal repeat; beta-globin_pA, human Beta-globulin polyadenylation signal; hDes, human desmin promoter; hMTM1, human myotubulin complement DNA.
FIG. 2 is a schematic illustration of a 3.0X10 use as described in example 2 below 14 vg/kg (3 e14; light grey) or 1.0X10) 14 A graph of the change in total bilirubin and/or direct bilirubin (exceeding a multiple of the Upper Limit of Normal (ULN)) in a human patient treated with vg/kg (1 e14; dark grey) versus rayleigh. Filled rectangles define the 25 th to 75 th percentiles; the crosses define the average; the lower whisker (lower whisker) defines a minimum observed value (excluding outliers) above the lower boundary; the upper whisker defines a maximum observation below the upper boundary (excluding outliers); circles represent outliers, defined as any value above the upper boundary or below the lower boundary [ greater than 75 th percentile + i.5 x IQR; or less than 25 th percentile-i.5 ]Where IQR is the quartile range (75 th to 25 th percentile).
FIG. 3 is a graph showing the use of 3.0X10 as described in example 2 below 14 vg/kg (light gray solid line) or 1.0x10 14 Regression plot of total bilirubin (mg/dL) versus baseline for vg/kg (dark gray solid line) versus human patients treated with Rayleigh. The regression curve for each group was applicable to all individual subjects dosed at the individual dose (3.0x10 14 vg/kg or 1.0x10 14 vg/kg of bimesol group; respectively light grey dashed line and dark grey dashed line).
Fig. 4A to 4C are graphs showing respiratory and motor function results of individual subjects after treatment with birefrenyl. The time course of ventilator dependence (fig. 4A), MIP (fig. 4B) and CHOP interval score (fig. 4C) over 24 hours for the treated ASPIRO patients is shown by the locally estimated scatter plot smooth regression curves fitted to the low dose patient, the high dose patient and the control group, respectively.
Fig. 5A to 5B are heat maps showing the response of T cells and B cells to MTM1 administration after specific rayleigh from Peripheral Blood Mononuclear Cells (PBMC)/serum samples. Figure 5A shows an ELISpot assay measuring interferon-gamma (IFN-gamma) release in response to stimulation of PBMCs of participants with MTM1 peptide pools over time in samples from participants treated by mutation types. IFN-gamma cytokine secretion data measured by the T cell ELISPot assay are shown. The results are expressed as every 10 6 SFC (spot forming cells) number of PBMCs. If average SFC/10 6 The results were considered significant when each cell minus two standard errors was 2 times that of the respective negative control wells, and where p.ltoreq.0.05. In addition, a.gtoreq.50 SFC/10 6 The cut-off value was used to determine positive response to AAV8 or MTM1 peptide pool stimulation. Common causes of "undetermined" results include insufficient available PBMCs and failure of the sample to respond to stimulation by the positive control. Although it cannot be concluded clearly based on ELISpot data, many clinical and histopathological observations do not support T cell mediated immune responses as causative factors for severe adverse effects of liver and gall (SAE). Among participants whose ELISpot results were negative at baseline, participants 12 and 01 later reported cholestatic SAE. Participant 23 eventually reported SAE for thrombocytopenia and myocarditis. Baseline samples of participant 09 were positive; during the course of the study, he developed severe cholestatic liver dysfunction and fatal sepsis, immune system disorders and liver disorders. Subjects with only negative (or negative and undetermined) results after dosing included 25, 12 (which eventually developed severe cholestatic liver dysfunction and fatal gastrointestinal bleeding) and 06 (which eventually developed severe cholestatic liver dysfunction and fatal sepsis). Patients 11, 33 and 38 did not have ELISpot data. FIG. 5B shows participation from treatment by mutation type Changes in anti-MTM 1 antibody titer over time in the samples. anti-MTM 1 antibody titer data measured before and after administration of bimirr to ASPIRO subjects are shown. The "undetected" results are also shown, while the presence of antibody titers is shown by a thermal gradient. The types of MTM1 gene mutations present in ASPIRO subjects were shown to be loss of function (LOF), partial loss of function (PLOF) and in-frame exon deletion (IFED).
Fig. 6 is a diagram of the experimental design of the patient group entry and administration trial in clinical trial ASPIRO.
Fig. 7A to 7D are graphs showing the breathing and ventilation results after bimatose. Figures 7A and 7B are graphs and quantifies, respectively, showing the percent change in the number of least squares average ventilator hours per 24 hours of the treated participants relative to baseline as compared to the pooled control participants. Fig. 7C and 7D are graphs and quantifications showing Maximum Inspiratory Pressure (MIP), respectively. With low dose group (1.0x10) 14 vg/kg of bimesol) compared to the high dose group (3.0x10 14 vg/kg than rayleigh) more gradual escape from ventilation using a more conservative algorithm and more frequent time points. Error bars represent standard error. The F test and related error bar values were from the mixed effect ANOVA model, indicating a highly significant decrease in the percentage change in the number of ventilation hours per day from baseline over time in the treatment group versus the control group. The ventilator-dependent data for the control and high-dose participants were collected by electronic diary (i.e., very frequent reports) and the ventilator-dependent data for the low-dose participants were collected in a discreet spot visit.
Fig. 8A and 8B are diagrams and quantification, respectively, showing the movement function after the moroxydine. The change from baseline in the least squares mean motor function score in the philadelphia child hospital neuromuscular disorder infant test (CHOP interval) scale is shown in treated participants compared to pooled control participants. The CHOP score scale ranges from 0 to 64, with higher scores indicating better function; a score of 4 increment is considered clinically significant. Error bars represent standard error.
Fig. 9A and 9B are graphs and quantifications showing the implementation of major movement milestones in individual birthwort treated patients and control patients, respectively. White boxes began with the age of administration or age of the group (incoptus) in the X-linked myotubulo myopathy gene transfer clinical study (ASPIRO). The length of the box represents the study time of the patient. The icon represents the age at which the athletic milestone was achieved.
Fig. 10A to 10B are a graph and a set of photomicrographs showing myotubulin (MTM 1) protein expression and histopathological changes after the bimirradi treatment, respectively. FIG. 10A is a graph showing the separate application of 1X 10 14 vg/kg or 3X 10 14 Figure of immunoblots of MTM1 protein expression in muscle biopsy samples from individual patients after vg/kg of bimatoxyl. FIG. 10B is a set of images showing images taken from application 1X 10, respectively 14 vg/kg (patient 08) or 3X 10 14 Hematoxylin and eosin (H) in a vg/kg (patient 25) patient or an age-matched control muscle biopsy sample&E) And Nicotinamide Adenine Dinucleotide (NADH) staining; at baseline, 24 th week and 48 th week, respectively.
Fig. 11 is a heat map showing the inflammatory response (e.g., none, very mild, mild to moderate, moderate to severe or severe) of a patient receiving bimesosyl, such as by administration of a low dose (1 x 10) 14 vg/kg) or high dose (3 x 10 14 vg/kg) of CD3 in patients with bimesol.
FIG. 12 is a set of images showing inflammatory response of patients receiving Billebrand, as administered 1X 10 at baseline, week 24 and week 48, respectively 14 CD3 expression was assessed in vg/kg patients (patients 17 and 8).
Fig. 13 is a graph showing a Kaplan-Meier analysis of overall survival, where event time of occurrence analysis was based on death events since study entry. By the analysis expiration date, subjects without events were excluded.
Fig. 14 and 15 are liver biopsy histopathology taken from participant 12 (fig. 14) at day 85 post-dose and participant 06 (fig. 15) during necropsy. Hematoxylin and eosin (H & E) staining is shown with one bile transporter BSEP staining. Fig. 14 shows hepatocyte degeneration and giant cell formation, intracellular and extracellular bile aggregation, bile duct proliferation and minimal inflammation. Fig. 15 shows hepatocyte degeneration, necrosis and giant cell formation, intracellular and extracellular bile aggregation, biliary proliferation, severe fibrosis and no significant inflammation.
Detailed Description
Definition of the definition
As used herein, the term "about" refers to a value within 10% above or below that value. For example, "100 lbs" as used in the weight context described herein includes amounts within 10% above or below 100 lbs. Furthermore, when used in the context of a list of numerical quantities, it is to be understood that the term "about" applies to each individual quantity listed in the list as it precedes the list of numerical quantities.
As used herein, the terms "administering", "administering" and the like refer to directly administering a therapeutic agent to a patient by any effective route (e.g., a pharmaceutical composition comprising a viral vector comprising a nucleic acid sequence encoding a myotubulin 1 (MTM 1) gene operably linked to a muscle-specific promoter). Exemplary routes of administration are described herein and include systemic routes of administration, such as intravenous injection; and routes of administration directly to the central nervous system of a patient, such as by intrathecal injection or intraventricular injection, and the like.
As used herein, the term "age-adjusted specification" refers to a process of normalizing data by age, a technique that allows for comparison of a population of subjects when the age profiles of the population are different. As used herein, the term "canonical" refers to data that is not normalized by age, as the age profiles of a population of subjects are similar.
As used herein, the terms "alanine aminotransferase" and "ALT" refer to proteins whose amino acid sequences comprise or consist of the amino acid sequences of naturally occurring wild-type ALT proteins (e.g., ALT1 and ALT 2), and proteins whose amino acid sequences comprise or consist of the amino acid sequences of naturally occurring ALT allelic variants (GPT or GPT2, e.g., splice variants or allelic variants). The human GPT nucleic acid sequence is provided under NCBI RefSeq accession No. NM-005309.2 (SEQ ID NO: 6), and the exemplary wild-type ALT1 amino acid sequence is provided under NCBI RefSeq accession No. NP-005300.1 (SEQ ID NO: 7). The human GPT2 nucleic acid sequence is provided under NCBI RefSeq accession No. NM-001142466.2 (SEQ ID NO: 8), and an exemplary wild-type ALT2 amino acid sequence is provided under NCBI RefSeq accession No. NP-001135938.1 (SEQ ID NO: 9).
As used herein, the terms "alkaline phosphatase" and "ASP" refer to proteins whose amino acid sequence comprises or consists of the amino acid sequence of a naturally occurring wild-type ASP protein, and whose amino acid sequence comprises or consists of the amino acid sequence of a naturally occurring ASP allelic variant (e.g., splice variant or allelic variant). Human ASP nucleic acid sequence is provided under NCBI RefSeq accession No. NM-000478.5 (SEQ ID NO: 10), and exemplary wild-type ASP amino acid sequence is provided under NCBI RefSeq accession No. NP-000469.3 (SEQ ID NO: 11).
As used herein, the term "anti-cholestasis agent" refers to a substance, such as a small molecule, that is used to increase bile formation and/or antagonize the effects of hydrophobic bile acids on a biological membrane. As used herein, the term "antagonize" with respect to a protein refers to a molecule that reduces signal transduction resulting from the interaction of the protein with its one or more binding partners. Antagonists may result in reduced binding of a protein to one or more of its binding partners relative to binding of two proteins in the absence of the antagonist.
As used herein, the terms "aspartate aminotransferase" and "AST" refer to proteins whose amino acid sequence comprises or consists of the amino acid sequence of a naturally occurring wild-type AST protein, and whose amino acid sequence comprises or consists of the amino acid sequence of a naturally occurring AST allelic variant (e.g., splice variant or allelic variant). Human AST nucleic acid sequences are provided under NCBI RefSeq accession No. NM-002079.2 (SEQ ID NO: 12), and exemplary wild-type ASP amino acid sequences are provided under NCBI RefSeq accession No. NP-002070.1 (SEQ ID NO: 13).
As used herein, the terms "bile acid test" and "serum bile acid test" refer to procedures in which a pre-meal (i.e., pre-meal) blood sample is collected as a baseline, followed by a meal, and then a post-meal (i.e., post-meal) blood sample is collected after about two hours. Two blood samples were tested for bile acid levels and pre-meal samples were used as reference. As used herein, "bile acid" refers to a quasi-solid acid that is found predominantly in mammalian and other vertebrate bile.
As used herein, the terms "philadelphia hospital neuromuscular disorder infant test" and "CHOP end" refer to validated exercise outcome measures developed for assessing weak infants, such as infants suffering from skeletal muscle disease (e.g., X-linked myotubular myopathy (xltm)). CHOP end uses a 0-64 component table, with higher scores indicating better motor function. As used herein, the term "motor function score" refers to the score of a 0-64 component table of CHOP end (e.g., CHOP end table > 45).
As used herein, the term "cholestasis" refers to the situation where bile cannot flow from the liver to the duodenum. Two clinical differences are the "obstructive" cholestasis type, in which there is a mechanical blockage of the ductwork that may be caused by gallstones or malignancy; and "metabolic" cholestasis types, which are bile-forming disturbances that may be caused by genetic defects or obtained as a side effect of many drugs. As used herein, the term "bile" refers to digestive fluids secreted by the liver to aid in the digestion of fat.
As used herein, "combination therapy" means administration of two (or more) different agents or treatments to a subject as part of a treatment regimen defined for a particular disease or condition (e.g., neuromuscular disorder). In some embodiments, the "combination therapy" may include surgery. The treatment regimen defines the dose and administration period of each dose such that the effects of the individual doses on the subject overlap. In some embodiments, delivery of two or more agents is simultaneous or synchronized and the agents may be co-formulated. In other embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, the combined administration of two or more agents or treatments results in a reduction in symptoms or other parameters associated with the disorder that is greater than that observed with one agent or treatment delivered alone or in the absence of the other agent or treatment. The effect of the two treatments may be partial addition, complete addition, or greater than addition (e.g., synergistic). Sequential or substantially simultaneous administration of the therapeutic agents may be accomplished by any suitable route including, but not limited to, oral route, intravenous route, intramuscular route, and direct absorption through mucosal tissue. The therapeutic agents may be administered by the same route or by different routes. For example, a first therapeutic agent in combination may be administered by intravenous injection, while a second therapeutic agent in combination may be administered enterally. In another embodiment, the agents of the therapeutic combination may be administered by intravenous injection, and surgery of the therapeutic combination may be performed (e.g., nasofreex drainage (NBD)).
As used herein, the term "dose" refers to the amount of a therapeutic agent, such as a viral vector described herein, that is administered to a subject in a particular instance to treat a disorder, such as to treat or ameliorate one or more symptoms of a neuromuscular disorder (e.g., xltm) described herein. The therapeutic agents as described herein may be administered in a single dose or in multiple doses during the course of a treatment period, as defined herein. In each case, the therapeutic agent may be administered using one or more unit dosage forms of the therapeutic agent, which refer to the term of one or more discrete compositions containing the therapeutic agent that together constitute a single dose of the agent.
As used herein, the terms "effective amount," "therapeutically effective amount," and the like, when used in reference to a therapeutic composition such as the vector constructs described herein, refer to an amount sufficient to produce a beneficial or desired result, such as a clinical result, when administered to a subject (including a mammal, e.g., a human). For example, in the context of treating a neuromuscular disorder such as XLM, these terms refer to the amount of a composition sufficient to effect a therapeutic response as compared to the response obtained when the composition of interest is not administered. Compositions such as "effective amount," "therapeutically effective amount," and the like of the vector constructs of the present disclosure also include amounts that produce beneficial or desired results in a subject as compared to a control.
As used herein, the terms "γ -glutamyl transferase" and "GGT" refer to proteins whose amino acid sequence comprises or consists of the amino acid sequence of a naturally occurring wild-type GGT protein, and whose amino acid sequence comprises or consists of the amino acid sequence of naturally occurring GGT allelic variants (GGT 1, GGT2, and GGT3, e.g., splice variants or allelic variants). Human GGT1 nucleic acid sequence is provided under NCBI RefSeq accession No. NM-001288833.1 (SEQ ID NO: 14), and exemplary wild-type GGT1 amino acid sequence is provided under NCBI RefSeq accession No. NP-001275762.1 (SEQ ID NO: 15).
As used herein, the term "gestational age" describes how long a particular pregnancy is, and is measured from the first day to the current day of the last menstrual cycle of a pregnant female subject. As used herein, the term "delivery" (also referred to as birth) relates to the expulsion of the fetus and placenta from the uterus of a pregnant female subject. For normal pregnancy, delivery may occur at about 40 weeks gestational age.
As used herein, the term "hyperbilirubinemia" refers to a condition in which bilirubin levels in the blood are higher than normal. As used herein, the term "bilirubin" refers to a compound that occurs in the normal catabolic pathway of heme breakdown in vertebrates. This catabolism is the necessary process for the body to clear waste products from aging or abnormal red blood cell destruction. As used herein, "bilirubin test" refers to measuring the amount of bilirubin in a patient's blood.
As used herein, the term "level" refers to the level of a protein as compared to a reference. The reference may be any useful reference as defined herein. By "reduced level" and "increased level" of a protein is meant a reduction or increase in protein level (e.g., by a factor of less than about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more) compared to a reference, by a factor of greater than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, by a factor of less than about 0.01, about 0.02, about 0.1, about 0.3, about 0.5, about 0.8, or less, or by a factor of greater than about 1.2, about 1.4, about 1.5, about 1.8, about 2.0, about 3.0, about 3.5, about 5, about 10, about 40, about 30, or more than about 100%, or more) compared to a reference. Protein levels may be expressed in terms of mass/volume (e.g., g/dL, mg/mL, μg/mL, or ng/mL) or as a percentage relative to the total protein in the sample.
As used herein, the terms "liver function test" and "LFT" refer to a liver stack (e.g., a set of blood tests that provide information about the liver status of a patient). The liver stack may include measuring gamma-glutamyl transferase level, alkaline phosphatase level, aspartic aminotransferase level, alanine aminotransferase level, albumin level, bilirubin level, prothrombin time, activated partial thromboplastin time, or a combination thereof.
As used herein, the terms "maximum inspiratory pressure" and "MIP" refer to variables in mechanical ventilation, including total airway pressure delivered, typically used to overcome respiratory compliance as well as airway resistance. In pressure control mode, MIP comprises the sum of positive end expiratory pressure and "delta pressure". As used herein, the term "delta pressure" refers to a variable in mechanical ventilation, including the difference between MIP and positive end-expiratory pressure.
As used herein, the term "mechanical ventilation support" refers to the medical term of artificial ventilation, wherein mechanical devices are used to assist or replace spontaneous breathing. As used herein, the term "invasive mechanical ventilation support" refers to the medical term of artificial ventilation, wherein air is delivered via a tube inserted through the mouth or nose into the patient's trachea, and mechanical devices are used to assist or replace spontaneous breathing. As used herein, the term "non-invasive mechanical ventilation support" refers to mechanical ventilation support in which air is delivered to a patient through a sealing mask that may be placed over the mouth, nose, or whole face.
As used herein, the term "operably linked" refers to a first molecule that is linked to a second molecule, wherein the molecules are arranged such that the first molecule affects the function of the second molecule. The two molecules may or may not be part of a single contiguous molecule, and may or may not be contiguous. For example, a promoter is operably linked to a transcribable polynucleotide molecule if the promoter regulates the transcription of the transcribable polynucleotide molecule of interest in a cell. In addition, two parts of a transcriptional regulatory element are operably linked to each other if they are joined such that the transcriptional activation function of one part is not adversely affected by the presence of the other part. The two transcriptional regulatory elements may be operably linked to each other by way of a linker nucleic acid (e.g., an intervening non-coding nucleic acid) or may be operably linked to each other in the absence of intervening nucleotides.
As used herein, the term "pharmaceutical composition" refers to a mixture containing a therapeutic compound to be administered to a subject (such as a mammal, e.g., a human) to prevent, treat, or control a particular disease or condition affecting or likely affecting the subject.
As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are suitable for contact with the tissue of a subject, such as a mammal (e.g., a human), without undue toxicity, irritation, allergic response, and other problem complications commensurate with a reasonable benefit/risk ratio.
As used herein, the term "promoter" refers to a recognition site on DNA that is bound by an RNA polymerase. The polymerase drives transcription of the transgene. Exemplary promoters suitable for use with the compositions and methods described herein are described, for example, in Sandelin et al, nature Reviews Genetics 8:424 (2007), the disclosure of which is incorporated herein by reference for nucleic acid regulatory elements. Furthermore, the term "promoter" may refer to synthetic promoters, which are regulatory DNA sequences that are not naturally occurring in biological systems. Synthetic promoters contain naturally occurring promoter portions in combination with polynucleotide sequences that are not found in nature and can be optimized for expression of recombinant DNA using a variety of transgenes, vectors, and target cell types.
As used herein, a therapeutic agent is considered to be "provided" to a patient if it is administered directly to the patient, or if a substance that is processed or metabolized in the body to endogenously produce the therapeutic agent is administered to the patient. For example, a nucleic acid molecule encoding a therapeutic protein (e.g., MTM 1) can be provided to a patient, such as a patient suffering from a neuromuscular disorder described herein, by direct administration of the nucleic acid molecule or by administration of a substance (e.g., a viral vector or cell) that is processed in vivo to produce the desired nucleic acid molecule.
As used herein, the terms "patient" and "subject" refer to an organism that is receiving treatment for a particular disease or condition as described herein (such as a neuromuscular disorder, e.g., xltm). Examples of subjects and patients include mammals, such as humans, that receive treatment of the diseases or conditions described herein.
"reference" means any useful reference for comparing protein levels associated with cholestasis, hyperbilirubinemia, or one or more symptoms thereof. The reference may be any sample, standard curve or level used for comparison purposes. The reference may be a normal reference sample or a reference standard or level. The "reference sample" may be, for example, a control, e.g., a predetermined negative control value, such as a "normal control" or a previous sample taken from the same subject; a sample from a normal healthy subject, such as normal cells or normal tissue; a sample (e.g., a cell or tissue) from a subject not suffering from cholestasis, hyperbilirubinemia, or one or more symptoms thereof; a sample from a subject diagnosed as having cholestasis, hyperbilirubinemia, or one or more symptoms thereof; a sample from a subject who has been treated for cholestasis, hyperbilirubinemia, or one or more symptoms thereof; or a sample of purified protein (e.g., any of the proteins described herein) at a known normal concentration. "reference standard or level" means a value or numeric value derived from a reference sample. A "normal control value" is a predetermined value that is indicative of a non-disease state, such as that expected in healthy control subjects. Typically, the normal control value is expressed as a range ("between X and Y"), a high threshold ("no higher than X") or a low threshold ("no lower than X"). Subjects whose measured value is within the normal control value of a particular biomarker are generally said to be "within the normal limits of that biomarker". The normal reference standard or level may be a value or numeric value derived from a normal subject not suffering from cholestasis, hyperbilirubinemia, or one or more symptoms thereof. In preferred embodiments, the reference sample, standard or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, stage of disease and general health. Standard curves for the levels of purified protein (e.g., any of the proteins described herein) within normal reference ranges may also be used as references.
As used herein, the term "gestational age" refers to the age of a patient (e.g., a neonate) born between 37 and 42 weeks of gestational age. For example, if the patient is 35 weeks gestational age at birth, then the patient's foot is 14 days of month old.
As used herein, the term "transgene" refers to a recombinant nucleic acid (e.g., DNA or cDNA) encoding a gene product (e.g., a gene product described herein). The gene product may be RNA, peptide or protein. In addition to the coding region of the gene product, the transgene may also include or be operably linked to one or more elements to promote or enhance expression, such as promoters, enhancers, destabilizing domains, response elements, reporter elements, insulator elements, polyadenylation signals, and/or other functional elements. Embodiments of the present disclosure may utilize any known suitable promoter, enhancer, destabilizing domain, response element, reporter element, insulator element, polyadenylation signal and/or other functional element.
As used herein, the terms "treatment" and "treatment" refer to therapeutic treatment in which the aim is to prevent or slow down (lessen) the progression of an undesired physiological change or disorder, such as a neuromuscular disorder, such as XLMTM and the like. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms (e.g., stiffness and/or joint contracture); attenuation of disease extent; stabilizing (i.e., not worsening) the disease state; delay or slow down disease progression; improving or alleviating a disease state; and mitigation (whether partial or complete), whether detectable or undetectable. In the context of neuromuscular disorders (such as xltm), treatment of a patient may exhibit one or more detectable changes, such as an increase in the concentration of MTM1 protein or a nucleic acid encoding MTM1 (e.g., DNA or RNA, such as mRNA) or an increase in MTM1 activity (e.g., an increase of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900% or more.
As used herein, the terms "X-linked myotubulomyopathy" and "xltm" refer to hereditary neuromuscular disorders caused by mutations in the MTM1 gene and are characterized by symptoms including mild to severe muscle weakness, hypotonia (reduced muscle tone), feeding difficulties, and/or severe respiratory complications. Human MTM1 has NCBI gene ID code 4534. An exemplary wild-type human MTM1 nucleic acid sequence is provided under NCBI RefSeq accession No. NM-000252.3 (SEQ ID NO: 1), and an exemplary wild-type myotubulin 1 amino acid sequence is provided under NCBI RefSeq accession No. NP-000243.1 (SEQ ID NO: 2).
As used herein, the term "vector" refers to a nucleic acid, e.g., DNA or RNA, that can be used as a vehicle for delivering a gene of interest into a cell (e.g., a mammalian cell, such as a human cell), such as for replication and/or expression purposes. Exemplary vectors that can be used in conjunction with the compositions and methods described herein are plasmids, DNA vectors, RNA vectors, virions, or other suitable replicons (e.g., viral vectors). A variety of vectors have been developed for delivering polynucleotides encoding exogenous proteins into prokaryotic or eukaryotic cells. Examples of such expression vectors are disclosed, for example, in WO 1994/11026, the disclosure of which is incorporated herein by reference. The expression vectors described herein contain polynucleotide sequences and additional sequence elements, for example, for expressing proteins and/or integrating these polynucleotide sequences into the genome of mammalian cells. Some vectors useful for expressing the transgenes described herein include plasmids containing regulatory sequences (such as promoter and enhancer regions) that direct transcription of the genes. Other vectors useful for expressing transgenes contain polynucleotide sequences that enhance the translation rate of these genes or improve the stability or nuclear export of mRNA derived from transcription of the genes. These sequence elements include, for example, 5 'and 3' untranslated regions, internal Ribosome Entry Sites (IRES), and polyadenylation signal sites that direct efficient transcription of genes carried on expression vectors. The expression vectors described herein may also contain polynucleotides encoding markers for selecting cells containing such vectors. Examples of suitable markers include genes encoding antibiotic resistance such as ampicillin, chloramphenicol, kanamycin or nourseothricin.
Chemical terminology
The chemical terminology used herein is for the purpose of describing various aspects and embodiments of the present disclosure and is not intended to be limiting.
In the chemical definition below, a label in which an atomic symbol is followed by an integer represents the amount of atoms of the element present in a particular chemical moiety. As will be appreciated, other atoms (such as hydrogen atoms) or substituents described herein may be present as desired to satisfy the valences of a particular atom. For example, unsubstituted "C 2 Alkyl "has the formula-CH 2 CH 3 . When used in combination with the groups defined herein, reference to the number of carbon atoms includes the divalent carbons in the acetal and ketal groups, but does not include the carbonyl carbons in the acyl, ester, carbonate, amide or carbamate groups. For oxygen in heteroaryl,References to the number of nitrogen or sulfur atoms include only those atoms that form part of a heterocyclic ring.
As used herein, a phrase in the form of "optionally substituted X" (e.g., optionally substituted alkyl) is intended to be equivalent to "X", wherein X is optionally substituted "(e.g.," alkyl ", wherein alkyl is optionally substituted"). This is not intended to mean that feature "X" (e.g., alkyl) is itself optional. As described herein, certain compounds may contain one or more "optionally substituted" moieties. Generally, the term "substituted", whether preceded by the term "optional" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent (such as any of the substituents or groups described herein). Unless otherwise indicated, an "optionally substituted" group may have suitable substituents at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from the specified group, the substituents may be the same or different at each position. The combinations of substituents that can be used in combination with the compounds of the present disclosure are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when the compound is subjected to conditions that allow for its production, detection, and in certain embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.
As used herein, the term "aliphatic" refers to a saturated or unsaturated, straight, branched or cyclic hydrocarbon. The term "aliphatic" includes, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporates each of these definitions. In some embodiments, "aliphatic" is used to refer to those aliphatic groups having 1 to 20 carbon atoms. Aliphatic chains may be, for example, mono-, di-, tri-or polyunsaturated, or alkynyl. The unsaturated aliphatic group may be in cis or trans configuration. In some embodiments, the aliphatic group contains from 1 to about 12 carbon atoms, such as from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In some embodiments, the aliphatic group comprisesHaving from 1 to about 8 carbon atoms. In some embodiments, the aliphatic group is C 1 -C 2 、C 1 -C 3 、C 1 -C 4 、C 1 -C 5 Or C 1 -C 6 . The designation range as used herein means that each member of the range is described as an independent class of aliphatic groups. For example, the term "C" as used herein 1 -C 6 Aliphatic "means a straight or branched alkyl, alkenyl or alkynyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, and is intended to mean that each of these groups is described as an independent species. For example, the term "C" as used herein 1 -C 4 Aliphatic "means a straight or branched alkyl, alkenyl or alkynyl group having 1, 2, 3 or 4 carbon atoms, and is intended to mean that each of these groups is described as an independent species. In some embodiments, the aliphatic group is substituted with one or more functional groups that result in the formation of a stabilizing moiety.
As used herein, the term "heteroaliphatic" refers to an aliphatic moiety containing at least one heteroatom in its chain, such as an ammonia, carbonyl, carboxyl, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atom in place of a carbon atom. In some embodiments, the heteroatom present is nitrogen. In some embodiments, the heteroatom present is oxygen. In some embodiments, the heteroatom present is sulfur. The term "heteroaliphatic" includes, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In some embodiments, "heteroaliphatic" is used to refer to a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having from 1 to 20 carbon atoms. In some embodiments, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Non-limiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, glycolide, polylactic acid, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl, and alkyl-O-haloalkyl.
As used herein, the term "acyl" refers to a carbonyl substituent, such as one in which the carbonyl carbon is bound to an alkyl, alkenyl, alkynyl, optionally substituted oxygen moiety, optionally substituted nitrogen moiety, or the like. Exemplary acyl groups include, but are not limited to, formyl (i.e., carboxyaldehyde), acetyl, trifluoroacetyl, propionyl, and butyryl. Exemplary unsubstituted acyl groups include 1 to 6, 1 to 11, or 1 to 21 carbons.
The term "acyloxy" as used herein refers to the chemical moiety-OC (O) R, where R is C 1 -C 6 Alkyl, aryl, heteroaryl, C 1 -C 6 Alkylaryl or C 1 -C 6 Alkyl heteroaryl.
As used herein, the term "alkyl" refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms). As used herein, the term "alkylene" refers to a divalent alkyl group.
As used herein, the term "alkenyl", whether recited alone or in combination with other groups, refers to a straight or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 or 2 carbon atoms). As used herein, the term "alkenylene" refers to a divalent alkenyl group.
As used herein, the term "alkynyl", whether recited alone or in combination with other groups, refers to a straight or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 or 2 carbon atoms). As used herein, the term "alkynylene" refers to divalent alkynyl groups.
The term "amino" as used herein means-N (R N1 ) 2 Wherein each R is N1 Is independently H, OH, NO 2 、N(R N2 ) 2 、SO 2 OR N2 、SO 2 R N2 、SOR N2 N protecting groups, alkyl groups, alkoxy groups, aryl groups, arylalkyl groups, cycloalkyl groups, acyl groups (e.g., acetyl, trifluoroacetyl or other groups described herein), wherein these list R N1 The radicals may each optionally beIs substituted; or two R N1 Combining to form an alkylene or heteroalkylene group, and wherein each R N2 Independently is H, alkyl or aryl. The amino group of the compounds described herein may be an unsubstituted amino group (i.e., -NH 2 ) Or substituted amino (i.e. -N (R) N1 ) 2 )。
As used herein, the term "aryl" refers to an aromatic mono-or multi-carbocyclic group having at least one aromatic ring, e.g., 6 to 12 carbon atoms. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, 1, 2-dihydronaphthyl, indanyl, and 1H-indanyl.
As used herein, the term "arylalkyl" refers to an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are 7 to 30 carbons (e.g., 7 to 16 or 7 to 20 carbons, such as C 1 -C 6 Alkyl C 6 -C 10 Aryl, C 1 -C 10 Alkyl C 6 -C 10 Aryl or C 1 -C 20 Alkyl C 6 -C 10 Aryl) such as benzyl and phenethyl. In some embodiments, each of the alkyl and aryl groups may be further substituted with 1, 2, 3, or 4 substituents as defined herein for the respective groups.
As used herein, the term "bridged cyclic group" refers to a bridged polycyclic group of 5 to 20 atoms containing 1 to 3 bridges. Bridged cyclic groups include bridged carbocyclyl (e.g., norbornyl) and bridged heterocyclyl (e.g., 1, 4-diazabicyclo [2.2.2] octane).
As used herein, the term "carbocyclyl" refers to a non-aromatic C in which carbon atoms form a ring 3 -C 12 A monocyclic or polycyclic (e.g., bicyclic or tricyclic) structure. Carbocyclyl structures include cycloalkyl (e.g., cyclohexyl) and unsaturated carbocyclyl (e.g., cyclohexenyl). Polycyclic carbocyclyl includes spiro carbocyclyl, bridged carbocyclyl, and fused carbocyclyl. As used herein, the term "carbocyclylene" refers to a divalent carbocyclyl.
As used herein, the term "cycloalkyl" refers to a saturated, non-aromatic, monovalent mono-or multicyclic group of 3 to 10, preferably 3 to 6 carbon atoms. This term is further exemplified by groups such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and adamantyl.
As used herein, the terms "halo" and "halogen" mean fluoro (fluoro), chloro (chloro), bromo (bromo) or iodo (iodo).
As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein in which one or more of the constituent carbon atoms have been replaced with nitrogen, oxygen or sulfur. In some embodiments, the heteroalkyl group may be further substituted with 1, 2, 3, or 4 substituents as described herein for alkyl. Examples of heteroalkyl are "alkoxy", as used herein, which refers to alkyl-O- (e.g., methoxy and ethoxy); and "alkylamino", as used herein, refers to-N (alkyl) R Na Wherein R is Na Is H or alkyl (e.g., methylamino). As used herein, the term "heteroalkylene" refers to a divalent heteroalkyl group.
As used herein, the term "heteroalkenyl" refers to an alkenyl group as defined herein wherein one or more constituent carbon atoms have been replaced with nitrogen, oxygen or sulfur. In some embodiments, the heteroalkenyl may be further substituted with 1, 2, 3, or 4 substituents as described herein for alkenyl. An example of a heteroalkenyl is "alkenyloxy", which as used herein refers to alkenyl-O-. As used herein, the term "heteroalkenylene" refers to a divalent heteroalkenyl.
As used herein, the term "heteroalkynyl" refers to an alkynyl group as defined herein in which one or more of the constituent carbon atoms have been replaced with nitrogen, oxygen or sulfur. In some embodiments, the heteroalkynyl group is further substituted with 1, 2, 3, or 4 substituents as described herein for the alkynyl group. An example of a heteroalkynyl group is "alkynyloxy", which as used herein refers to alkynyl-O-. As used herein, the term "heteroalkynyl" refers to a divalent heteroalkynyl group.
As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic structure of 5 to 12 atoms having at least one aromatic ring containing 1, 2 or 3 ring atoms selected from nitrogen, oxygen and sulfur (the remaining ring atoms being carbon). In some embodiments, one or both ring carbon atoms of the heteroaryl group are replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxazolyl and thiazolyl. As used herein, the term "heteroarylene" refers to a divalent heteroaryl group.
As used herein, the term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups are 7 to 30 carbons (e.g., 7 to 16 or 7 to 20 carbons, such as C 1 -C 6 Alkyl C 2 -C 9 Heteroaryl, C 1 -C 10 Alkyl C 2 -C 9 Heteroaryl or C 1 -C 20 Alkyl C 2 -C 9 Heteroaryl). In some embodiments, each of the alkyl and heteroaryl groups may be further substituted with 1, 2, 3, or 4 substituents as defined herein for the respective groups.
As used herein, the term "heterocyclyl" refers to a monocyclic or polycyclic group (e.g., bicyclic or tricyclic) having 3 to 12 atoms, which has at least one non-aromatic ring containing 1, 2, 3, or 4 ring atoms selected from N, O or S, and which does not have an aromatic ring containing any N, O or S atoms. Polycyclic heterocyclic groups include spiro heterocyclic groups, bridged heterocyclic groups, and fused heterocyclic groups. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furanyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1, 3-dioxanyl. As used herein, the term "heterocyclylene" refers to a divalent heterocyclic group.
As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups are 7 to 30 carbons (e.g., 7 to 16 or 7 to 20 carbons, such as C 1 -C 6 Alkyl C 2 -C 9 Heterocyclyl, C 1 -C 10 Alkyl C 2 -C 9 Heterocyclyl or C 1 -C 20 Alkyl C 2 -C 9 A heterocyclic group). In some embodiments, each of the alkyl and heterocyclyl groups may be further substituted with 1, 2, 3, or 4 substituents as defined herein for the respective groups.
As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with an-OH group.
As used herein, the term "hydroxy" refers to an-OH group.
As used herein, the term "imino" refers to =nr N A group, wherein R is N For example H or alkyl.
As used herein, the term "N-protecting group" refers to those groups that are intended to protect an amino group from undesired reactions during the synthetic procedure. A common N-protecting group is disclosed in Greene, "Protective Groups in Organic Synthesis," 3 rd edition (John Wiley & Sons, new York, 1999). N protecting groups include, but are not limited to, acyl, aroyl or carbamoyl groups such as formyl, acetyl, propionyl, pentanoyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, o-nitrophenoxyacetyl, α -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliary such as protected or unprotected D-amino acids, L-amino acids or D, L-amino acids such as alanine, leucine and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl and p-toluenesulfonyl; urethane forming groups such as benzyloxycarbonyl, p-chlorobenzoxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzoxycarbonyl, 2-nitrobenzoxycarbonyl, p-bromobenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, 3, 5-dimethoxybenzyloxycarbonyl, 2,4-20 dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4, 5-dimethoxybenzyloxycarbonyl, 3,4, 5-trimethoxybenzyloxycarbonyl, 1- (p-biphenyl) -1-methylethoxycarbonyl, α -dimethyl-3, 5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2, -trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenyloxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, alkyloxycarbonyl, cyclohexyloxycarbonyl, phenylmethylfluorenyl and benzyloxycarbonyl, such as phenylmethylfluorenyl and trimethylsilyl groups. Preferred N protecting groups are allyloxycarbonyl, formyl, acetyl, benzoyl, pentanoyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The term "nitro" as used herein refers to-NO 2 A group.
As used herein, the term "oxo" refers to an =o group.
The term "sulfonyl" as used herein refers to the chemical moiety-SO 2 R, wherein R is hydrogen, aryl, heteroaryl, C 1 —C 6 Alkyl, C substituted by one or more halogens 1 —C 6 Alkyl radicals such as-SO 2 —CF 3 Substituent, C 1 —C 6 Alkylaryl or C 1 —C 6 Alkyl heteroaryl.
The term "sulfonylamino" as used herein refers to the chemical moiety-NRSO 2 -R ', wherein R and R' are each independently hydrogen, C 1 —C 6 Alkyl, aryl, heteroaryl, C 1 —C 6 Alkylaryl or C 1 –C 6 Alkyl heteroaryl.
The term "sulfonyloxy" as used herein refers to the chemical moiety-OSO 2 R, wherein R is hydrogen, C 1 —C 6 Alkyl, C substituted by one or more halogens 1 —C 6 Alkyl radicals such as-OSO 2 —CF 3 Substituents, aryl, heteroaryl, C 1 –C 6 Alkylaryl or C 1 –C 6 Alkyl heteroaryl.
As used herein, the term "thiol" refers to a-SH group.
The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups described herein may be substituted or unsubstituted. Unless otherwise indicated, when substituted, there will typically be 1 to 4 substituents. Substituents include, for example: alkyl (e.g., unsubstituted and substituted, wherein the substituents include any of the groups described herein, Such as aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxy, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH) 2 Or mono-or dialkylamino), azido, cyano, nitro, oxo, sulfonyl or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl may also be substituted with alkyl groups (unsubstituted and substituted, such as arylalkyl groups (e.g., substituted and unsubstituted benzyl groups)).
Description of chemical Structure
The compounds of the present disclosure may have one or more asymmetric carbon atoms and may exist as optically pure enantiomers, mixtures of enantiomers (e.g., racemates), optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, or mixtures of diastereomeric racemates. Optically active forms can be obtained, for example, by resolution of the racemate, by asymmetric synthesis or asymmetric chromatography (chromatography using chiral adsorbents or eluents). Thus, the compounds disclosed herein can exist in a variety of stereoisomeric forms.
Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are non-overlapping, most often because they contain asymmetrically substituted carbon atoms that serve as chiral centers. The term "enantiomer" means one of a pair of molecules that are mirror images of each other and that are non-overlapping. Diastereomers are stereoisomers that are not related in mirror image, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms.
Enantiomers of a compound may be prepared, for example, by separating the enantiomer from the racemate using one or more well-known techniques and methods, such as chiral chromatography and chiral chromatography-based separation methods, for example. The terms "racemate" and "racemic mixture" refer to compounds containing two enantiomers, wherein such mixtures do not exhibit optical activity; i.e. they do not rotate the plane of polarized light. The term "geometric isomer" refers to isomers that differ in the orientation of the substituent atoms associated with a carbon-carbon double bond, cycloalkyl ring, or bridged bicyclic ring system. The atoms on each side of the carbon-carbon double bond (except H) may be in the E (substituent on the opposite side of the carbon-carbon double bond) or Z (substituent oriented on the same side of the carbon-carbon double bond) configuration. "R", "S", "R", "E", "Z", "cis" and "trans" indicate configuration relative to the core molecule.
When a stereochemistry of a compound disclosed herein is named or depicted according to the structure, the named or depicted stereoisomer is greater than 50% by weight (e.g., at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight) relative to its other stereoisomers. For example, when a single enantiomer is named or depicted by structure, the depicted or named enantiomer is greater than 50% by weight (e.g., at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight) optically pure. Similarly, when a single diastereomer is named or depicted by structure, the depicted or named diastereomer is greater than 50% pure by weight (e.g., at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight). The percent optical purity is the ratio of the weight of an enantiomer to the weight of its optical isomer. The diastereoisomeric purity by weight is the ratio of the weight of one diastereoisomer to the weight of all diastereoisomers.
Further, when a stereochemistry of a compound disclosed herein is named or depicted according to the structure, the named or depicted stereoisomer is greater than 50% by mole fraction relative to its other stereoisomers (e.g., at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction). For example, when a single enantiomer is named or depicted according to structure, the depicted or named enantiomer is greater than 50% by mole fraction relative to the other enantiomers (e.g., at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction). When a single diastereomer is named or depicted according to structure, the depicted or named diastereomer is greater than 50% by mole fraction relative to the other diastereomers of the compound shown (e.g., at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction). For the mirror-image compounds, the percent purity in mole fractions is calculated as the ratio of the molar amount of enantiomer of interest to the sum of the molar amounts of (i) enantiomer of interest and (ii) optical isomer. Similarly, for a diastereomeric compound, the percent purity in mole fraction is calculated as the ratio of the molar amount of the diastereomer of interest to the total molar amount of all diastereomers present for the compound indicated.
When a disclosed compound is named or depicted according to structure without indicating stereochemistry and the compound has at least one chiral center, it is to be understood that the name or structure encompasses the enantiomer of the compound that does not contain the corresponding optical isomer, the racemic mixture of the compound, or a mixture enriched in one enantiomer relative to its corresponding optical isomer.
When the disclosed compounds are named or depicted according to structure without indicating stereochemistry and have two or more chiral centers, it is to be understood that the name or structure encompasses diastereomers which are free of other diastereomers, multiple diastereomers which are free of other diastereomers, mixtures of diastereomers pairs, mixtures of diastereomers which are enriched in one diastereomer relative to other diastereomers, or mixtures of diastereomers which are enriched in one or more diastereomers relative to other diastereomers. The present disclosure includes all such forms.
Polymorphic compounds
As will be appreciated by those skilled in the art, many chemical entities may take a variety of different solid forms, such as, for example, amorphous forms or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present disclosure may be used in any of the described forms, including any solid forms. In some embodiments, the compounds described or depicted herein may be provided or used in the form of a hydrate or solvate.
Detailed description of the preferred embodiments
The present disclosure provides compositions and methods useful for treating neuromuscular disorders, particularly X-linked myotubulomyopathy (xltm). According to the compositions and methods described herein, a viral vector, such as an adeno-associated virus (AAV) vector, containing a transgene encoding myotubulin 1 (MTM 1), may be administered to a patient (e.g., a human patient) having xltm. The AAV vector may be, for example, a pseudotyped AAV vector, such as an AAV vector (AAV 2/8) containing AAV2 inverted terminal repeats packaged within a capsid protein from AAV 8. In some embodiments, the transgene is operably linked to transcriptional regulatory elements, such as promoters that induce gene expression in muscle cells. An exemplary promoter that can be used in conjunction with the compositions and methods of the present disclosure is a desmin promoter. In some embodiments, the AAV2/8 viral vector comprising a transgene encoding MTM1 is birearyl.
The present disclosure is based, at least in part, on the discovery of therapeutic and prophylactic treatment methods that address significant medical needs associated with existing gene therapies that involve the delivery of MTM1 to a patient in need thereof (e.g., a patient with xltm). The present disclosure is also based in part on the following findings: existing gene therapies involving the delivery of MTM1 to a patient in need thereof (e.g., a patient with xltm) are associated with risks, including cholestasis syndrome such as cholestasis, hyperbilirubinemia, or one or more symptoms thereof. More specifically, the present invention relates to the discovery of a method comprising administering a viral vector (e.g., birthwort) comprising a transgene encoding MTM1 and an anti-cholestasis agent (e.g., bile acid, farnesol X Receptor (FXR) ligand, fibroblast growth factor 19 (FGF-19) mimetic, takeda-G protein receptor 5 (TGR 5) agonist, peroxisome proliferator-activated receptor (PPAR) agonist, PPAR-alpha agonist, PPAR-delta agonist, dual PPAR-alpha and PPAR-delta agonist, apical sodium-dependent bile acid transporter (ASBT) inhibitor, immunomodulatory drug, anti-fibrotic therapy, and nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor) as a prophylactic treatment of cholestasis syndrome associated with existing gene therapy involving the delivery of MTM1 to a patient in need thereof (e.g., a patient suffering from xltm). In some embodiments, the anti-cholestasis agent is a bile acid. In some embodiments, the bile acid is ursodeoxycholic acid (e.g., xiong Erchun).
In some embodiments, the disclosure describes a method of treating or preventing cholestasis or hyperbilirubinemia in a human patient suffering from xltm and having administered a therapeutically effective amount of a viral vector comprising a transgene encoding MTM1, comprising administering to the patient an anti-cholestasis agent.
In some embodiments, the present disclosure describes a method of treating xltm in a human patient in need of and previously administered an anti-cholestasis agent, the method comprising administering to the patient a therapeutically effective amount of a viral vector comprising a transgene encoding MTM 1.
In some embodiments, the present disclosure describes a method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm, the method comprising administering to the patient a viral vector comprising a transgene encoding MTM1 and an anti-cholestasis agent.
In some embodiments, the present disclosure describes a method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm, the method comprising administering to the patient a viral vector comprising a transgene encoding MTM1 and an anti-cholestasis agent.
In some embodiments, the disclosure describes a method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm and previously administered an anti-cholestasis agent, the method comprising administering to the patient a therapeutically effective amount of a viral vector comprising a transgene encoding MTM 1.
In some embodiments, the present disclosure describes a method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm and previously administered an anti-cholestatic agent, the method comprising administering to the patient a therapeutically effective amount of a viral vector comprising a transgene encoding MTM 1.
The following section provides a description of therapeutic agents and parameters for assessing cholestasis, hyperbilirubinemia, or one or more symptoms thereof, which result in administration of an anti-cholestasis agent described herein. The following sections also describe a variety of transduction agents that can be used in conjunction with the compositions and methods of the present disclosure.
Therapeutic method
In some embodiments, the patient is a neonate (e.g., 0-4 months), infant (e.g., 0-5 months), young child (e.g., 6-12 months), child of 1-3 years of age, or child of 3-5 years of age at the time of administration of the viral vector.
In some embodiments, the patient is a neonate (e.g., 0-4 months) at the time of administration of the viral vector. For example, in some embodiments, the patient is a neonate from about 0 to about 4 months (e.g., from 0 months to about 4 months, from 1 month to about 4 months, from 2 months to about 4 months, or from 3 months to about 4 months). In some embodiments, the patient is 0 months. In some embodiments, the patient is 1 month. In some embodiments, the patient is 2 months. In some embodiments, the patient is 3 months. In some embodiments, the patient is 4 months.
In some embodiments, the patient is a neonate (e.g., less than about 4 months) at the time of administration of the viral vector. For example, in some embodiments, the patient is a neonate less than about 4 months. In some embodiments, the patient is less than about 4 months. In some embodiments, the patient is less than about 3 months. In some embodiments, the patient is less than about 2 months. In some embodiments, the patient is less than about 1 month.
In some embodiments, the patient is an infant (e.g., 0-5 months) at the time of administration of the viral vector. For example. In some embodiments, the patient is an infant from about 0 month to about 5 months (e.g., from 0 month to about 5 months, from 1 month to about 5 months, from 2 months to about 5 months, from 3 months to about 5 months, or from 4 months to about 5 months). In some embodiments, the patient is 0 months. In some embodiments, the patient is 1 month. In some embodiments, the patient is 2 months. In some embodiments, the patient is 3 months. In some embodiments, the patient is 4 months. In some embodiments, the patient is 3 months. In some embodiments, the patient is 5 months.
In some embodiments, the patient is an infant (e.g., less than about 5 months) at the time of administration of the viral vector. For example, in some embodiments, the patient is an infant that is less than about 5 months old. In some embodiments, the patient is less than about 5 months. In some embodiments, the patient is less than about 4 months. In some embodiments, the patient is less than about 3 months. In some embodiments, the patient is less than about 2 months. In some embodiments, the patient is less than about 1 month.
In some embodiments, the patient is a young child (e.g., 6-12 months) at the time of administration of the viral vector. For example. In some embodiments, the patient is an infant from about 6 months to about 12 months (e.g., from 6 months to about 12 months, from 7 months to about 12 months, from 8 months to about 12 months, from 9 months to about 12 months, from 10 months to about 12 months, or from 11 months to about 12 months). In some embodiments, the patient is 6 months. In some embodiments, the patient is 7 months. In some embodiments, the patient is 8 months. In some embodiments, the patient is 9 months. In some embodiments, the patient is 10 months. In some embodiments, the patient is 11 months. In some embodiments, the patient is 12 months.
In some embodiments, the patient is a young child (e.g., less than about 12 months) at the time of administration of the viral vector. For example, in some embodiments, the patient is a young child less than about 12 months. In some embodiments, the patient is less than about 12 months. In some embodiments, the patient is less than about 11 months. In some embodiments, the patient is less than about 10 months. In some embodiments, the patient is less than about 9 months. In some embodiments, the patient is less than about 8 months. In some embodiments, the patient is less than about 7 months. In some embodiments, the patient is less than about 6 months. In some embodiments, the patient is less than about 5 months. In some embodiments, the patient is less than about 4 months. In some embodiments, the patient is less than about 3 months. In some embodiments, the patient is less than about 2 months. In some embodiments, the patient is less than about 1 month.
In some embodiments, the patient is a child 1-3 years old when the viral vector is administered. For example, in some embodiments, the patient is a child from about 1 year old to about 3 years old (e.g., from 1 year old to about 3 years old or from 2 years old to about 3 years old). In some embodiments, the patient is 1 year old. In some embodiments, the patient is 2 years old. In some embodiments, the patient is 3 years old.
In some embodiments, the patient is a child (e.g., less than about 3 years old) at the time of administration of the viral vector. For example, in some embodiments, the patient is a child less than about 3 years old. In some embodiments, the patient is less than about 3 years old. In some embodiments, the patient is less than about 2 years old. In some embodiments, the patient is less than about 1 year old. In some embodiments, the patient is less than about 12 months. In some embodiments, the patient is less than about 11 months. In some embodiments, the patient is less than about 10 months. In some embodiments, the patient is less than about 9 months. In some embodiments, the patient is less than about 8 months. In some embodiments, the patient is less than about 7 months. In some embodiments, the patient is less than about 6 months. In some embodiments, the patient is less than about 5 months. In some embodiments, the patient is less than about 4 months. In some embodiments, the patient is less than about 3 months. In some embodiments, the patient is less than about 2 months. In some embodiments, the patient is less than about 1 month.
In some embodiments, the patient is a child 3-5 years old at the time of administration of the viral vector. For example, in some embodiments, the patient is a child from about 3 years to about 5 years (e.g., from 3 years to about 5 years or from 4 years to about 5 years). In some embodiments, the patient is 3 years old. In some embodiments, the patient is 4 years old. In some embodiments, the patient is 5 years old.
In some embodiments, the patient is a child (e.g., less than about 5 years old) at the time of administration of the viral vector. For example, in some embodiments, the patient is a child less than about 5 years old. In some embodiments, the patient is less than about 5 years old. In some embodiments, the patient is less than about 4 years old. In some embodiments, the patient is less than about 3 years old. In some embodiments, the patient is less than about 2 years old. In some embodiments, the patient is less than about 1 year old. In some embodiments, the patient is less than about 12 months. In some embodiments, the patient is less than about 11 months. In some embodiments, the patient is less than about 10 months. In some embodiments, the patient is less than about 9 months. In some embodiments, the patient is less than about 8 months. In some embodiments, the patient is less than about 7 months. In some embodiments, the patient is less than about 6 months. In some embodiments, the patient is less than about 5 months. In some embodiments, the patient is less than about 4 months. In some embodiments, the patient is less than about 3 months. In some embodiments, the patient is less than about 2 months. In some embodiments, the patient is less than about 1 month.
In some embodiments, the patient is about 1 month to about 5 years old (e.g., about 1 month to about 5 years old, about 2 months to about 5 years old, about 3 months to about 5 years old, about 4 months to about 5 years old, about 5 months to about 5 years old, about 6 months to about 5 years old, about 1 year to about 5 years old, about 2 years to about 5 years old, about 3 years to about 5 years old, or about 4 years to about 5 years old) when the viral vector is administered.
In some embodiments, the patient is greater than or equal to 35 weeks gestational age at birth (e.g., 35 weeks gestational age, 36 weeks gestational age, 37 weeks gestational age, 38 weeks gestational age, 39 weeks gestational age, 40 weeks gestational age, 41 weeks gestational age, and 42 weeks gestational age) and between adjusted term age (e.g., 37 weeks gestational age or greater) and about 5 years of age when the viral vector is administered. For example, if the patient is 35 weeks gestational age at birth, then the patient's foot is 14 days of month old.
In some embodiments, the patient is 35 weeks gestational age at birth and is between adjusted term and about 5 years of age (e.g., 14 days to about 5 years of age, 15 days to about 5 years of age, 16 days to about 5 years of age, 17 days to about 5 years of age, 18 days to about 5 years of age, 19 days to about 5 years of age, 20 days to about 5 years of age, 25 days to about 5 years of age, one month to about 5 years of age, two months to about 5 years of age, 3 months to about 5 years of age, 4 months to about 5 years of age, 5 months to about 5 years of age, 6 months to about 5 years of age, 1 year to about 5 years of age, 2 years to about 5 years of age, 3 years to about 5 years of age, and 4 years to about 5 years of age) when the viral vector is administered.
In some embodiments, the patient is about 36 weeks of gestational age at birth and is between about 7 days to about 5 years old, 8 days to about 5 years old, 9 days to about 5 years old, 10 days to about 5 years old, 11 days to about 5 years old, 12 days to about 5 years old, 13 days to about 5 years old, 14 days to about 5 years old, 15 days to about 5 years old, 16 days to about 5 years old, 17 days to about 5 years old, 18 days to about 5 years old, 19 days to about 5 years old, 20 days to about 5 years old, 25 days to about 5 years old, one month to about 5 years old, two months to about 5 years old, 3 months to about 5 years old, 4 months to about 5 years old, 6 months to about 5 years old, 1 year to about 5 years old, 2 years to about 5 years old, 3 years to about 5 years old, and 4 years to about 5 years old when the viral vector is administered.
In some embodiments, the patient is 37 weeks gestational age at birth and is between adjusted term to about 5 years of age (e.g., 1 day to about 5 years of age, 2 days to about 5 years of age, 3 days to about 5 years of age, 4 days to about 5 years of age, 5 days to about 5 years of age, 6 days to about 5 years of age, 7 days to about 5 years of age, 8 days to about 5 years of age, 9 days to about 5 years of age, 10 days to about 5 years of age, 11 days to about 5 years of age, 12 days to about 5 years of age, 13 days to about 5 years of age, 14 days to about 5 years of age, 15 days to about 5 years of age, 16 days to about 5 years of age, 17 days to about 5 years of age, 18 days to about 5 years of age, 19 days to about 5 years of age, 20 days to about 5 years of age, 25 days to about 5 years of age, one month to about 5 years of age, two months to about 5 years of age, 3 months to about 5 years of age, 4 months to about 5 years of age, 5 years to about 5 years of age, 6 days to about 5 years of age, 1 day to about 5 years of age, 2 to about 5 years of age, and about 5 years of age).
In some embodiments, the patient is male.
In some embodiments, the patient is female.
X-linked myomicrotubule myopathy
Xltm is a rare, life-threatening congenital myopathy caused by loss of function mutations of the MTM1 gene, and most patients are characterized by severe muscle weakness and hypotonia at birth, resulting in severe respiratory insufficiency, inability to sit, stand or walk, and premature death.
Myopathy associated with xltm can impair development of motor skills such as sitting, standing and walking. Affected infants may also be difficult to feed due to muscle weakness. Individuals suffering from this condition typically have no muscle strength to breathe themselves and must be supported with mechanical ventilation. Some affected individuals need only be mechanically ventilated regularly, such as during sleep, while others need to be mechanically ventilated continuously. Patients with xltm may also develop muscle weakness that controls eye movement (eye paralysis), other muscle weakness of the face, and loss of reflex (loss of reflex).
In xltm, muscle weakness often disrupts normal skeletal development and can lead to skeletal weakness, abnormal spinal curvature (scoliosis), and hip and knee joint deformities (contractures). Patients with xltm may have a large head, a narrow and slender face, and a high, arched-topped oral cavity (the palate). Patients may also suffer from liver disease, recurrent ear and respiratory tract infections or seizures.
Patients with xltm often survive only to childhood due to their severe dyspnea; however, some patients with this condition have been alive to adulthood. The compositions and methods of the present disclosure provide an important medical benefit, namely the ability to extend the life of such patients by restoring functional MTM1 expression. In addition, the compositions and methods described herein can be used to improve the quality of life of a patient after treatment (e.g., reduce stiffness and/or joint contracture or increase diaphragmatic and/or respiratory progression) because the present disclosure provides a series of guidelines that can be used to determine the eligibility of a patient to break away from mechanical ventilation.
Bile stasis and hyperbilirubinemia
Cholestasis is any condition in which bile acid flow from the liver is slowed or blocked, whereas hyperbilirubinemia refers to a condition in which bilirubin accumulates in the blood and serum bile acid appears to remain normal. In contrast, cholestasis syndrome is characterized by pronounced cholestasis and normal to slightly elevated bilirubin levels.
In some embodiments, the patient is monitored for the development of cholestasis. In some embodiments, the patient is monitored for the development of hyperbilirubinemia. In some embodiments, the patient is monitored for development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof. In some embodiments, the progression of cholestasis, hyperbilirubinemia, or one or more symptoms thereof in a patient is monitored by assessing a parameter of a blood sample obtained from the patient, wherein finding the parameter above a reference level identifies the patient as suffering from cholestasis, hyperbilirubinemia, or one or more symptoms thereof
In some embodiments, the patient is monitored for the development of hyperbilirubinemia, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, a patient is determined to exhibit cholestasis or one or more symptoms thereof when the patient exhibits one or more parameters (e.g., total bile acid level, gamma-glutamyl transferase (GGT) level, alkaline phosphatase (ASP) level, aspartate Aminotransferase (AST) level, and/or alanine Aminotransferase (ALT) level) that are greater than or less than an age-adjusted specification, as measured in a serum bile acid test and/or a blood test (e.g., liver Function Test (LFT)).
In some embodiments, when the patient exhibits bilirubin levels greater than normals, as measured in a blood test (e.g., bilirubin test), the patient is determined to exhibit hyperbilirubinemia or one or more symptoms thereof.
In some embodiments, the present disclosure provides a method of treating cholestasis in a human patient having xltm and having previously been administered a viral vector (e.g., birnesyl) comprising a transgene encoding MTM1, the method comprising administering an anti-cholestasis agent to the patient.
In some embodiments, the present disclosure provides a method of treating hyperbilirubinemia in a human patient having xltm and having previously been administered a viral vector (e.g., birnesyl) comprising a transgene encoding MTM1, the method comprising administering an anti-cholestasis agent to the patient.
In some embodiments, the present disclosure provides a method of preventing cholestasis in a human patient having xltm and having previously been administered a viral vector (e.g., birnesyl) comprising a transgene encoding MTM1, the method comprising administering an anti-cholestasis agent to the patient.
In some embodiments, the present disclosure provides a method of preventing hyperbilirubinemia in a human patient suffering from xltm and having previously been administered a viral vector (e.g., birnesyl) comprising a transgene encoding MTM1, the method comprising administering an anti-cholestasis agent to the patient.
In some embodiments, the patient has no history of cholestasis or hyperbilirubinemia. In some embodiments, the patient does not have any history of potential liver disease.
Vector for delivering exogenous nucleic acid to target cell
Viral vectors for nucleic acid delivery
The viral genome provides a rich source of vectors that can be used to efficiently deliver a gene of interest (e.g., a transgene encoding MTM 1) into the genome of a target cell (e.g., a mammalian cell, such as a human cell). Viral genomes are particularly useful vectors for gene delivery because polynucleotides contained within such genomes are typically incorporated into the genome of a target cell by general or specialized transduction. These processes occur as part of the natural viral replication cycle and do not require the addition of proteins or agents to induce gene integration. Examples of viral vectors include AVV, retrovirus, adenovirus (e.g., ad5, ad26, ad34, ad35, and Ad 48), picornavirus (e.g., adeno-associated virus), coronavirus, negative strand RNA virus (such as orthomyxovirus, e.g., influenza virus), rhabdovirus (e.g., rabies and vesicular stomatitis virus), paramyxovirus (e.g., measles and Sendai virus (Sendai)), positive strand RNA virus (such as picornavirus and alphavirus), and double stranded DNA virus, including adenovirus, herpes virus (e.g., type 1 and type 2 herpes simplex virus, ai Sitan-barter virus (Epstein-Barr virus), cytomegalovirus), and poxvirus (e.g., vaccinia, modified ankara (modified vaccinia Ankara, MVA), chicken pox, and canary pox). Other viruses that may be used to deliver polynucleotides encoding the antibody light and heavy chains or antibody fragments of the invention include, for example, norwalk, togavirus, flavivirus, reovirus, papovavirus, hepadnavirus, and hepatitis virus. Examples of retroviruses include: avian leukemia sarcomas, mammalian type C, type B viruses, type D viruses, HTLV-BLV group, lentiviruses, foamy viruses (Coffin, J.M., retroviridae: the viruses and their replication, in Fundamental Virology, third edition, B.N.fields, et al, editors, lippincott-Raven Publishers, philadelphia, 1996). Other examples include murine leukemia virus, murine sarcoma virus, mouse mammary tumor virus, bovine leukemia virus, feline sarcoma virus, avian leukemia virus, human T cell leukemia virus, baboon endogenous virus, gibbon ape leukemia virus, mersen fei chou virus (Mason Pfizer monkey virus), simian immunodeficiency virus, simian sarcoma virus, rous sarcoma virus (Rous sarcoma virus), and lentivirus. Other examples of vectors are described, for example, in U.S. patent No. 5,801,030, the disclosure of which is incorporated herein by reference with respect to viral vectors used in gene therapy.
AAV vectors for nucleic acid delivery
In some embodiments, the nucleic acids of the compositions and methods described herein are incorporated into recombinant AAV (rAAV) vectors and/or virions to facilitate their introduction into cells. rAAV vectors useful in the invention are recombinant nucleic acid constructs comprising (1) a transgene to be expressed (e.g., a polynucleotide encoding an MTM1 protein) and (2) a viral nucleic acid that facilitates integration and expression of a heterologous gene. Viral nucleic acids may include those AAV sequences required for DNA cis replication and packaging (e.g., functional Inverted Terminal Repeats (ITRs)) into virions. In a typical application, the transgene encodes MTM1, which can be used to correct MTM1 mutations in patients suffering from neuromuscular disorders such as xltm. Such rAAV vectors may also contain markers or reporter genes. Useful rAAV vectors have one or more AAV wild-type genes deleted in whole or in part, but retain functional flanking ITR sequences. AAV ITRs can have any serotype suitable for a particular application (e.g., derived from serotype 2). Methods of using rAAV vectors are described, for example, in Tal et al, J.biomed.Sci.7:279-291 (2000) and Monahan and Samulski, gene Delivery 7:24-30 (2000), the disclosures of each of which are incorporated herein by reference for AAV vectors for Gene Delivery.
The nucleic acids and vectors described herein can be incorporated into rAAV virions to facilitate the introduction of the nucleic acids or vectors into cells. The capsid protein of AAV constitutes the outer non-nucleic acid portion of the virion and is encoded by the AAV cap gene. The cap gene encodes three viral coat proteins VP1, VP2, and VP3, which are necessary for virion assembly. Construction of rAAV virions has been described, for example, in U.S. Pat. nos. 5,173,414;5,139,941;5,863,541;5,869,305;6,057,152; and 6,376,237; and Rabinowitz et al, J.Virol.76:791-801 (2002) and Bowles et al, J.Virol.77:423-432 (2003), the disclosures of each of which are incorporated herein by reference with respect to AAV vectors for gene delivery.
rAAV virions that can be used in conjunction with the compositions and methods described herein include those derived from a variety of AAV serotypes (including AAV 1, 2, 3,4, 5, 6, 7, 8, and 9). rAAV virions comprising at least one serotype 1 capsid protein may be particularly useful for targeting muscle cells. rAAV virions comprising at least one serotype 6 capsid protein may also be particularly useful because the serotype 6 capsid protein is similar in structure to the serotype 1 capsid protein and thus is expected to also result in high expression of MTM1 in muscle cells. rAAV serotype 9 was also found to be a highly efficient transducer for muscle cells. Construction and use of AAV vectors and AAV proteins of different serotypes is described, for example, in Chao et al, mol. Ther.2:619-623 (2000); davidson et al, proc.Natl.Acad.Sci.USA 97:3428-3432 (2000); xiao et al, J.Virol.72:2224-2232 (1998); halbert et al, J.Virol.74:1524-1532 (2000); halbert et al, J.Virol.75:6615-6624 (2001); and Auricchio et al, hum. Molecular. Genet.10:3075-3081 (2001), the disclosures of each of which are incorporated herein by reference in their entirety for AAV vectors for gene delivery.
Also useful in conjunction with the compositions and methods described herein are pseudotyped rAAV vectors. Pseudotyped vectors include AAV vectors of a given serotype (e.g., AAV 9) pseudotyped with capsid genes derived from serotypes other than the given serotype (e.g., AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, etc.). For example, a representative pseudotyped vector is an AAV8 vector that encodes a therapeutic protein pseudotyped with a capsid gene derived from AAV serotype 2. Techniques involving the construction and use of pseudotyped rAAV virions are known in the art and are described, for example, in Duan et al, J.Virol.75:7662-7671 (2001); halbert et al, J.Virol.74:1524-1532 (2000); zolotukhin et al Methods,28:158-167 (2002); and Auricchio et al, hum. Molecular. Genet.,10:3075-3081 (2001).
AAV virions having mutations within the virion capsid can be used to infect specific cell types more effectively than non-mutated capsid virions. For example, suitable AAV mutants may have ligand insertion mutations that help AAV target a particular cell type. Construction and characterization of AAV capsid mutants, including insertion mutants, alanine screening mutants and epitope tag mutants, is described in Wu et al, J.Virol.74:8635-45 (2000). Other rAAV virions that can be used in the methods of the invention include those capsid hybrids produced by molecular breeding of the virus and by exon shuffling. See, for example, soong et al, nat.Genet.,25:436-439 (2000) and Kolman and Stemmer, nat.Biotechnol.19:423-428 (2001).
Birella base
As described herein, pseudotyped AAV vectors include a nucleic acid sequence encoding the MTM1 gene (SEQ ID NO: 4) operably linked to a desmin promoter flanking the AAV2 ITR (SEQ ID NO: 3) and packaged within a capsid protein from AAV8 (AAV 2/8), as well as other genetic components listed in Table 1, refer to compounds known under the international designation of Rayleigh (INN).
The birnesyl group is a non-replicating recombinant AAV8 vector that expresses non-codon optimized human MTM1 cDNA under the control of a muscle-specific human desmin promoter. The MTM1 expression cassette was constructed by cloning a synthetic DNA sequence complementary to the coding part (nucleotides 43-1864) of the wild type human MTM1 transcript (NCBI Ref. Seq NM-000252.3) downstream of the 1.05-kb human desmin enhancer/promoter region. The second intron of the human beta-globulin gene (HBB) and polyadenylation sequence were inserted upstream and downstream, respectively, of the MTM1 synthetic cDNA to mediate RNA processing. The expression cassette is flanked by AAV serotype 2 (AAV 2) Inverted Terminal Repeats (ITRs). Vectors were generated by double plasmid transfection into AAV8 capsids in HEK293 cells in bioreactor suspension culture during whole GMP.
In some embodiments, a method of treating a disorder (e.g., xltm) or alleviating one or more symptoms (e.g., stiffness and/or joint contracture or the need for diaphragmatic and/or respiratory muscle progression) in a human patient in need thereof, comprises administering to the patient a therapeutically effective amount of birthwort during the treatment.
In some embodiments, the method of weaning a human patient from mechanical ventilation comprises a patient who has previously been administered a therapeutically effective amount of birnesyl. The components of the specific rayleigh are shown in table 1 below:
TABLE 1 Billerenyl nucleic acid sequence (SEQ ID NO: 5)
As described herein, birimyl refers to an AAV vector having the nucleic acid sequence of SEQ ID NO:5, as shown below:
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method for delivering exogenous nucleic acid to target cells
Transfection technique
Techniques useful for introducing transgenes (such as the MTM1 transgenes described herein) into target cells are known in the art. For example, electroporation can be used to permeabilize mammalian cells by applying an electrostatic potential to a cell of interest (e.g., a human target cell). Mammalian cells (such as human cells) that are subjected to an external electric field in this manner are then susceptible to uptake of exogenous nucleic acids (e.g., nucleic acids that can be expressed in, for example, neurons, glial cells, or non-neural cells such as colon and kidney cells). Electroporation of mammalian cells is described in detail, for example, in Chu et al Nucleic Acids Research 15:1311 (1987), the disclosure of which is incorporated herein by reference. Similar technology NUCLEOFECTION TM The applied electric field is used to stimulate uptake of the exogenous polynucleotide into the nucleus of the eukaryotic cell. Nucleofction TM And schemes that may be used to implement this technology are described in detail in, for example, distler et al, experimental Dermatology 14:315 (2005) and US2010/0317114, the disclosures of each of which are incorporated herein by reference.
Other techniques that can be used to transfect target cells are extrusion-perforation methods. This technique induces rapid mechanical deformation of the cells to stimulate the foreign DNA through the membrane Kong Shequ formed in response to the applied stress. The advantage of this technique is that the vector is not necessary for delivery of the nucleic acid into a cell, such as a human target cell. Extrusion-perforation is described in detail, for example, in Share et al, J.Vis. Exp.81:e50980 (2013), the disclosure of which is incorporated herein by reference.
Lipofection represents another technique that can be used to transfect target cells. The method involves loading nucleic acids into liposomes that typically exhibit cationic functional groups, such as quaternary amines or protonated amines, towards the outside of the liposome. Thus facilitating electrostatic interactions between the liposome and the cell due to the anionic nature of the cell membrane, ultimately leading to uptake of exogenous nucleic acids, for example, by directing liposome fusion with the cell membrane or by endocytosis of the complex. Lipofection is described in detail in, for example, US 7,442,386, the disclosure of which is incorporated herein by reference. A similar technique that utilizes ionic interactions with cell membranes to cause uptake of exogenous nucleic acids is to contact the cells with cationic polymer-nucleic acid complexes. Exemplary cationic molecules that associate with polynucleotides to impart positive charges that facilitate interaction with cell membranes are activated dendrimers (described, for example, in Dennig, top Curr chem.228:227 (2003), the disclosures of which are incorporated herein by reference), polyethylenimine, and DEAE-dextran, the use of which as transfection agents are described in detail, for example, in Gulick et al, curr Protoc Mol biol.40:1:9.2:9.2.1 (1997), the disclosures of which are incorporated herein by reference.
Another tool that can be used to induce uptake of exogenous nucleic acid by target cells is laser transfection, also known as optical transfection, which is a technique that involves exposing cells to electromagnetic radiation of a specific wavelength to gently permeabilize the cells and allow the polynucleotides to pass through the cell membrane. The biological activity of this technique is similar to electroporation and in some cases was found to be superior to electroporation.
Puncture transfection (Impalefection) is another technique that can be used to deliver genetic material to target cells. Depending on the use of nanomaterials such as carbon nanofibers, carbon nanotubes and nanowires. Needle-like nanostructures are synthesized perpendicular to the surface of the substrate. DNA containing genes intended for intracellular delivery is attached to the nanostructure surface. The wafer with the array of pins is then pressed against the cells or tissue. The cells pierced by the nanostructure can express the delivered gene. Examples of this technology are described in Shalek et al, PNAS107:25 1870 (2010), the disclosure of which is incorporated herein by reference.
MAGNETOFECTION may also be used TM Delivering the nucleic acid to the target cell. MAGNETOFECTION TM The principle of (a) is to associate a nucleic acid with a cationic magnetic nanoparticle. The magnetic nanoparticles are made of fully biodegradable iron oxide and are coated with specific cation-specific molecules that vary depending on the application. Its association with gene vectors (DNA, siRNA, viral vectors, etc.) is achieved by salt-induced colloidal aggregation and electrostatic interactions. The magnetic particles are then concentrated on the target cells by influencing the external magnetic field generated by the magnet. This technique is described in detail in Scherer et al, gene Ther.9:102 (2002), the disclosure of which is incorporated herein by reference. Magnetic beads are another tool that can be used to transfect target cells in a gentle and efficient manner, as this method utilizes an applied magnetic field to direct uptake of nucleic acids. This technique is described in detail in, for example, US2010/0227406, the disclosure of which is incorporated herein by reference.
Another tool that can be used to induce uptake of exogenous nucleic acid by target cells is sonoporation, a technique that involves using sound (typically ultrasonic frequencies) to alter the permeability of the cytoplasmic membrane to permeabilize the cells and allow polynucleotides to pass through the cell membrane. This technique is described in detail, for example, in Rhodes et al, methods Cell biol.82:309 (2007), the disclosure of which is incorporated herein by reference.
Microvesicles represent another potential vehicle that may be used to modify the genome of a target cell according to the methods described herein. For example, microvesicles that have been induced by co-overexpression of the glycoprotein VSV-G with, for example, a genome-modified protein (such as a nuclease) can be used to efficiently deliver the protein into a cell, followed by catalyzing site-specific cleavage of the endogenous polynucleotide sequence to prepare the genome of the cell for covalent incorporation of a polynucleotide of interest (such as a gene or regulatory sequence). The use of such vesicles (also known as nanovesicles (gesicles)) for the genetic modification of eukaryotic cells is described in detail, for example, in Quinn et al, genetic Modification of Target Cells by Direct Delivery of Active Protein [ abstract ]. Methylation changes in early embryonic genes in cancer [ abstract ], proceedings of the 18th Annual Meeting of the American Society of Gene and Cell Therapy; the 2015, 5 and 13 days, abstract number 122.
Incorporation of target genes by gene editing techniques
In addition to the above, a variety of tools have been developed for incorporating genes of interest into target cells, such as human cells. One such method that may be used to incorporate a polynucleotide encoding a target gene into a target cell involves the use of transposons. Transposons are polynucleotides encoding transposases and contain polynucleotide sequences or genes of interest flanking 5 'and 3' excision sites. Once the transposon is delivered into the cell, expression of the transposase gene begins and an active enzyme is produced that cleaves the gene of interest from the transposon. This activity is mediated by site-specific recognition of transposon excision sites by transposases. In some cases, these excision sites may be terminal repeats or inverted terminal repeats. Once excised from the transposon, the gene of interest may be integrated into the genome of the mammalian cell by transposase-catalyzed cleavage of a similar excision site present in the genome of the cell nucleus. This allows the insertion of the gene of interest into the cleaved nuclear DNA at the complementary excision site, followed by covalent attachment of the phosphodiester bond that joins the gene of interest to the DNA of the mammalian cell genome, completing the incorporation process. In some cases, the transposon may be a retrotransposon such that the gene encoding the target gene is first transcribed into an RNA product and then reverse transcribed into DNA prior to incorporation into the genome of a mammalian cell. Exemplary transposon systems are piggybac transposons (described in detail in, for example, WO 2010/085699) and sleeping beauty transposons (described in detail in, for example, US 2005/012764), the disclosures of each of which are incorporated herein by reference for transposons for delivering genes into relevant cells.
Another tool for integrating a target gene into the target cell genome is Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas systems, which originally evolved as an adaptive defense mechanism for bacteria and archaea against viral infections. The CRISPR/Cas system includes palindromic repeats within plasmid DNA and associated Cas9 nucleases. This collection of DNA and proteins directs site-specific DNA cleavage of the target sequence by first incorporating exogenous DNA into the CRISPR locus. The polynucleotides containing these exogenous sequences and the repeat-spacer elements of the CRISPR locus are then transcribed in the host cell to produce guide RNAs, which can then anneal to the target sequence and localize the Cas9 nuclease to this site. In this way, highly site-specific cas9 mediated DNA cleavage can be generated in exogenous polynucleotides, as interactions that bring cas9 close to the target DNA molecule are controlled by RNA: DNA hybridization. Thus, one can design a CRISPR/Cas system to cleave any target DNA molecule of interest. This technique has been used to edit eukaryotic genomes (Hwang et al, nature Biotechnology 31:227 (2013)) and can be used as an efficient means of site-specific editing of target cell genomes to cleave DNA prior to incorporation of genes encoding the target genes. Modulation of gene expression using CRISPR/Cas has been described, for example, in U.S. patent No. 8,697,359, the disclosure of using a CRISPR/Cas system for gene editing is incorporated herein by reference. Alternative methods for site-specific cleavage of genomic DNA prior to incorporation of a gene of interest into a target cell include the use of Zinc Finger Nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). Unlike the CRISPR/Cas system, these enzymes do not contain guide polynucleotides for localization to specific target sequences. Instead, target specificity is controlled by the DNA binding domains within these enzymes. The use of ZFNs and TALENs in genome editing applications is described, for example, in urn ov et al, nat. Rev. Genet.11:636 (2010); and Joung et al, nat.Rev.mol.cell biol.14:49 (2013), the disclosures of each of which are incorporated herein by reference in their entirety for compositions and methods for genome editing.
Other genome editing techniques that may be used to incorporate polynucleotides encoding target genes into the genome of a target cell include the use of arcus meganucleases, which can be rationally designed to site-specifically cleave genomic DNA. In view of the established structure-activity relationships that have been established for such enzymes, it is advantageous to use these enzymes to incorporate genes encoding target genes into the genome of mammalian cells. Single-stranded meganucleases can be modified at certain amino acid positions to produce nucleases that selectively cleave DNA at desired positions, thereby enabling site-specific incorporation of a target gene into the nuclear DNA of a target cell. These single stranded nucleases have been widely described, for example, in U.S. Pat. nos. 8,021,867 and 8,445,251, the disclosures of each of which are incorporated herein by reference for compositions and methods for genome editing.
Pharmaceutical compositions and routes of administration
The gene therapeutics described herein can contain a transgene, such as a transgene encoding MTM1, and can be incorporated into a vehicle for administration to a patient, such as a human patient suffering from a neuromuscular disorder (e.g., xltm). Pharmaceutical compositions containing vectors, such as viral vectors, containing transcriptional regulatory elements (e.g., desmin promoters) described herein operably linked to a therapeutic transgene can be prepared using methods known in the art. For example, such compositions may be prepared using, for example, physiologically acceptable carriers, excipients, or stabilizers (Remington' sPharmaceutical Sciences, 16 th edition, osol, a. Editions (1980); incorporated herein by reference) and in a desired form, e.g., in the form of a lyophilized formulation or an aqueous solution.
Viral vectors, such as AAV vectors and other vectors described herein, containing transcriptional regulatory elements operably linked to a therapeutic transgene can be administered to a patient (e.g., a human patient) by a variety of routes of administration. The route of administration may vary, for example, with the onset and severity of the disease, and may include, for example, intradermal, transdermal (parenteral), intravenous, intramuscular, intranasal, subcutaneous, transdermal (transdermal), intratracheal, intraperitoneal, intraarterial, intravascular, inhalation, infusion, lavage, and oral administration. Intravascular administration includes delivery into the vasculature of a patient. In some embodiments, administration is into a blood vessel considered a vein (intravenous), and in some administration is into a blood vessel considered an artery (intra-arterial). Veins include, but are not limited to, internal jugular vein, peripheral vein, coronary vein, hepatic vein, portal vein, great saphenous vein, pulmonary vein, superior vena cava, inferior vena cava, gastric vein, splenic vein, inferior mesenteric vein, superior mesenteric vein, cephalic vein, and/or femoral vein. Arteries include, but are not limited to, the coronary, pulmonary, brachial, internal carotid, aortic arch, femoral, peripheral and/or ciliary arteries. It is contemplated that delivery may be through or to an arteriole or capillary.
The mixtures of nucleic acids and viral vectors described herein may be prepared in a suitable mixture of water and one or more excipients, carriers or diluents. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under normal storage and use conditions, these formulations may contain preservatives to prevent microbial growth. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (described in U.S. Pat. No. 5,466,468, the disclosure of which is incorporated herein by reference). In any case, the formulation may be sterile and may be a fluid that is easy to inject. The formulations may be stable under manufacturing and storage conditions and may prevent the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycols, and the like), suitable mixtures thereof, and/or vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. The action of microorganisms can be prevented by a variety of antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like). In many cases, it is preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the composition of delayed absorption agents, for example, aluminum monostearate and gelatin.
For example, if desired, solutions containing the pharmaceutical compositions described herein may be suitably buffered, and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In view of this, those skilled in the art will recognize in light of this disclosure that sterile aqueous media may be employed. For example, a dose may be dissolved in 1mL of NaCl isotonic solution and added to 1000mL of subcutaneous infusion solution or injected at the proposed infusion site. Depending on the condition of the subject being treated, the dose will necessarily vary somewhat. The person responsible for administration will in any case determine the appropriate dose for the individual subject. Furthermore, for human administration, the formulation should meet sterility, pyrogenicity, general safety, and purity standards as required by the FDA office of biological standards (FDA Office of Biological Standards).
Medicine box
The compositions described herein may be provided in a kit for treating a neuromuscular disorder (e.g., xltm). In some embodiments, a kit may include one or more viral vectors as described herein. The kit may include a package insert instructing a user of the kit (such as a physician in the art) to perform any of the methods described herein. The kit may optionally include a syringe or other device for administering the composition. In some embodiments, the kit may include one or more additional therapeutic agents.
In some embodiments, the kit may include one or more anti-cholestasis agents as described herein. The kit may include a package insert instructing a user of the kit (such as a physician in the art) to perform any of the methods described herein. The kit may optionally include a syringe or other device for administering the composition. In some embodiments, the kit may include one or more additional therapeutic agents.
Dosing regimen
Dosing regimen involving AAV-MTM1 vectors
Using the compositions and methods of the present disclosure, AVV vectors (e.g., birnesyl) containing a transgene encoding MTM1 in an amount of about 1.3x 10 can be administered to a patient suffering from a neuromuscular disorder (e.g., xltm) 14 vg/kg. Administration of the vector to a patient in such an amount may achieve the benefit of increasing MTM1 expression in the patient, e.g., to wild-type levelsWithin 50% or 200% of the total weight of the composition without causing toxic or side effects.
In some embodiments, the AVV vector is at less than about 3x 10 14 An amount of vg/kg (e.g., less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to a patient. For example, an AAV vector can be about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 The amount of vg/kg is administered to the patient.
In some embodiments, the AVV vector is at less than about 2.5x10 14 An amount of vg/kg (e.g., less than about 2.5x10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to a patient. For example, an AAV vector may be about 2.5x10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 The amount of vg/kg is administered to the patient.
In some embodiments, the AVV vector is present at less than about 2x 10 14 An amount of vg/kg (e.g., less than about 2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to a patient. For example, an AAV vector can be about 2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 The amount of vg/kg is administered to the patient.
In some embodiments, the AVV vector is at less than about 1.5x10 14 An amount of vg/kg (e.g., less than about 1.5x10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to a patient. For example, an AAV vector may be about 1.5x10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 The amount of vg/kg is administered to the patient.
In some embodiments, the AVV vector is at less than about 1x 10 14 An amount of vg/kg (e.g., less than about 1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to a patient. For example, an AAV vector can be about 1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 The amount of vg/kg is administered to the patient.
In some embodiments, the AAV vector is at about 3x 10 13 vg/kg to about 2.3X10 14 An amount of vg/kg (e.g., about 3x 10 13 vg/kg to about 2.3x 10 14 The amount of vg/kg) to the patient. For example, an AVV vector may be about 3x 10 13 vg/kg、3.1x 10 13 vg/kg、3.2x10 13 vg/kg、3.3x 10 13 vg/kg、3.4x 10 13 vg/kg、3.5x 10 13 vg/kg、3.6x 10 13 vg/kg、3.7x 10 13 vg/kg、3.8x 10 13 vg/kg、3.9x 10 13 vg/kg、4x 10 13 vg/kg、4.1x 10 13 vg/kg、4.2x 10 13 vg/kg、4.3x 10 13 vg/kg、4.4x 10 13 vg/kg、4.5x 10 13 vg/kg、4.6x 10 13 vg/kg、4.7x 10 13 vg/kg、4.8x 10 13 vg/kg、4.9x 10 13 vg/kg、5x 10 13 vg/kg、5.1x 10 13 vg/kg、5.2x 10 13 vg/kg、5.3x 10 13 vg/kg、5.4x 10 13 vg/kg、5.5x 10 13 vg/kg、5.6x 10 13 vg/kg、5.7x 10 13 vg/kg、5.8x 10 13 vg/kg、5.9x 10 13 vg/kg、6x 10 13 vg/kg、6.1x 10 13 vg/kg、6.2x 10 13 vg/kg、6.3x 10 13 vg/kg、6.4x 10 13 vg/kg、6.5x10 13 vg/kg、6.6x 10 13 vg/kg、6.7x 10 13 vg/kg、6.8x 10 13 vg/kg、6.9x 10 13 vg/kg、7x 10 13 vg/kg、7.1x 10 13 vg/kg、7.2x 10 13 vg/kg、7.3x 10 13 vg/kg、7.4x 10 13 vg/kg、7.5x 10 13 vg/kg、7.6x 10 13 vg/kg、7.7x 10 13 vg/kg、7.8x 10 13 vg/kg、7.9x 10 13 vg/kg、8x 10 13 vg/kg、8.1x 10 13 vg/kg、8.2x 10 13 vg/kg、8.3x 10 13 vg/kg、8.4x 10 13 vg/kg、8.5x 10 13 vg/kg、8.6x 10 13 vg/kg、8.7x 10 13 vg/kg、8.8x 10 13 vg/kg、8.9x 10 13 vg/kg、9x 10 13 vg/kg、9.1x 10 13 vg/kg、9.2x 10 13 vg/kg、9.3x 10 13 vg/kg、9.4x 10 13 vg/kg、9.5x 10 13 vg/kg、9.6x 10 13 vg/kg、9.7x 10 13 vg/kg、9.8x10 13 vg/kg、9.9x 10 13 vg/kg、1x 10 14 vg/kg、1.1x 10 14 vg/kg、1.2x 10 14 vg/kg、1.3x 10 14 vg/kg、1.4x 10 14 vg/kg、1.5x 10 14 vg/kg、1.6x 10 14 vg/kg、1.7x 10 14 vg/kg、1.8x 10 14 vg/kg、1.9x 10 14 vg/kg、2x 10 14 vg/kg、2.1x 10 14 vg/kg、2.2x 10 14 vg/kg or 2.3X10 14 The amount of vg/kg is administered to the patient.
In some embodiments, the AVV vector is at about 4x 10 13 vg/kg to about 2.3X10 14 An amount of vg/kg, such as at about 4x 10 13 vg/kg、4.1x 10 13 vg/kg、4.2x 10 13 vg/kg、4.3x 10 13 vg/kg、4.4x 10 13 vg/kg、4.5x 10 13 vg/kg、4.6x 10 13 vg/kg、4.7x 10 13 vg/kg、4.8x 10 13 vg/kg、4.9x 10 13 vg/kg、5x 10 13 vg/kg、5.1x 10 13 vg/kg、5.2x 10 13 vg/kg、5.3x 10 13 vg/kg、5.4x 10 13 vg/kg、5.5x10 13 vg/kg、5.6x 10 13 vg/kg、5.7x 10 13 vg/kg、5.8x 10 13 vg/kg、5.9x 10 13 vg/kg、6x 10 13 vg/kg、6.1x 10 13 vg/kg、6.2x 10 13 vg/kg、6.3x 10 13 vg/kg、6.4x 10 13 vg/kg、6.5x 10 13 vg/kg、6.6x 10 13 vg/kg、6.7x 10 13 vg/kg、6.8x 10 13 vg/kg、6.9x 10 13 vg/kg、7x 10 13 vg/kg、7.1x 10 13 vg/kg、7.2x 10 13 vg/kg、7.3x 10 13 vg/kg、7.4x 10 13 vg/kg、7.5x 10 13 vg/kg、7.6x 10 13 vg/kg、7.7x 10 13 vg/kg、7.8x 10 13 vg/kg、7.9x 10 13 vg/kg、8x 10 13 vg/kg、8.1x 10 13 vg/kg、8.2x 10 13 vg/kg、8.3x 10 13 vg/kg、8.4x 10 13 vg/kg、8.5x 10 13 vg/kg、8.6x 10 13 vg/kg、8.7x 10 13 vg/kg、8.8x 10 13 vg/kg、8.9x 10 13 vg/kg、9x 10 13 vg/kg、9.1x 10 13 vg/kg、9.2x 10 13 vg/kg、9.3x 10 13 vg/kg、9.4x 10 13 vg/kg、9.5x 10 13 vg/kg、9.6x 10 13 vg/kg、9.7x 10 13 vg/kg、9.8x 10 13 vg/kg、9.9x 10 13 vg/kg、1x 10 14 vg/kg、1.1x 10 14 vg/kg、1.2x 10 14 vg/kg、1.3x 10 14 vg/kg、1.4x 10 14 vg/kg、1.5x 10 14 vg/kg、1.6x 10 14 vg/kg、1.7x 10 14 vg/kg、1.8x 10 14 vg/kg、1.9x 10 14 vg/kg、2x 10 14 vg/kg、2.1x 10 14 vg/kg、2.2x 10 14 vg/kg or 2.3X10 14 The amount of vg/kg is administered to the patient.
In some embodiments, the AVV vector is at about 5x 10 13 vg/kg to about 2.3X10 14 An amount of vg/kg, such as about 5x 10 13 vg/kg、5.1x 10 13 vg/kg、5.2x 10 13 vg/kg、5.3x 10 13 vg/kg、5.4x 10 13 vg/kg、5.5x 10 13 vg/kg、5.6x 10 13 vg/kg、5.7x 10 13 vg/kg、5.8x 10 13 vg/kg、5.9x 10 13 vg/kg、6x 10 13 vg/kg、6.1x 10 13 vg/kg、6.2x 10 13 vg/kg、6.3x 10 13 vg/kg、6.4x 10 13 vg/kg、6.5x10 13 vg/kg、6.6x 10 13 vg/kg、6.7x 10 13 vg/kg、6.8x 10 13 vg/kg、6.9x 10 13 vg/kg、7x 10 13 vg/kg、7.1x 10 13 vg/kg、7.2x 10 13 vg/kg、7.3x 10 13 vg/kg、7.4x 10 13 vg/kg、7.5x 10 13 vg/kg、7.6x 10 13 vg/kg、7.7x 10 13 vg/kg、7.8x 10 13 vg/kg、7.9x 10 13 vg/kg、8x 10 13 vg/kg、8.1x 10 13 vg/kg、8.2x 10 13 vg/kg、8.3x 10 13 vg/kg、8.4x 10 13 vg/kg、8.5x 10 13 vg/kg、8.6x 10 13 vg/kg、8.7x 10 13 vg/kg、8.8x 10 13 vg/kg、8.9x 10 13 vg/kg、9x 10 13 vg/kg、9.1x 10 13 vg/kg、9.2x 10 13 vg/kg、9.3x 10 13 vg/kg、9.4x 10 13 vg/kg、9.5x 10 13 vg/kg、9.6x 10 13 vg/kg、9.7x 10 13 vg/kg、9.8x 10 13 vg/kg、9.9x 10 13 vg/kg、1x 10 14 vg/kg、1.1x 10 14 vg/kg、1.2x 10 14 vg/kg、1.3x 10 14 vg/kg、1.4x 10 14 vg/kg、1.5x 10 14 vg/kg、1.6x 10 14 vg/kg、1.7x 10 14 vg/kg、1.8x 10 14 vg/kg、1.9x 10 14 vg/kg、2x 10 14 vg/kg、2.1x 10 14 vg/kg、2.2x 10 14 vg/kg or 2.3X10 14 The amount of vg/kg is administered to the patient.
In some embodiments, the AVV vector is at about 6x 10 13 vg/kg to about 2.3X10 14 The amount of vg/kg, e.g. at about 6x 10 13 vg/kg、6.1x 10 13 vg/kg、6.2x 10 13 vg/kg、6.3x 10 13 vg/kg、6.4x 10 13 vg/kg、6.5x 10 13 vg/kg、6.6x 10 13 vg/kg、6.7x 10 13 vg/kg、6.8x 10 13 vg/kg、6.9x 10 13 vg/kg、7x 10 13 vg/kg、7.1x 10 13 vg/kg、7.2x 10 13 vg/kg、7.3x 10 13 vg/kg、7.4x 10 13 vg/kg、7.5x10 13 vg/kg、7.6x 10 13 vg/kg、7.7x 10 13 vg/kg、7.8x 10 13 vg/kg、7.9x 10 13 vg/kg、8x 10 13 vg/kg、8.1x 10 13 vg/kg、8.2x 10 13 vg/kg、8.3x 10 13 vg/kg、8.4x 10 13 vg/kg、8.5x 10 13 vg/kg、8.6x 10 13 vg/kg、8.7x 10 13 vg/kg、8.8x 10 13 vg/kg、8.9x 10 13 vg/kg、9x 10 13 vg/kg、9.1x 10 13 vg/kg、9.2x 10 13 vg/kg、9.3x 10 13 vg/kg、9.4x 10 13 vg/kg、9.5x 10 13 vg/kg、9.6x 10 13 vg/kg、9.7x 10 13 vg/kg、9.8x 10 13 vg/kg、9.9x 10 13 vg/kg、1x 10 14 vg/kg、1.1x 10 14 vg/kg、1.2x 10 14 vg/kg、1.3x 10 14 vg/kg、1.4x 10 14 vg/kg、1.5x 10 14 vg/kg、1.6x 10 14 vg/kg、1.7x 10 14 vg/kg、1.8x 10 14 vg/kg、1.9x 10 14 vg/kg or 2X 10 14 The amount of vg/kg is administered to the patient。
In some embodiments, the AVV vector is at about 7x 10 13 vg/kg to about 2.3X10 14 An amount of vg/kg, such as at about 7x 10 13 vg/kg、7.1x 10 13 vg/kg、7.2x 10 13 vg/kg、7.3x 10 13 vg/kg、7.4x 10 13 vg/kg、7.5x 10 13 vg/kg、7.6x 10 13 vg/kg、7.7x 10 13 vg/kg、7.8x 10 13 vg/kg、7.9x 10 13 vg/kg、8x 10 13 vg/kg、8.1x 10 13 vg/kg、8.2x 10 13 vg/kg、8.3x 10 13 vg/kg、8.4x 10 13 vg/kg、8.5x10 13 vg/kg、8.6x 10 13 vg/kg、8.7x 10 13 vg/kg、8.8x 10 13 vg/kg、8.9x 10 13 vg/kg、9x 10 13 vg/kg、9.1x 10 13 vg/kg、9.2x 10 13 vg/kg、9.3x 10 13 vg/kg、9.4x 10 13 vg/kg、9.5x 10 13 vg/kg、9.6x 10 13 vg/kg、9.7x 10 13 vg/kg、9.8x 10 13 vg/kg、9.9x 10 13 vg/kg、1x 10 14 vg/kg、1.1x 10 14 vg/kg、1.2x 10 14 vg/kg、1.3x 10 14 vg/kg、1.4x 10 14 vg/kg、1.5x 10 14 vg/kg、1.6x 10 14 vg/kg、1.7x 10 14 vg/kg、1.8x 10 14 vg/kg、1.9x 10 14 vg/kg、2x 10 14 vg/kg、2.1x 10 14 vg/kg、2.2x 10 14 vg/kg or 2.3X10 14 The amount of vg/kg is administered to the patient.
In some embodiments, the AVV vector is at about 8x 10 13 vg/kg to about 2.3X10 14 The amount of vg/kg, e.g. at about 8x 10 13 vg/kg、8.1x 10 13 vg/kg、8.2x 10 13 vg/kg、8.3x 10 13 vg/kg、8.4x 10 13 vg/kg、8.5x 10 13 vg/kg、8.6x 10 13 vg/kg、8.7x 10 13 vg/kg、8.8x 10 13 vg/kg、8.9x 10 13 vg/kg、9x 10 13 vg/kg、9.1x 10 13 vg/kg、9.2x 10 13 vg/kg、9.3x 10 13 vg/kg、9.4x 10 13 vg/kg、9.5x10 13 vg/kg、9.6x 10 13 vg/kg、9.7x 10 13 vg/kg、9.8x 10 13 vg/kg、9.9x 10 13 vg/kg、1x 10 14 vg/kg、1.1x 10 14 vg/kg、1.2x 10 14 vg/kg、1.3x 10 14 vg/kg、1.4x 10 14 vg/kg、1.5x 10 14 vg/kg、1.6x 10 14 vg/kg、1.7x 10 14 vg/kg、1.8x 10 14 vg/kg、1.9x 10 14 vg/kg、2x 10 14 vg/kg、2.1x 10 14 vg/kg、2.2x 10 14 vg/kg or 2.3X10 14 The amount of vg/kg is administered to the patient.
In some embodiments, the AVV vector is at about 9x 10 13 vg/kg to about 2.3X10 14 The amount of vg/kg, e.g. at 9X 10 13 vg/kg、9.1x 10 13 vg/kg、9.2x 10 13 vg/kg、9.3x 10 13 vg/kg、9.4x 10 13 vg/kg、9.5x 10 13 vg/kg、9.6x 10 13 vg/kg、9.7x 10 13 vg/kg、9.8x 10 13 vg/kg、9.9x 10 13 vg/kg、1x 10 14 vg/kg、1.1x 10 14 vg/kg、1.2x 10 14 vg/kg、1.3x 10 14 vg/kg、1.4x 10 14 vg/kg、1.5x10 14 vg/kg、1.6x 10 14 vg/kg、1.7x 10 14 vg/kg、1.8x 10 14 vg/kg、1.9x 10 14 vg/kg、2x 10 14 vg/kg、2.1x 10 14 vg/kg、2.2x 10 14 vg/kg or 2.3X10 14 The amount of vg/kg is administered to the patient.
In some embodiments, the AVV vector is at about 1x 10 14 vg/kg to about 2.3X10 14 The amount of vg/kg, e.g. in 1X 10 14 vg/kg、1.1x 10 14 vg/kg、1.2x 10 14 vg/kg、1.3x 10 14 vg/kg、1.4x 10 14 vg/kg、1.5x 10 14 vg/kg、1.6x 10 14 vg/kg、1.7x 10 14 vg/kg、1.8x 10 14 vg/kg、1.9x 10 14 vg/kg、2x 10 14 vg/kg、2.1x 10 14 vg/kg、2.2x 10 14 vg/kg or 2.3X10 14 The amount of vg/kg is administered to the patient.
In some embodiments, the AAV vector is at about 3x 10 13 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 4x 10 13 vg/An amount of kg is administered to the patient. In some embodiments, the AAV vector is at about 5x 10 13 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 6x 10 13 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 7x 10 13 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 8x 10 13 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 9x 10 13 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 1x 10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 1.1x10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 1.2x10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 1.3x 10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 1.4x10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 1.5x10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 1.6x10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 1.7x10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 1.8x10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 1.9x10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 2x 10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 2.1x10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 2.2x10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 2.3x 10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 2.4x10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 2.5x10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 2.6x10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vectorAt about 2.7x10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 2.8x10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 2.9x10 14 The amount of vg/kg is administered to the patient. In some embodiments, the AAV vector is at about 3x10 14 The amount of vg/kg is administered to the patient.
In some embodiments, the AAV vector is in an amount comprising the amount (e.g., less than about 3x10 14 vg/kg) is administered to the patient.
In some embodiments, the AAV vectors are in a composition comprising the amounts (e.g., less than about 3x 10 14 vg/kg) is administered to the patient.
In some embodiments, the AAV vector is in an amount that each individually comprises the amount (e.g., less than about 3x 10 14 vg/kg) is administered to the patient.
In some embodiments, two or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) doses are separated from each other by one year or more (e.g., one year zero day, one year zero one month, one year zero six months, two years, three years, four years, or five years).
In some embodiments, two or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) doses are administered to a patient within about 12 months (e.g., about 12 months, about 11 months, about 10 months, about 9 months, about 8 months, about 7 months, about 6 months, about 5 months, about 4 months, about 3 months, about 2 months, or about 1 month) of each other
Combination therapy
AAV vectors (e.g., birthwort) containing the MTM 1-encoding transgenes described herein can be administered in combination with one or more additional therapeutic procedures (e.g., nasofibritus drainage (NBD)) and/or agents (e.g., anti-cholestasis agents) for treating neuromuscular disorders (e.g., XLMTM).
Treatment of surgery
In some embodiments, the one or more additional therapeutic procedures is NBD. NBD is a therapeutic procedure that helps drain bile (e.g., biliary drainage can help bile flow from the liver into the gut when bile ducts are occluded). In some embodiments, NBD is performed using a biliary drainage tube (also known as a biliary stent), which is a thin, hollow, flexible tube with several small holes along the sides. The biliary tract drainage tube may be inserted into a patient's bile duct to drain it.
Therapeutic agent
In some embodiments, the one or more additional therapeutic agents are anti-cholestasis agents (e.g., bile acids, farnesol X Receptor (FXR) ligands, fibroblast growth factor 19 (FGF-19) mimetics, takeda-G protein receptor 5 (TGR 5) agonists, peroxisome proliferator-activated receptor (PPAR) agonists, PPAR-alpha agonists, PPAR-delta agonists, dual PPAR-alpha and PPAR-delta agonists, apical sodium-dependent bile acid transporter (ASBT) inhibitors, immunomodulatory drugs, anti-fibrotic therapies, and nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitors), or a combination thereof.
In some embodiments, the anti-cholestasis agent is administered to the patient in one or more (e.g., one, two, three, four, five, six, seven, eight, nine, ten, fifteen, twenty, thirty, forty, fifty, sixty, and seventy) doses beginning within about six weeks (e.g., about six weeks before or after administration, about five weeks before or after administration, about four weeks before or after administration, about two weeks before or about one week before or after administration) before or after administration of the viral vector to the patient.
In some embodiments, the anti-cholestasis agent is administered to the patient at one or more (e.g., one, two, three, four, five, six, seven, eight, nine, ten, fifteen, twenty, thirty, forty, fifty, sixty, and seventy) doses beginning within about five weeks (e.g., about five weeks before or after administration, about four weeks before or after administration, about three weeks before or after administration, about two weeks before or about one week after administration) before or after administration of the viral vector to the patient.
In some embodiments, the anti-cholestasis agent is administered to the patient at one or more (e.g., one, two, three, four, five, six, seven, eight, nine, ten, fifteen, twenty, thirty, forty, fifty, sixty, and seventy) doses beginning within about one week (e.g., about one week before or after administration, about six days before or after administration, about five days before or after administration, about three days before or after administration, about two days before or about one day before or after administration) before or after administration of the viral vector to the patient.
In some embodiments, the anti-cholestasis agent is administered to the seventy patients in one or more (e.g., one, two, three, four, five, six, seven, eight, nine, ten, fifteen, twenty, thirty, forty, fifty) doses beginning within the same day (e.g., 24 th, 23 th, 22 th, 21 th, 20 th, 19 th, 18 th, 17 th, 16 th, 15 th, 14 th, 13 th, 12 th, 11 th, 10 th, 9 th, 8 th, 7 th, 6 th, 5 th, 4 th, 3 rd, 2 nd, 1 h, 60 th, 59 th, 58 th, 57 th, 56 th, 55 th, 50 th, 40 th, 30 th, 20 th, 10 th, or the same minute) as the viral vector is administered to the patient.
In some embodiments, the anti-cholestasis agent is a bile acid. In some embodiments, the bile acid is ursodeoxycholic acid or a derivative thereof or norursodeoxycholic acid. In some embodiments, the bile acid is bear diol.
In some embodiments, the anti-cholestasis agent is an FXR ligand. In some embodiments, the FXR ligand is obeticholic acid, cilofaci, te Luo Fasuo, tretinoin, or EDP-305.
In some embodiments, the one or more anti-cholestasis agents are FGF-19 mimics. In some embodiments, the FGF-19 mimetic is Aldrimin.
In some embodiments, the anti-cholestasis agent is a TGR5 agonist. In some embodiments, the TGR5 agonist is INT-777 or INT-767.
In some embodiments, the anti-cholestasis agent is a PPAR agonist. In some embodiments, the PPAR agonist is bezafibrate, seladelphia, or elabeno.
In some embodiments, the anti-cholestasis agent is a PPAR-alpha agonist. In some embodiments, the PPAR-alpha agonist is fenofibrate.
In some embodiments, the anti-cholestasis agent is a PPAR-delta agonist. In some embodiments, the PPAR-delta agonist is seladelphia.
In some embodiments, the anti-cholestasis agent is a dual PPAR-alpha and PPAR-delta agonist. In some embodiments, the dual PPAR-alpha-delta agonist is erifeinum.
In some embodiments, the one or more anti-cholestasis agents are ASBT inhibitors. In some embodiments, the ASBT inhibitor is aldvalacibazole, maraglixibazole, or linexibazole.
In some embodiments, the anti-cholestasis agent is an immunomodulatory drug. In some embodiments, the immunomodulatory drug is rituximab, abamectin, ulipristal, infliximab, barytetratinib, or FFP104.
In some embodiments, the anti-cholestasis agent is anti-fibrotic therapy. In some embodiments, the anti-fibrotic therapy is a Vitamin D Receptor (VDR) agonist or Xin Tuozhu mab.
In some embodiments, the anti-cholestasis agent is a NOX inhibitor. In some embodiments, the NOX inhibitor is celecoxib.
In some embodiments, a therapeutically effective amount of a viral vector (e.g., biri-yl) comprising a transgene encoding MTM1 and an anti-cholestasis agent are administered to a patient in need thereof. In some embodiments, a therapeutically effective amount of a birthwort and an anti-cholestasis agent is administered to a patient in need thereof. In some embodiments, a therapeutically effective amount of a biri-renyl and an anti-cholestasis agent is administered to a patient in need thereof, wherein the anti-cholestasis agent is a bile acid. In some embodiments, a therapeutically effective amount of a birthwort and an anti-cholestasis agent is administered to a patient in need thereof, wherein the anti-cholestasis agent is bear glycol. In some embodiments, a therapeutically effective amount of birnesyl and Xiong Erchun are administered to a patient in need thereof.
Anti-cholestasis agent
Using the compositions and methods of the present disclosure, AVV vectors containing a transgene encoding MTM1 and an anti-cholestasis agent can be administered to a patient suffering from a neuromuscular disorder (e.g., xltm).
In some embodiments, an anti-cholestasis agent is administered to the patient.
In some embodiments, an anti-cholestasis agent is administered to a patient when monitoring the patient for cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and determining that the patient exhibits cholestasis or hyperbilirubinemia, or one or more symptoms thereof.
In some embodiments, when the patient is determined to exhibit cholestasis or hyperbilirubinemia or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient.
In some embodiments, the anti-cholestasis agent is selected from the list comprising: bile acids, farnesol X Receptor (FXR) ligands, fibroblast growth factor 19 (FGF-19) mimics, takeda-G protein receptor 5 (TGR 5) agonists, peroxisome proliferator-activated receptor (PPAR) agonists, PPAR-alpha agonists, PPAR-delta agonists, dual PPAR-alpha and PPAR-delta agonists, apical sodium-dependent bile acid transporter (ASBT) inhibitors, immunomodulatory drugs, anti-fibrotic therapies, and nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitors.
In some embodiments, the anti-cholestasis agent is a bile acid. In some embodiments, the bile acid is ursodeoxycholic acid or a derivative thereof or norursodeoxycholic acid. In some embodiments, the bile acid is bear diol.
In some embodiments, the anti-cholestasis agent is an FXR ligand. In some embodiments, the FXR ligand is obeticholic acid, cilofaci, te Luo Fasuo, tretinoin, or EDP-305.
In some embodiments, the one or more anti-cholestasis agents are FGF-19 mimics. In some embodiments, the FGF-19 mimetic is Aldrimin.
In some embodiments, the anti-cholestasis agent is a TGR5 agonist. In some embodiments, the TGR5 agonist is INT-777 or INT-767.
In some embodiments, the anti-cholestasis agent is a PPAR agonist. In some embodiments, the PPAR agonist is bezafibrate, seladelphia, or elabeno.
In some embodiments, the anti-cholestasis agent is a PPAR-alpha agonist. In some embodiments, the PPAR-alpha agonist is fenofibrate.
In some embodiments, the anti-cholestasis agent is a PPAR-delta agonist. In some embodiments, the PPAR-delta agonist is seladelphia.
In some embodiments, the anti-cholestasis agent is a dual PPAR-alpha and PPAR-delta agonist. In some embodiments, the dual PPAR-alpha-delta agonist is erifeinum.
In some embodiments, the one or more anti-cholestasis agents are ASBT inhibitors. In some embodiments, the ASBT inhibitor is aldvalacibazole, maraglixibazole, or linexibazole.
In some embodiments, the anti-cholestasis agent is an immunomodulatory drug. In some embodiments, the immunomodulatory drug is rituximab, abamectin, ulipristal, infliximab, barytetratinib, or FFP104.
In some embodiments, the anti-cholestasis agent is anti-fibrotic therapy. In some embodiments, the anti-fibrotic therapy is a Vitamin D Receptor (VDR) agonist or Xin Tuozhu mab.
In some embodiments, the anti-cholestasis agent is a NOX inhibitor. In some embodiments, the NOX inhibitor is celecoxib.
I. Bile acid
Bile acids may be administered to a subject using the methods described herein. In some embodiments, the bile acid is ursodeoxycholic acid or a derivative thereof or norursodeoxycholic acid. In some embodiments, the bile acid is bear diol.
Xiong Erchun and other known variants have the generic structure shown below:
wherein R is 1 And R is 2 Each independently is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
R 3 is OR (OR) 4 、NHR 4 Or SR (S.J) 4 ；
Wherein R is 4 Is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and is also provided with
n is an integer of 0 to 4,
or a pharmaceutically acceptable salt thereof.
Such compounds are described, for example, in U.S. patent No. 4,828,763, the disclosure of which is incorporated herein by reference.
Dosage regimen involving bile acids
The bile acids described herein may be administered in an amount of about 5 mg/kg/dose to about 20 mg/kg/dose (e.g., in an amount of about 5 mg/kg/dose to about 20 mg/kg/dose). For example, bile acids may be administered to a patient in an amount of about 5 mg/kg/dose, 5.1 mg/kg/dose, 5.2 mg/kg/dose, 5.3 mg/kg/dose, 5.4 mg/kg/dose, 5.5 mg/kg/dose, 6 mg/kg/dose, 6.5 mg/kg/dose, 7 mg/kg/dose, 8 mg/kg/dose, 9 mg/kg/dose, 10 mg/kg/dose, 11 mg/kg/dose, 12 mg/kg/dose, 13 mg/kg/dose, 14 mg/kg/dose, 15 mg/kg/dose, 16 mg/kg/dose, 17 mg/kg/dose, 18 mg/kg/dose, 19 mg/kg/dose, or 20 mg/kg/dose.
For example, in some embodiments, bile acids are present in an amount of about 5 mg/kg/dose to about 11 mg/kg/dose, such as about 5 mg/kg/dose, 5.1 mg/dose, 5.2 mg/dose, 5.3 mg/dose, 5.4 mg/dose, 5.5 mg/kg/dose, 5.6 mg/dose, 5.7 mg/kg/dose, 5.8 mg/dose, 5.9 mg/dose, 6.3 mg/dose, 6.4 mg/dose, 6.5 mg/dose, 6.6 mg/dose, 6.7 mg/dose, 6.8 mg/dose, 6.9 mg/kg/dose, 7 mg/dose, 7.1 mg/dose, 7.2 mg/kg/dose, 7.3 mg/dose, 7.4 mg/dose, 7.5 mg/dose, 7.4 mg/dose, 7.5 mg/dose, 6.5 mg/dose, 6.6 mg/dose, 8 mg/dose, 8.7.7 mg/dose, 7.7.1 mg/dose, 7.2 mg/dose, 7.3 mg/dose, 7.4 mg/dose, 7.5 mg/dose, 7.3 mg/dose, 8 mg/dose, 8.9 mg/dose, 8.5 mg/dose, 8 mg/dose, 8.9 mg/dose and 5.1 mg/dose, an amount of 9.7 mg/kg/dose, 9.8 mg/kg/dose, 9.9 mg/kg/dose, 10 mg/kg/dose, 10.1 mg/kg/dose, 10.2 mg/kg/dose, 10.3 mg/kg/dose, 10.4 mg/kg/dose, 10.5 mg/kg/dose, 10.6 mg/kg/dose, 10.7 mg/kg/dose, 10.8 mg/kg/dose, 10.9 mg/kg/dose or 11 mg/kg/dose is administered to the patient.
In some embodiments, the bile acid is administered to the patient in a single dose.
In some embodiments, the bile acid is administered to the patient in multiple doses.
In some embodiments, the bile acid is administered in one or more daily doses (one dose per day, two doses per day, three doses per day, four doses per day, five doses per day, six doses per day, seven doses per day, eight doses per day, nine doses per day and ten doses per day), one or more weekly doses (one dose per week, two doses per week, three doses per week, four doses per week, five doses per week, six doses per week, seven doses per week, eight doses per week, nine doses per week, ten doses per week, eleven doses per week, twelve doses per week, thirteen doses per week and twenty-four doses per month) or one or more monthly doses (one dose per month, two doses per month, three doses per month, four doses per month, five doses per month, six doses per month, seven doses per month, eight doses per month, nine doses per month, ten doses per month, eleven doses per month, twelve doses per month, thirteen doses per month, fifteen doses per month, sixteen doses per month, fifteen doses per sixteen doses, sixteen doses per month, sixteen doses, twelve doses per month, twenty-ten doses per month, twenty-ten doses, twenty-eight doses per month, twenty-ten doses, twenty-four doses per month.
For example, in some embodiments, bile acid is administered to the patient in one or more doses per day, such as one dose per day, two doses per day, three doses per day, four doses per day, five doses per day, six doses per day, seven doses per day, eight doses per day, nine doses per day, or ten doses per day.
In some embodiments, two or more doses of bile acid together totaling a specified amount are spaced apart from each other, for example one hour or more. In some embodiments, two or more doses are administered to the patient within about 24 hours of each other (e.g., within about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours of each other).
In some embodiments, the bile acid is administered to the patient in one dose per day, two doses per day, three doses per day, four doses per day, or five doses per day.
In some embodiments, the bile acid is administered to the patient at one dose per day.
In some embodiments, xiong Erchun is administered in an amount of about 5 mg/kg/day to about 40 mg/kg/day (e.g., in an amount of about 5 mg/kg/day to about 40 mg/kg/day). For example, xiong Erchun can be administered to a patient in an amount of about 5 mg/kg/day, 5.1 mg/kg/day, 5.2 mg/kg/day, 5.3 mg/kg/day, 5.4 mg/kg/day, 5.5 mg/kg/day, 6 mg/kg/day, 6.5 mg/kg/day, 7 mg/kg/day, 8 mg/kg/day, 9 mg/kg/day, 10 mg/kg/day, 11 mg/kg/day, 12 mg/kg/day, 13 mg/kg/day, 14 mg/kg/day, 15 mg/kg/day, 16 mg/kg/day, 17 mg/kg/day, 18 mg/kg/day, 19 mg/kg/day, 20 mg/kg/day, 25 mg/kg/day, 30 mg/kg/day, 35 mg/kg/day, or 40 mg/kg/day.
For example, in some embodiments Xiong Erchun is administered to the patient in an amount of about 15 mg/kg/day to about 25 mg/kg/day, such as in an amount of about 15 mg/kg/day, 15.1 mg/kg/day, 15.2 mg/kg/day, 15.3 mg/kg/day, 15.4 mg/kg/day, 15.5 mg/kg/day, 15.6 mg/kg/day, 15.7 mg/kg/day, 15.8 mg/kg/day, 15.9 mg/kg/day, 16 mg/kg/day, 17 mg/kg/day, 18 mg/kg/day, 19 mg/kg/day, 20 mg/kg/day, 21 mg/kg/day, 22 mg/kg/day, 23 mg/kg/day, 24 mg/kg/day, or 25 mg/kg/day.
For example, in some embodiments Xiong Erchun is administered to the patient in an amount of about 16 mg/kg/day to about 24 mg/kg/day, such as in an amount of about 16 mg/kg/day, 16.1 mg/kg/day, 16.2 mg/kg/day, 16.3 mg/kg/day, 16.4 mg/kg/day, 16.5 mg/kg/day, 16.6 mg/kg/day, 16.7 mg/kg/day, 16.8 mg/kg/day, 16.9 mg/kg/day, 17 mg/kg/day, 18 mg/kg/day, 19 mg/kg/day, 20 mg/kg/day, 21 mg/kg/day, 22 mg/kg/day, 23 mg/kg/day, or 24 mg/kg/day.
For example, in some embodiments Xiong Erchun is administered to the patient in an amount of about 17 mg/kg/day to about 23 mg/kg/day, such as in an amount of about 17 mg/kg/day, 17.1 mg/kg/day, 17.2 mg/kg/day, 17.3 mg/kg/day, 17.4 mg/kg/day, 17.5 mg/kg/day, 17.6 mg/kg/day, 17.7 mg/kg/day, 17.8 mg/kg/day, 17.9 mg/kg/day, 18 mg/kg/day, 19 mg/kg/day, 20 mg/kg/day, 21 mg/kg/day, 22 mg/kg/day, or 23 mg/kg/day.
For example, in some embodiments Xiong Erchun is administered to the patient in an amount of about 18 mg/kg/day to about 22 mg/kg/day, such as in an amount of about 18 mg/kg/day, 18.1 mg/kg/day, 18.2 mg/kg/day, 18.3 mg/kg/day, 18.4 mg/kg/day, 18.5 mg/kg/day, 18.6 mg/kg/day, 18.7 mg/kg/day, 18.8 mg/kg/day, 18.9 mg/kg/day, 19 mg/kg/day, 20 mg/kg/day, 21 mg/kg/day, or 22 mg/kg/day.
For example, in some embodiments Xiong Erchun is administered to a patient in an amount of about 19 mg/kg/day to about 21 mg/kg/day, e.g., in an amount of about 19 mg/kg/day, 19.1 mg/kg/day, 19.2 mg/kg/day, 19.3 mg/kg/day, 19.4 mg/kg/day, 19.5 mg/kg/day, 19.6 mg/kg/day, 19.7 mg/kg/day, 19.8 mg/kg/day, 19.9 mg/kg/day, 20 mg/kg/day, 20.1 mg/kg/day, 20.2 mg/kg/day, 20.3 mg/kg/day, 20.4 mg/kg/day, 20.5 mg/kg/day, 20.6 mg/kg/day, 20.7 mg/kg/day, 20.8 mg/kg/day, 20.9 mg/kg/day, or 21 mg/kg/day.
In some embodiments, xiong Erchun is administered to a patient in an amount of 20 mg/kg/day.
In some embodiments, xiong Erchun is administered to the patient in one or more doses per week, such as one dose per week, two doses per week, three doses per week, four doses per week, five doses per week, ten doses per week, fifteen doses per week, twenty doses per week, thirty doses per week, fifty doses per week, sixty doses per week, and seventy doses per week.
In some embodiments, xiong Erchun is administered to the patient in one or more doses per month, such as one dose per month, two doses per month, three doses per month, four doses per month, five doses per month, ten doses per month, fifteen doses per month, twenty doses per month, thirty doses per month, fifty doses per month, sixty doses per month, seventy doses per month, eighty doses per month, ninety doses per month, one hundred doses per month, two hundred doses per month, and three hundred doses per month.
In some embodiments, xiong Erchun is administered to a patient by a unit dosage form comprising 250mg of bear glycol.
In some embodiments, xiong Erchun is administered to a patient by a unit dosage form comprising 500mg of bear diol.
Ia. Norursodeoxycholic acid
Using the methods described herein, norursodeoxycholic acid can be administered to a subject.
Norursodeoxycholic acid is INN of a compound having a chemical structure as shown below.
Ib. ursodeoxycholic acid and derivatives
Ursodeoxycholic acid or a derivative thereof may be administered to a subject using the methods described herein.
Ursodeoxycholic acid is the INN of the compound, also known as 128-13-2 and the drug name bear diol.
The chemical structure of Xiong Erchun is shown below.
Ibi dosing regimen involving bear diol
Xiong Erchun described herein can be administered in an amount of about 5 mg/kg/dose to about 20 mg/kg/dose (e.g., in an amount of about 5 mg/kg/dose to about 20 mg/kg/dose). For example, xiong Erchun can be administered to a patient in an amount of about 5 mg/kg/dose, 5.1 mg/kg/dose, 5.2 mg/kg/dose, 5.3 mg/kg/dose, 5.4 mg/kg/dose, 5.5 mg/kg/dose, 6 mg/kg/dose, 6.5 mg/kg/dose, 7 mg/kg/dose, 8 mg/kg/dose, 9 mg/kg/dose, 10 mg/kg/dose, 11 mg/kg/dose, 12 mg/kg/dose, 13 mg/kg/dose, 14 mg/kg/dose, 15 mg/kg/dose, 16 mg/kg/dose, 17 mg/kg/dose, 18 mg/kg/dose, 19 mg/kg/dose, or 20 mg/kg/dose.
For example, in some embodiments, xiong Erchun is present in an amount of about 5 mg/kg/dose to about 11 mg/kg/dose, such as about 5 mg/kg/dose, 5.1 mg/dose, 5.2 mg/dose, 5.3 mg/dose, 5.4 mg/dose, 5.5 mg/kg/dose, 5.6 mg/dose, 5.7 mg/kg/dose, 5.8 mg/dose, 5.9 mg/dose, 6.3 mg/dose, 6.4 mg/dose, 6.5 mg/dose, 6.6 mg/dose, 6.7 mg/dose, 6.8 mg/dose, 6.9 mg/kg/dose, 7 mg/dose, 7.1 mg/dose, 7.2 mg/kg/dose, 7.3 mg/dose, 7.4 mg/dose, 7.5 mg/dose, 7.4 mg/dose, 7.5 mg/dose, 6.5 mg/dose, 6.6 mg/dose, 8 mg/dose, 8.7.7 mg/dose, 7.7.1 mg/dose, 7.2 mg/dose, 7.3 mg/dose, 7.4 mg/dose, 7.5 mg/dose, 7.3 mg/dose, 8 mg/dose, 8.9 mg/dose, 8.5 mg/dose, 8 mg/dose, 8.9 mg/dose and 5.1 mg/dose, an amount of 9.7 mg/kg/dose, 9.8 mg/kg/dose, 9.9 mg/kg/dose, 10 mg/kg/dose, 10.1 mg/kg/dose, 10.2 mg/kg/dose, 10.3 mg/kg/dose, 10.4 mg/kg/dose, 10.5 mg/kg/dose, 10.6 mg/kg/dose, 10.7 mg/kg/dose, 10.8 mg/kg/dose, 10.9 mg/kg/dose or 11 mg/kg/dose is administered to the patient.
In some embodiments, xiong Erchun is administered to a patient in a single dose.
In some embodiments, xiong Erchun is administered to a patient in multiple doses.
In some embodiments, xiong Erchun is administered in one or more daily doses (one dose per day, two doses per day, three doses per day, four doses per day, five doses per day, six doses per day, seven doses per day, eight doses per day, nine doses per day and ten doses per day), one or more weekly doses (one dose per week, two doses per week, three doses per week, four doses per week, five doses per week, six doses per week, seven doses per week, eight doses per week, nine doses per week, ten doses per month, eleven doses per week, twelve doses per week, thirteen doses per week and twenty-four doses per month) or one or more monthly doses (one dose per month, two doses per month, three doses per month, four doses per month, five doses per month, six doses per month, seven doses per month, eight doses per month, nine doses per month, ten doses per month, eleven doses per month, twelve doses per month, thirteen doses per month, fifteen doses per month, sixteen doses per sixteen doses, sixteen doses per month, sixteen doses, eighteen doses, twenty-ten doses, twenty-eight doses per month, twenty-ten doses, twenty-four doses per month, twenty-four doses per month.
For example, in some embodiments Xiong Erchun is administered to the patient in one or more doses per day, such as one dose per day, two doses per day, three doses per day, four doses per day, five doses per day, six doses per day, seven doses per day, eight doses per day, nine doses per day, or ten doses per day.
In some embodiments, xiong Erchun together totaling a specified amount of two or more doses are spaced from each other, for example, one hour or more. In some embodiments, two or more doses are administered to the patient within about 24 hours of each other (e.g., within about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours of each other).
In some embodiments, the bear glycol is administered to the patient in one dose per day, two doses per day, three doses per day, four doses per day, or five doses per day.
In some embodiments, xiong Erchun is administered to a patient at one dose per day.
In some embodiments, xiong Erchun is administered in an amount of about 5 mg/kg/day to about 40 mg/kg/day (e.g., in an amount of about 5 mg/kg/day to about 40 mg/kg/day). For example, xiong Erchun can be administered to a patient in an amount of about 5 mg/kg/day, 5.1 mg/kg/day, 5.2 mg/kg/day, 5.3 mg/kg/day, 5.4 mg/kg/day, 5.5 mg/kg/day, 6 mg/kg/day, 6.5 mg/kg/day, 7 mg/kg/day, 8 mg/kg/day, 9 mg/kg/day, 10 mg/kg/day, 11 mg/kg/day, 12 mg/kg/day, 13 mg/kg/day, 14 mg/kg/day, 15 mg/kg/day, 16 mg/kg/day, 17 mg/kg/day, 18 mg/kg/day, 19 mg/kg/day, 20 mg/kg/day, 25 mg/kg/day, 30 mg/kg/day, 35 mg/kg/day, or 40 mg/kg/day.
For example, in some embodiments Xiong Erchun is administered to the patient in an amount of about 15 mg/kg/day to about 25 mg/kg/day, such as in an amount of about 15 mg/kg/day, 15.1 mg/kg/day, 15.2 mg/kg/day, 15.3 mg/kg/day, 15.4 mg/kg/day, 15.5 mg/kg/day, 15.6 mg/kg/day, 15.7 mg/kg/day, 15.8 mg/kg/day, 15.9 mg/kg/day, 16 mg/kg/day, 17 mg/kg/day, 18 mg/kg/day, 19 mg/kg/day, 20 mg/kg/day, 21 mg/kg/day, 22 mg/kg/day, 23 mg/kg/day, 24 mg/kg/day, or 25 mg/kg/day.
For example, in some embodiments Xiong Erchun is administered to the patient in an amount of about 16 mg/kg/day to about 24 mg/kg/day, such as in an amount of about 16 mg/kg/day, 16.1 mg/kg/day, 16.2 mg/kg/day, 16.3 mg/kg/day, 16.4 mg/kg/day, 16.5 mg/kg/day, 16.6 mg/kg/day, 16.7 mg/kg/day, 16.8 mg/kg/day, 16.9 mg/kg/day, 17 mg/kg/day, 18 mg/kg/day, 19 mg/kg/day, 20 mg/kg/day, 21 mg/kg/day, 22 mg/kg/day, 23 mg/kg/day, or 24 mg/kg/day.
For example, in some embodiments Xiong Erchun is administered to the patient in an amount of about 17 mg/kg/day to about 23 mg/kg/day, such as in an amount of about 17 mg/kg/day, 17.1 mg/kg/day, 17.2 mg/kg/day, 17.3 mg/kg/day, 17.4 mg/kg/day, 17.5 mg/kg/day, 17.6 mg/kg/day, 17.7 mg/kg/day, 17.8 mg/kg/day, 17.9 mg/kg/day, 18 mg/kg/day, 19 mg/kg/day, 20 mg/kg/day, 21 mg/kg/day, 22 mg/kg/day, or 23 mg/kg/day.
For example, in some embodiments Xiong Erchun is administered to the patient in an amount of about 18 mg/kg/day to about 22 mg/kg/day, such as in an amount of about 18 mg/kg/day, 18.1 mg/kg/day, 18.2 mg/kg/day, 18.3 mg/kg/day, 18.4 mg/kg/day, 18.5 mg/kg/day, 18.6 mg/kg/day, 18.7 mg/kg/day, 18.8 mg/kg/day, 18.9 mg/kg/day, 19 mg/kg/day, 20 mg/kg/day, 21 mg/kg/day, or 22 mg/kg/day.
For example, in some embodiments Xiong Erchun is administered to a patient in an amount of about 19 mg/kg/day to about 21 mg/kg/day, e.g., in an amount of about 19 mg/kg/day, 19.1 mg/kg/day, 19.2 mg/kg/day, 19.3 mg/kg/day, 19.4 mg/kg/day, 19.5 mg/kg/day, 19.6 mg/kg/day, 19.7 mg/kg/day, 19.8 mg/kg/day, 19.9 mg/kg/day, 20 mg/kg/day, 20.1 mg/kg/day, 20.2 mg/kg/day, 20.3 mg/kg/day, 20.4 mg/kg/day, 20.5 mg/kg/day, 20.6 mg/kg/day, 20.7 mg/kg/day, 20.8 mg/kg/day, 20.9 mg/kg/day, or 21 mg/kg/day.
In some embodiments, xiong Erchun is administered to a patient in an amount of 20 mg/kg/day.
In some embodiments, xiong Erchun is administered to the patient in one or more doses per week, such as one dose per week, two doses per week, three doses per week, four doses per week, five doses per week, ten doses per week, fifteen doses per week, twenty doses per week, thirty doses per week, fifty doses per week, sixty doses per week, and seventy doses per week.
In some embodiments, xiong Erchun is administered to the patient in one or more doses per month, such as one dose per month, two doses per month, three doses per month, four doses per month, five doses per month, ten doses per month, fifteen doses per month, twenty doses per month, thirty doses per month, fifty doses per month, sixty doses per month, seventy doses per month, eighty doses per month, ninety doses per month, one hundred doses per month, two hundred doses per month, and three hundred doses per month.
In some embodiments, xiong Erchun is administered to a patient by a unit dosage form comprising 250mg of bear glycol.
In some embodiments, xiong Erchun is administered to a patient by a unit dosage form comprising 500mg of bear diol.
FXR ligand
FXR ligands can be administered to a subject using the methods described herein. In some embodiments, the FXR ligand is obeticholic acid, cilofaci, te Luo Fasuo, tretinoin, or EDP-305.
IIa, obeticholic acid
Using the methods described herein, obeticholic acid may be administered to a subject. Obeticholic acid is INN of the compound, also known as INT-747. Obeticholic acid has a chemical structure as shown below.
IIb. cilofacial
Cilofaxolol may be administered to a subject using the methods described herein. Cilofacitin is the INN of the compound, also known under the code GS-9674. Cilofacial has the chemical structure shown below.
IIc. Japanese patent No. Luo Fasuo
Using the methods described herein, ter Luo Fasuo can be administered to a subject. Japanese patent Luo Fasuo is the INN of the compound and is also known under the code LJN452,452. The terlazine has the chemical structure shown below.
IId. tretinoin
Tretinoin can be administered to a subject using the methods described herein. Tretinoin is the INN of the compound, also known as code number 302-79-4. Tretinoin has the chemical structure shown below.
IIe.EDP-305
EDP-305 may be administered to a subject using the methods described herein. EDP-305 is the code of the compound, and its chemical structure is shown below.
Fibroblast growth factor 19 (FGF-19) mimics
FGF-19 mimetics can be administered to a subject using the methods described herein. In some embodiments, the FGF-19 mimetic is Aldrimin.
IIIa Aldarifemin
Aldrimin may be administered to a subject using the methods described herein. Aldrimin is the INN of the compound, also known as NGM282, and has the formula C 940 -H 1472 N 266 O 279 S 11 。
Takeda-G protein receptor 5 (TGR 5) agonists
Using the methods described herein, a TGR5 agonist can be administered to a subject. In some embodiments, the TGR5 agonist is INT-777 or INT-767.
IVa.INT-777
INT-777 can be administered to a subject using the methods described herein. INT-777 is the code of the compound and is also known as S-EMCA.
IVb.INT-767
INT-767 can be administered to a subject using the methods described herein. INT-767 is the code of the compound, the chemical structure of which is shown below.
V. peroxisome proliferator-activated receptor (PPAR) agonists
Using the methods described herein, PPAR agonists can be administered to a subject. In some embodiments, the PPAR agonist is bezafibrate, seladelphia, or elabeno.
Va. bezafibrate
Using the methods described herein, bezafibrate can be administered to a subject. Bezafibrate is the INN of the compound, also known under the code C10AB02. Bezafibrate has the chemical structure shown below.
Vb. Serader Pa
Using the methods described herein, seladarpa can be administered to a subject. Serad Pa is the INN of the compound, also known as MBX-8025. The serradpa has a chemical structure as shown below.
Vc. Alabebeno
Using the methods described herein, alabeno can be administered to a subject. INN, also known as GFT505, is the compound of Erabeprunox. The alabeno has the chemical structure shown below.
PPAR-alpha agonists
PPAR-alpha agonists may be administered to a subject using the methods described herein. In some embodiments, the PPAR-alpha agonist is fenofibrate.
VIa fenofibrate
Fenofibrate may be administered to a subject using the methods described herein. Fenofibrate is the INN of a compound having the chemical structure shown below.
PPAR-delta agonists
Using the methods described herein, PPAR-delta agonists can be administered to a subject. In some embodiments, the PPAR-delta agonist is seladelphia.
VIIa, serrader Pa
Using the methods described herein, seladarpa can be administered to a subject. Serad Pa is the INN of the compound, also known as MBX-8025. The serradpa has a chemical structure as shown below.
Dual PPAR-alpha and PPAR-delta agonists
Dual PPAR-alpha and PPAR-delta agonists may be administered to a subject using the methods described herein. In some embodiments, the dual PPAR-alpha-delta agonist is erifeinum.
Viiia Eiafeno
Using the methods described herein, alabeno can be administered to a subject. INN, also known as GFT505, is the compound of Erabeprunox. The alabeno has the chemical structure shown below.
IX. apical sodium-dependent bile acid transporter (ASBT) inhibitors
Using the methods described herein, an ASBT inhibitor can be administered to a subject. In some embodiments, the ASBT inhibitor is aldvalacibazole, maraglixibazole, or linexibazole.
IXa, aldevixibat
Using the methods described herein, aldvitamin xibat can be administered to a subject. InN, also known as A4250, is the compound InN. The aldvxibat has a chemical structure as shown below.
IXb, malacixibat
Maraglixibat may be administered to a subject using the methods described herein. Malacinib is the INN of a compound having the chemical structure shown below.
IXc Li Naixi Batt
Li Naixi bar can be administered to a subject using the methods described herein. Li Naixi Bart is the INN of a compound having the chemical structure shown below.
X-ray immunoregulatory medicine
Using the methods described herein, an immunomodulatory drug may be administered to a subject. In some embodiments, the immunomodulatory drug is rituximab, abamectin, ulipristal, infliximab, barytetratinib, or FFP104.
Xa. rituximab
Rituximab may be administered to a subject using the methods described herein. Rituximab is a drug having the formula C 6416 -H 9874 -N 1688 -O 1987 -S 44 To the INN of the antibodies of (a).
Xb. Abacalcet
Using the methods described herein, abacavir can be administered to a subject. Abasic acid of formula C 3498 H 5458 N 922 O 1090 S 32 To the INN of the antibodies of (a).
Xc. Uteclmumab
Using the methods described herein, you can administer you can't you the subjects. The Utility model monoclonal antibody is shown as a chemical formula C 6482 H 10004 N 1712 O 2016 S 46 To the INN of the antibodies of (a).
Xd. infliximab
Infliximab may be administered to a subject using the methods described herein. Infliximab is of formula C 6428 H 9912 N 1694 O 1987 S 46 To the INN of the antibodies of (a).
Xe. barytinib
Using the methods described herein, baratinib can be administered to a subject. Baratinib is the INN of a compound having the chemical structure shown below.
Xf.FFP104
FFP104 may be administered to a subject using the methods described herein. FFP104 is an anti-CD 40 monoclonal antibody.
XI anti-fibrosis therapy
Anti-fibrotic chemotherapy may be administered to a subject using the methods described herein. In some embodiments, the anti-fibrotic therapy is a Vitamin D Receptor (VDR) agonist or Xin Tuozhu mab.
Xia. VDR agonists
Using the methods described herein, a VDR agonist can be administered to a subject. Exemplary VDR agonists include, but are not limited to, compounds known under the INN name seocalcitol (seocalcitol), ai Luo calcitol (elocalcitol), and calcipotriol (calcipotriol).
XIai Seocalcitol
Using the methods described herein, seocalcitol may be administered to a subject. Seocalcitol is the INN of a compound having the chemical structure shown below.
XIaii Ai Luo calcitol
Ai Luo calcitol may be administered to a subject using the methods described herein. Ai Luo calcitol is INN of a compound having the chemical structure shown below.
XIaiii calcipotriol
Using the methods described herein, calcipotriol can be administered to a subject. Calcipotriol is the INN of a compound having the chemical structure shown below.
XIb Xin Tuozhu monoclonal antibodies
Xin Tuozhu mab can be administered to a subject using the methods described herein. Xin Tuozhu monoclonal antibody INN, also known as GS-6624, of the formula C 6558 H 10134 N 1736 O 2037 S 50 。
XII nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor
Using the methods described herein, NOX inhibitors can be administered to a subject. In some embodiments, the NOX inhibitor is celecoxib.
XIIa celecoxib
Celecoxib may be administered to a subject using the methods described herein. Celecoxib is the INN of the compound known under the code GKT831. Celecoxib has the chemical structure shown below.
Recommended clinical parameters for monitoring the progression of cholestasis or hyperbilirubinemia in a patient
In some embodiments, the progression of cholestasis in a patient is monitored by a serum bile acid test and/or a blood test (e.g., LFT), as described herein.
In some embodiments, the progression of hyperbilirubinemia in a patient is monitored by a blood test (e.g., bilirubin test), as described herein.
In some embodiments, the patient is monitored for the development of cholestasis, and if the patient exhibits cholestasis or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is monitored for the development of hyperbilirubinemia, and if the patient exhibits hyperbilirubinemia or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is monitored for development of cholestasis or hyperbilirubinemia by a blood test (e.g., a serum bile acid test or a liver function test). In some embodiments, the progression of cholestasis or hyperbilirubinemia in a patient is monitored by a blood test (e.g., a serum bile acid test or a liver function test), and an anti-cholestasis agent is administered to the patient if the patient exhibits cholestasis or hyperbilirubinemia or one or more symptoms thereof.
In some embodiments, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof by finding that the patient exhibits an increase in a parameter (e.g., serum bile acid level) in a blood test (e.g., serum bile acid test) relative to a reference level.
In some embodiments, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof by finding that the patient exhibits an increased level of serum bile acid (e.g., cholic acid, chenodeoxycholic acid, deoxycholic acid, or ursodeoxycholic acid) relative to a reference level in a blood test (e.g., a serum bile acid test).
In some embodiments, the blood test is a liver function test.
In some embodiments, the progression of cholestasis or hyperbilirubinemia in a patient is monitored by a liver function test, and an anti-cholestasis agent is administered to the patient if the patient exhibits cholestasis or hyperbilirubinemia or one or more symptoms thereof.
In some embodiments, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof by finding that the patient exhibits an increase or decrease in a parameter (e.g., aspartate aminotransferase level or alanine aminotransferase level) in the liver function test relative to a reference level.
I. Serum bile acid test
In some embodiments, the patient is monitored for the development of cholestasis or hyperbilirubinemia. In some embodiments, the patient is monitored for development of cholestasis or hyperbilirubinemia with a serum bile acid test. In some embodiments, the patient is monitored for the development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient if the patient exhibits cholestasis or hyperbilirubinemia, or one or more symptoms thereof. In some embodiments, the patient is monitored for development of cholestasis or hyperbilirubinemia with a serum bile acid test, and an anti-cholestasis agent is administered to the patient if the patient exhibits cholestasis or hyperbilirubinemia or one or more symptoms thereof.
In some embodiments, the patient is monitored for cholestasis or hyperbilirubinemia by bile acid (e.g., cholic acid, chenodeoxycholic acid, deoxycholic acid, or ursodeoxycholic acid) levels of the patient as measured with a serum bile acid test.
In some embodiments, when one or more of the patient's bile acid (e.g., cholic acid, chenodeoxycholic acid, deoxycholic acid, or ursodeoxycholic acid) levels as measured with a serum bile acid test is greater than norm, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, a patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof when the patient's cholic acid level is greater than 5nmol/mL (e.g., 5nmol/mL, 6nmol/mL, 7nmol/mL, 8 nmol/mL, 9nmol/mL, 10nmol/mL, 15nmol/mL, 20nmol/mL, 30nmol/mL, 40nmol/mL, 50nmol/mL, 60nmol/mL, 70nmol/mL, 80nmol/mL, 90nmol/mL, and 100 nmol/mL) as measured with a serum bile acid test.
In some embodiments, when the patient's cholic acid level is greater than 5nmol/mL (e.g., 5nmol/mL, 6nmol/mL, 7nmol/mL, 8 nmol/mL, 9nmol/mL, 10nmol/mL, 15nmol/mL, 20nmol/mL, 30nmol/mL, 40nmol/mL, 50nmol/mL, 60nmol/mL, 70nmol/mL, 80nmol/mL, 90nmol/mL, and 100 nmol/mL) as measured with the serum bile acid test, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, when the patient's chenodeoxycholic acid level is greater than 6nmol/mL (e.g., 6nmol/mL, 7nmol/mL, 8 nmol/mL, 9nmol/mL, 10nmol/mL, 15nmol/mL, 20nmol/mL, 30nmol/mL, 40nmol/mL, 50nmol/mL, 60nmol/mL, 70nmol/mL, 80nmol/mL, 90nmol/mL, and 100 nmol/mL) as measured with the serum bile acid test, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof.
In some embodiments, when the patient's chenodeoxycholic acid level is greater than 6nmol/mL (e.g., 6nmol/mL, 7nmol/mL, 8 nmol/mL, 9nmol/mL, 10nmol/mL, 15nmol/mL, 20nmol/mL, 30nmol/mL, 40nmol/mL, 50nmol/mL, 60nmol/mL, 70nmol/mL, 80nmol/mL, 90nmol/mL, and 100 nmol/mL) as measured with the serum bile acid test, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof when the patient's deoxycholate level is greater than 6nmol/mL (e.g., 6nmol/mL, 7nmol/mL, 8 nmol/mL, 9nmol/mL, 10nmol/mL, 15nmol/mL, 20nmol/mL, 30nmol/mL, 40nmol/mL, 50nmol/mL, 60nmol/mL, 70nmol/mL, 80nmol/mL, 90nmol/mL, and 100 nmol/mL) as measured with the serum bile acid test.
In some embodiments, when the patient's deoxycholic acid level is greater than 6nmol/mL (e.g., 6nmol/mL, 7nmol/mL, 8 nmol/mL, 9nmol/mL, 10nmol/mL, 15nmol/mL, 20nmol/mL, 30nmol/mL, 40nmol/mL, 50nmol/mL, 60nmol/mL, 70nmol/mL, 80nmol/mL, 90nmol/mL, and 100 nmol/mL) as measured with the serum bile acid test, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, when the patient's ursodeoxycholic acid level is greater than 2nmol/mL (e.g., 2nmol/mL, 3nmol/mL, 4nmol/mL, 5nmol/mL, 6nmol/mL, 7nmol/mL, 8 nmol/mL, 9nmol/mL, 10nmol/mL, 15nmol/mL, 20nmol/mL, 30nmol/mL, 40nmol/mL, 50nmol/mL, 60nmol/mL, 70nmol/mL, 80nmol/mL, 90nmol/mL, and 100 nmol/mL) as measured by the serum bile acid test, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof.
In some embodiments, when the patient's ursodeoxycholic acid level is greater than 5nmol/mL (e.g., 2nmol/mL, 3nmol/mL, 4nmol/mL, 5nmol/mL, 6nmol/mL, 7nmol/mL, 8 nmol/mL, 9nmol/mL, 10nmol/mL, 15nmol/mL, 20nmol/mL, 30nmol/mL, 40nmol/mL, 50nmol/mL, 60nmol/mL, 70nmol/mL, 80nmol/mL, 90nmol/mL, and 100 nmol/mL) as measured by the serum bile acid test, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
II liver function test
In some embodiments, LFTs are used to monitor the progression of cholestasis or hyperbilirubinemia in a patient. In some embodiments, the patient is monitored for the development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient if the patient exhibits cholestasis or hyperbilirubinemia, or one or more symptoms thereof. In some embodiments, the development of cholestasis or hyperbilirubinemia in a patient is monitored with an LFT, and if the patient exhibits cholestasis or hyperbilirubinemia or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient.
In some embodiments, when a parameter of the patient's LFT (e.g., ASP level or AST level) is greater than an age-adjusted specification as described herein, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
IIa, aspartate aminotransferase
In some embodiments, the progression of cholestasis or hyperbilirubinemia in a patient is monitored by measuring the AST level of the patient in the LFT. In some embodiments, the patient is monitored for the development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient if the patient exhibits cholestasis or hyperbilirubinemia, or one or more symptoms thereof. In some embodiments, the progression of cholestasis or hyperbilirubinemia in a patient is monitored by measuring the AST level of the patient in the LFT, and if the patient exhibits cholestasis or hyperbilirubinemia or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient.
In some embodiments, the progression of cholestasis or hyperbilirubinemia in the patient is monitored by measuring the patient's AST level in the LFT, and when the patient's AST level is greater than norm, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof when the patient's AST level is greater than 50U/L (e.g., 51U/L, 52U/L, 53U/L, 54U/L, 55U/L, 56U/L, 57U/L, 58U/L, 59U/L, 60U/L, 61U/L, 62U/L, 63U/L, 64U/L, 65U/L, 66U/L, 67U/L, 68U/L, 69U/L, 70U/L, 75U/L, 80U/L, 85U/L, 90U/L, 100U/L, 110U/L, 120U/L, 130U/L, 140U/L, 150U/L, 200U/L, 300U/L, 400U/L, and 500U/L).
In some embodiments, when the patient's AST level is greater than 50U/L (e.g., 51U/L, 52U/L, 53U/L, 54U/L, 55U/L, 56U/L, 57U/L, 58U/L, 59U/L, 60U/L, 61U/L, 62U/L, 63U/L, 64U/L, 65U/L, 66U/L, 67U/L, 68U/L, 69U/L, 70U/L, 75U/L, 80U/L, 85U/L, 90U/L, 100U/L, 110U/L, 120U/L, 130U/L, 140U/L, 150U/L, 200U/L, 300U/L, 400U/L, and 500U/L), the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
IIb alanine aminotransferase
In some embodiments, the progression of cholestasis or hyperbilirubinemia in a patient is monitored by measuring the ALT level of the patient in an LFT. In some embodiments, the patient is monitored for the development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient if the patient exhibits cholestasis or hyperbilirubinemia, or one or more symptoms thereof. In some embodiments, the progression of cholestasis or hyperbilirubinemia in a patient is monitored by measuring the ALT level of the patient in the LFT, and an anti-cholestasis agent is administered to the patient if the patient exhibits cholestasis or hyperbilirubinemia or one or more symptoms thereof.
In some embodiments, the progression of cholestasis or hyperbilirubinemia in a patient is monitored by measuring the ALT level of the patient in the LFT, and when the ALT level of the patient is greater than norm, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, a patient is determined to exhibit cholestasis or one or more symptoms thereof when the patient's ALT level is greater than 50U/L (e.g., 51U/L, 52U/L, 53U/L, 54U/L, 55U/L, 56U/L, 57U/L, 58U/L, 59U/L, 60U/L, 61U/L, 62U/L, 63U/L, 64U/L, 65U/L, 66U/L, 67U/L, 68U/L, 69U/L, 70U/L, 75U/L, 80U/L, 85U/L, 90U/L, 100U/L, 110U/L, 120U/L, 130U/L, 140U/L, 150U/L, 200U/L, 300U/L, 400U/L, and 500U/L).
In some embodiments, when the patient's ALT level is greater than 50U/L (e.g., 51U/L, 52U/L, 53U/L, 54U/L, 55U/L, 56U/L, 57U/L, 58U/L, 59U/L, 60U/L, 61U/L, 62U/L, 63U/L, 64U/L, 65U/L, 66U/L, 67U/L, 68U/L, 69U/L, 70U/L, 75U/L, 80U/L, 85U/L, 90U/L, 100U/L, 110U/L, 120U/L, 130U/L, 140U/L, 150U/L, 200U/L, 300U/L, 400U/L and 500U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
Recommended clinical parameters for monitoring progression of cholestasis in a patient
I. Serum bile acid test
In some embodiments, the patient is monitored for the development of cholestasis. In some embodiments, the patient is monitored for the development of cholestasis using a serum bile acid test. In some embodiments, the patient is monitored for the development of cholestasis, and if the patient exhibits cholestasis or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient. In some embodiments, the patient is monitored for the development of cholestasis with a serum bile acid test, and an anti-cholestasis agent is administered to the patient if the patient exhibits cholestasis or one or more symptoms thereof.
In some embodiments, when the patient's total bile acid level as measured with the serum bile acid test is greater than specification, the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient's total bile acid level is greater than 14 μmol/L (e.g., 15. Mu. Mol/L, 16. Mu. Mol/L, 17. Mu. Mol/L, 18. Mu. Mol/L, 19. Mu. Mol/L, 20. Mu. Mol/L, 21. Mu. Mol/L, 22. Mu. Mol/L, 23. Mu. Mol/L, 24. Mu. Mol/L, 25. Mu. Mol/L, 26. Mu. Mol/L, 27. Mu. Mol/L, 28. Mu. Mol/L, 29. Mu. Mol/L, 30. Mu. Mol/L, 31. Mu. Mol/L, 32. Mu. Mol/L, 33. Mu. Mol/L, 34. Mu. Mol/L, 35. Mu. Mol/L, 36. Mu. Mol/L, 37. Mu. Mol/L, 38. Mu. Mol/L, 39. Mu. Mol/L, 40. Mu. Mol/L, 41. Mu. Mol/L, 42. Mu. Mol/L, 43. Mu. Mol/L, 44. Mu. Mol/L45. Mu. Mol/L, 46. Mu. Mol/L, 47. Mu. Mol/L, 48. Mu. Mol/L, 49. Mu. Mol/L, 50. Mu. Mol/L, 51. Mu. Mol/L, 52. Mu. Mol/L, 53. Mu. Mol/L, 54. Mu. Mol/L, 55. Mu. Mol/L, 56. Mu. Mol/L, 57. Mu. Mol/L, 58. Mu. Mol/L, 59. Mu. Mol/L, 60. Mu. Mol/L, 61. Mu. Mol/L, 62. Mu. Mol/L, 63. Mu. Mol/L, 64. Mu. Mol/L, 65. Mu. Mol/L, 66. Mu. Mol/L, 67. Mu. Mol/L, 68. Mu. Mol/L, 69. Mu. Mol/L, 70. Mu. Mol/L, 71. Mu. Mol/L, 72. Mu. Mol/L, 73. Mu. Mol/L, 74 μmol/L, 75 μmol/L, 76 μmol/L, 77 μmol/L, 78 μmol/L, 79 μmol/L, 80 μmol/L, 81 μmol/L, 82 μmol/L, 83 μmol/L, 84 μmol/L, 85 μmol/L, 86 μmol/L, 87 μmol/L, 88 μmol/L, 89 μmol/L, 90 μmol/L, 91 μmol/L, 92 μmol/L, 93 μmol/L, 94 μmol/L, 95 μmol/L, 96 μmol/L, 97 μmol/L, 98 μmol/L, 99 μmol/L, and 100 μmol/L), determining that the patient exhibits cholestasis or one or more symptoms thereof, and administering an anti-cholestasis agent to the patient. A step of
II blood test
In some embodiments, the development of cholestasis in the patient is monitored with a blood test (e.g., LFT or bilirubin test). In some embodiments, the patient is monitored for the development of cholestasis, and if the patient exhibits cholestasis or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient. In some embodiments, the patient is monitored for the development of cholestasis with an LFT, and if the patient exhibits cholestasis or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient.
In some embodiments, when one or more parameters (e.g., GGT level, ASP level, AST level, ALT level, and bilirubin level) of a patient's blood test (e.g., LFT or bilirubin test) are greater than an age-adjusted specification as described herein, the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
IIa liver function test
In some embodiments, LFTs are used to monitor the progression of cholestasis in a patient. In some embodiments, the patient is monitored for the development of cholestasis, and if the patient exhibits cholestasis or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient. In some embodiments, the patient is monitored for the development of cholestasis with an LFT, and if the patient exhibits cholestasis or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient.
In some embodiments, when one or more parameters of the patient's LFT (e.g., GGT levels, ASP levels, AST levels, and ALT levels) are greater than the age-adjusted specifications as described herein, the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
IIai gamma-glutamyl transferase
In some embodiments, the progression of cholestasis in the patient is monitored by measuring the patient's GGT level in the LFT. In some embodiments, the patient is monitored for the development of cholestasis, and if the patient exhibits cholestasis or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient. In some embodiments, the progression of cholestasis in the patient is monitored by measuring the patient's GGT level in the LFT, and if the patient exhibits cholestasis or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient.
In some embodiments, when the patient exhibits GGT levels greater than the age-adjusted specification, the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a neonate (e.g., 0-6 months), a young child (e.g., 6-12 months), or a child aged 1-5 years. In some embodiments, the patient is a neonate for 0-6 months. In some embodiments, the patient is a young child for 6-12 months. In some embodiments, the patient is a child aged 1-5 years.
In some embodiments, the patient is a neonate (e.g., 0-6 months), and when the patient's GGT level is outside of a normal range of about 12-122U/L (e.g., 12-122U/L, 13-122U/L, 14-122U/L, 15-122U/L, 16-122U/L, 17-122U/L, 18-122U/L, 19-122U/L, 20-122U/L, 25-122U/L, 30-122U/L, 40-122U/L, 50-122U/L, 60-122U/L, 70-122U/L, 80-122U/L, 90-122U/L, 100-122U/L, 110-122U/L, 120-122U/L, or 121-122U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a male neonate (e.g., 0-6 months), and the patient is determined to exhibit cholestasis or one or more symptoms thereof when the patient's GGT level is less than 12U/L (e.g., 11U/L, 10U/L, 9U/L, 8U/L, 7U/L, 6U/L, 5U/L, 4U/L, 3U/L, 2U/L, or 1U/L), and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a male neonate (e.g., 0-6 months), and the patient is determined to exhibit cholestasis or one or more symptoms thereof when the patient's GGT level is greater than 122U/L (e.g., 123U/L, 124U/L, 125U/L, 126U/L, 127U/L, 128U/L, 129U/L, 130U/L, 135U/L, 140U/L, 150U/L, 160U/L, 170U/L, 180U/L, 190U/L, and 200U/L), and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a male pediatric (e.g., 6-12 months), and when the patient's GGT level is in the normal range of 1-39U/L (e.g., 2-39U/L, 3-39U/L, 4-39U/L, 5-39U/L, 6-39U/L, 7-39U/L, 8-39U/L, 9-39U/L, 10-39U/L, 11-39U/L, 12-39U/L, 13-39U/L, 14-39U/L, 15-39U/L, 16-39U/L, 17-39U/L, 18-39U/L, 19-39U/L, 20-39U/L, 21-39U/L, 22-39U/L, 23-39U/L, 24-39U/L, 25-39U/L, 26-39U/L, 27-39U/L, 28-39U/L, 29-39U/L, 30-39U/L, 31-39U/L, 32-39U/L, 33-39U/L, 34-39U/L, 35-39U/L, 37-39U/L, or 37-39U/L when a plurality of bile is administered to a patient and/or a plurality of bile is indicated.
In some embodiments, the patient is a male pediatric (e.g., 6-12 months), and when the patient's GGT level is greater than 39U/L (e.g., 40U/L, 41U/L, 42U/L, 43U/L, 44U/L, 45U/L, 46U/L, 47U/L, 48U/L, 49U/L, 50U/L, 55U/L, 60U/L, 70U/L, 80U/L, 90U/L, 100U/L, 110U/L, 1120U/L, 130U/L, 140U/L, 150U/L, 160U/L, 170U/L, 180U/L, 190U/L, and 200U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a male child aged 1-5 years, and when the patient's GGT level is outside of the normal range of about 3-22U/L (e.g., about 3-22U/L, 4-22U/L, 5-22U/L, 6-22U/L, 7-22U/L, 8-22U/L, 9-22U/L, 10-22U/L, 11-22U/L, 12-22U/L, 13-22U/L, 14-22U/L, 15-22U/L, 16-22U/L, 17-22U/L, 18-22U/L, 19-22U/L, 20-22U/L, and 21-22U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a male child aged 1-5 years, and when the patient's GGT level is less than 3U/L (e.g., 2U/L and 1U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a male child aged 1-5 years, and when the patient's GGT level is greater than 22U/L (e.g., 23U/L, 24U/L, 25U/L, 26U/L, 27U/L, 28U/L, 29U/L, 30U/L, 35U/L, 40U/L, 50U/L, 60U/L, 70U/L, 80U/L, 90U/L, 100U/L, 110U/L, 1120U/L, 130U/L, 140U/L, 150U/L, 160U/L, 170U/L, 180U/L, 190U/L, and 200U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a female neonate (e.g., 0-6 months), and when the patient's GGT level is outside of the normal range of about 15-132U/L (e.g., 15-132U/L, 16-132U/L, 17-132U/L, 18-132U/L, 19-132U/L, 20-132U/L, 25-132U/L, 30-132U/L, 40-132U/L, 50-132U/L, 60-132U/L, 70-132U/L, 80-132U/L, 90-132U/L, 100-132U/L, 110-132U/L, 120-132U/L, 130-132U/L, and 131-132U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a female neonate (e.g., 0-6 months), and when the patient's GGT level is less than 15U/L (e.g., 14U/L, 13U/L, 12U/L, 11U/L, 10U/L, 9U/L, 8U/L, 7U/L, 6U/L, 5U/L, 4U/L, 3U/L, 2U/L, or 1U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a female neonate (e.g., 0-6 months), and when the patient's GGT level is greater than 132U/L (e.g., 133U/L, 134U/L, 135U/L, 136U/L, 137U/L, 138U/L, 139U/L, 140U/L, 145U/L, 150U/L, 160U/L, 170U/L, 180U/L, 190U/L, and 200U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a female pediatric (e.g., 6-12 months), when the patient's GGT level is in the normal range of 1-39U/L (e.g., 2-39U/L, 3-39U/L, 4-39U/L, 5-39U/L, 6-39U/L, 7-39U/L, 8-39U/L, 9-39U/L, 10-39U/L, 11-39U/L, 12-39U/L, 13-39U/L, 14-39U/L, 15-39U/L, 16-39U/L, 17-39U/L, 18-39U/L, 19-39U/L, 20-39U/L, 21-39U/L, 22-39U/L, 23-39U/L, 24-39U/L, 25-39U/L, 26-39U/L, 27-39U/L, 28-39U/L, 29-39U/L, 30-39U/L, 31-39U/L, 32-39U/L, 33-39U/L, 34-39U/L, 35-39U/L, 37-39U/L, or 37-39U/L when a plurality of bile is administered to a patient and/or a plurality of bile is indicated.
In some embodiments, the patient is a female pediatric (e.g., 6-12 months), and when the patient's GGT level is greater than 39U/L (e.g., 40U/L, 41U/L, 42U/L, 43U/L, 44U/L, 45U/L, 46U/L, 47U/L, 48U/L, 49U/L, 50U/L, 55U/L, 60U/L, 70U/L, 80U/L, 90U/L, 100U/L, 110U/L, 1120U/L, 130U/L, 140U/L, 150U/L, 160U/L, 170U/L, 180U/L, 190U/L, and 200U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a female child aged 1-5 years, and when the patient's GGT level is outside of the normal range of about 3-22U/L (e.g., about 3-22U/L, 4-22U/L, 5-22U/L, 6-22U/L, 7-22U/L, 8-22U/L, 9-22U/L, 10-22U/L, 11-22U/L, 12-22U/L, 13-22U/L, 14-22U/L, 15-22U/L, 16-22U/L, 17-22U/L, 18-22U/L, 19-22U/L, 20-22U/L, and 21-22U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a female child aged 1-5 years, and when the patient's GGT level is less than 3U/L (e.g., 2U/L and 1U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a female child aged 1-5 years, and when the patient's GGT level is greater than 22U/L (e.g., 23U/L, 24U/L, 25U/L, 26U/L, 27U/L, 28U/L, 29U/L, 30U/L, 35U/L, 40U/L, 50U/L, 60U/L, 70U/L, 80U/L, 90U/L, 100U/L, 110U/L, 1120U/L, 130U/L, 140U/L, 150U/L, 160U/L, 170U/L, 180U/L, 190U/L, and 200U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
IIaii alkaline phosphatase
In some embodiments, the development of cholestasis in the patient is monitored by measuring the patient's ASP level in the LFT. In some embodiments, the patient is monitored for the development of cholestasis, and if the patient exhibits cholestasis or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient. In some embodiments, the development of cholestasis in a patient is monitored by measuring the patient's ASP level in the LFT, and if the patient exhibits cholestasis or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient.
In some embodiments, the development of cholestasis in the patient is monitored by measuring the patient's ASP level in the LFT, and when the patient's ASP level is greater than norm, the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, when the patient's ASP level is outside of the normal range of about 50 to 300U/L (e.g., about 51 to 300U/L, about 52 to U/L, about 53 to 300U/L, about 54 to 300U/L, about 55 to 300U/L, about 56 to 300U/L, about 57 to 300U/L, about 58 to 300U/L, about 59 to 300U/L, about 60 to 300U/L, about 65 to 300U/L, about 70 to 300U/L, about 80 to 300U/L, about 90 to 300U/L, about 100 to 300U/L, about 125 to 300U/L, about 150 to 300U/L, about 175 to 300U/L, about 200 to 300U/L, about 225 to 300U/L, about 250 to 300U/L, or about 275 to 300U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, when the patient has an ASP level of less than 50U/L (e.g., 50U/L, 49U/L, 48U/L, 47U/L, 46U/L, 45U/L, 44U/L, 43U/L, 42U/L, 41U/L, 40U/L, 39U/L, 38U/L, 37U/L, 36U/L, 35U/L, 34U/L, 33U/L, 32U/L, 31U/L, 30U/L, 29U/L, 28U/L, 27U/L, 26U/L, 25U/L, 24U/L, 23U/L, 22U/L, 21U/L, 20U/L, 19U/L, 18U/L, 17U/L, 16U/L, 15U/L, 14U/L, 13U/L, 12U/L, 11U/L, 10U/L, 9U/L, 8U/L, 7U/L, 6U/L, 4U/L) and/or a bile is administered to the patient and/or a plurality of the anti-cholestasis agent.
In some embodiments, when the patient's ASP level is greater than 300U/L (e.g., 300U/L, 301U/L, 302U/L, 303U/L, 304U/L, 305U/L, 306U/L, 307U/L, 308U/L, 309U/L, 310U/L, 311U/L, 312U/L, 313U/L, 314U/L, 315U/L, 316U/L, 317U/L, 318U/L, 319U/L, 320U/L, 321U/L, 322U/L, 323U/L, 324U/L, 325U/L, 330U/L, 340U/L, 350U/L, 400U/L, and 500U/L) the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
IIaiii aspartate aminotransferase
In some embodiments, the development of cholestasis in the patient is monitored by measuring the AST level of the patient in the LFT. In some embodiments, the patient is monitored for the development of cholestasis, and if the patient exhibits cholestasis or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient. In some embodiments, the progression of cholestasis in the patient is monitored by measuring the AST level of the patient in the LFT, and if the patient exhibits cholestasis or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient.
In some embodiments, the progression of cholestasis in the patient is monitored by measuring the patient's AST level in the LFT, and when the patient's AST level is greater than norm, the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, when the patient's AST level is greater than 50U/L (e.g., 51U/L, 52U/L, 53U/L, 54U/L, 55U/L, 56U/L, 57U/L, 58U/L, 59U/L, 60U/L, 61U/L, 62U/L, 63U/L, 64U/L, 65U/L, 66U/L, 67U/L, 68U/L, 69U/L, 70U/L, 75U/L, 80U/L, 85U/L, 90U/L, 100U/L, 110U/L, 120U/L, 130U/L, 140U/L, 150U/L, 200U/L, 300U/L, 400U/L and 500U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
IIaiv alanine aminotransferase
In some embodiments, the progression of cholestasis in the patient is monitored by measuring the ALT level of the patient in the LFT. In some embodiments, the patient is monitored for the development of cholestasis, and if the patient exhibits cholestasis or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient. In some embodiments, the progression of cholestasis in the patient is monitored by measuring the ALT level of the patient in the LFT, and an anti-cholestasis agent is administered to the patient if the patient exhibits cholestasis or one or more symptoms thereof.
In some embodiments, the progression of cholestasis in the patient is monitored by measuring the patient's ALT level in the LFT, and when the patient's ALT level is greater than norm, the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, when the patient's ALT level is greater than 50U/L (e.g., 51U/L, 52U/L, 53U/L, 54U/L, 55U/L, 56U/L, 57U/L, 58U/L, 59U/L, 60U/L, 61U/L, 62U/L, 63U/L, 64U/L, 65U/L, 66U/L, 67U/L, 68U/L, 69U/L, 70U/L, 75U/L, 80U/L, 85U/L, 90U/L, 100U/L, 110U/L, 120U/L, 130U/L, 140U/L, 150U/L, 200U/L, 300U/L, 400U/L and 500U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
Recommended clinical parameters for monitoring the development of hyperbilirubinemia in patients
Bilirubin test
In some embodiments, the patient is monitored for the development of hyperbilirubinemia. In some embodiments, the patient is monitored for the development of hyperbilirubinemia using a bilirubin test. In some embodiments, the patient is monitored for the development of hyperbilirubinemia, and if the patient exhibits hyperbilirubinemia or one or more symptoms thereof, an anti-cholestasis agent is administered to the patient. In some embodiments, the patient is monitored for the development of hyperbilirubinemia with a bilirubin test, and an anti-cholestasis agent is administered to the patient if the patient exhibits hyperbilirubinemia or one or more symptoms thereof.
In some embodiments, when the patient exhibits bilirubin levels greater than norms, the patient is determined to exhibit hyperbilirubinemia or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the total bilirubin level of the patient is greater than 1.2mg/dL (e.g., 1.2mg/dL, 1.3mg/dL, 1.4mg/dL, 1.5mg/dL, 1.6mg/dL, 1.7mg/dL, 1.8mg/dL, 1.9mg/dL, 2mg/dL, 2.1mg/dL, 2.2mg/dL, 2.3mg/dL, 2.4mg/dL, 2.5mg/dL, 2.6mg/dL, 2.7mg/dL, 2.8mg/dL, 2.9mg/dL, 3mg/dL, 3.1mg/dL, 3.2mg/dL, 3.3.mg/dL, 3.4mg/dL, 3.5mg/dL, 3.6mg/dL 3.7mg/dL, 3.8mg/dL, 3.9mg/dL, 4mg/dL, 4.1mg/dL, 4.2mg/dL, 4.3mg/dL, 4.4mg/dL, 4.5mg/dL, 4.6mg/dL, 4.7mg/dL, 4.8mg/dL, 4.9mg/dL, 5mg/dL, 10mg/dL, 15mg/dL, 20mg/dL, 30mg/dL, 40mg/dL, 50mg/dL, 60mg/dL, 70mg/dL, 80mg/dL, 90mg/dL and 100 mg/dL), determining that the patient exhibits hyperbilirubinemia or one or more symptoms thereof, and administering an anti-cholestasis agent to the patient.
In some embodiments, when the patient's direct bilirubin level is greater than 0.2mg/dL (e.g., 0.2mg/dL, 0.3mg/dL, 0.4mg/dL, 0.5mg/dL, 0.6mg/dL, 0.7mg/dL, 0.8mg/dL, 0.9mg/dL, 1mg/dL, 1.1mg/dL, 1.2mg/dL, 1.3mg/dL, 1.4mg/dL, 1.5mg/dL, 1.6mg/dL, 1.7mg/dL, 1.8mg/dL, 1.9mg/dL, 2mg/dL, 2.1mg/dL, 2.2mg/dL, 2.3mg/dL, 2.4mg/dL, 2.5mg/dL, 2.6mg/dL, 2.7mg/dL, 2.8mg/dL, 2.9mg/dL, 3mg/dL, 3.1mg/dL, 1.8mg/dL, 1.9mg/dL, 2.4mg/dL, 2mg/dL, 2.1mg/dL, 2.3mg/dL, and 0.3mg/dL 3.2mg/dL, 3.3 mg/dL, 3.4mg/dL, 3.5mg/dL, 3.6mg/dL, 3.7mg/dL, 3.8mg/dL, 3.9mg/dL, 4mg/dL, 4.1mg/dL, 4.2mg/dL, 4.3mg/dL, 4.4mg/dL, 4.5mg/dL, 4.6mg/dL, 4.7mg/dL, 4.8mg/dL, 4.9mg/dL, 5mg/dL, 10mg/dL, 15mg/dL, 20mg/dL, 30mg/dL, 40mg/dL, 50mg/dL, 60mg/dL, 70mg/dL, 80mg/dL, 90mg/dL and 100 mg/dL), determining that the patient exhibits hyperbilirubinemia or one or more symptoms thereof, and administering an anti-cholestasis agent to the patient.
In some embodiments, when the patient exhibits a bilirubin level of greater than 1mg/dL in the bilirubin test (e.g., greater than 1mg/dL, 1.1mg/dL, 1.2mg/dL, 1.3mg/dL, 1.4mg/dL, 1.5mg/dL, 1.6mg/dL, 1.7mg/dL, 1.8mg/dL, 1.9mg/dL, 2mg/dL, 2.1mg/dL, 2.2mg/dL, 2.3mg/dL, 2.4mg/dL, 2.5mg/dL, 2.6mg/dL, 2.7mg/dL, 2.8mg/dL, 2.9mg/dL, 3mg/dL, 3.1mg/dL, 3.2mg/dL, 3.3 mg/dL, 3.4mg/dL, 3.5mg/dL 3.6mg/dL, 3.7mg/dL, 3.8mg/dL, 3.9mg/dL, 4mg/dL, 4.1mg/dL, 4.2mg/dL, 4.3mg/dL, 4.4mg/dL, 4.5mg/dL, 4.6mg/dL, 4.7mg/dL, 4.8mg/dL, 4.9mg/dL, 5mg/dL, 10mg/dL, 15mg/dL, 20mg/dL, 30mg/dL, 40mg/dL, 50mg/dL, 60mg/dL, 70mg/dL, 80mg/dL, 90mg/dL or 100 mg/dL), determining that the patient exhibits hyperbilirubinemia or one or more symptoms thereof, and administering an anti-cholestasis agent to the patient.
Recommended clinical parameters for determining patients exhibiting cholestasis or hyperbilirubinemia or symptoms thereof
In some embodiments, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof by determining that one or more parameters of the patient's serum bile acid test and/or blood test (e.g., LFT) (e.g., total bile acid level, GGT level, ASP level, AST level, and ALT level) are greater than or less than an age-adjusted specification as described herein, and administering an anti-cholestasis agent to the patient.
In some embodiments, by determining that one or more parameters (e.g., bilirubin levels) of a patient's blood test (e.g., bilirubin test) are greater than the specifications as described herein, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, when one or more of the patient's bile acid (e.g., cholic acid, chenodeoxycholic acid, deoxycholic acid, or ursodeoxycholic acid) levels as measured with a serum bile acid test is greater than norm, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, when a parameter of the patient's LFT (e.g., ASP level or AST level) is greater than an age-adjusted specification as described herein, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
I. Serum bile acid test
In some embodiments, when one or more of the patient's bile acid (e.g., cholic acid, chenodeoxycholic acid, deoxycholic acid, or ursodeoxycholic acid) levels as measured with a serum bile acid test is greater than norm, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, a patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof when the patient's cholic acid level is greater than 5nmol/mL (e.g., 5nmol/mL, 6nmol/mL, 7nmol/mL, 8 nmol/mL, 9nmol/mL, 10nmol/mL, 15nmol/mL, 20nmol/mL, 30nmol/mL, 40nmol/mL, 50nmol/mL, 60nmol/mL, 70nmol/mL, 80nmol/mL, 90nmol/mL, and 100 nmol/mL) as measured with a serum bile acid test.
In some embodiments, when the patient's cholic acid level is greater than 5nmol/mL (e.g., 5nmol/mL, 6nmol/mL, 7nmol/mL, 8 nmol/mL, 9nmol/mL, 10nmol/mL, 15nmol/mL, 20nmol/mL, 30nmol/mL, 40nmol/mL, 50nmol/mL, 60nmol/mL, 70nmol/mL, 80nmol/mL, 90nmol/mL, and 100 nmol/mL) as measured with the serum bile acid test, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, when the patient's chenodeoxycholic acid level is greater than 6nmol/mL (e.g., 6nmol/mL, 7nmol/mL, 8 nmol/mL, 9nmol/mL, 10nmol/mL, 15nmol/mL, 20nmol/mL, 30nmol/mL, 40nmol/mL, 50nmol/mL, 60nmol/mL, 70nmol/mL, 80nmol/mL, 90nmol/mL, and 100 nmol/mL) as measured with the serum bile acid test, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof.
In some embodiments, when the patient's chenodeoxycholic acid level is greater than 6nmol/mL (e.g., 6nmol/mL, 7nmol/mL, 8 nmol/mL, 9nmol/mL, 10nmol/mL, 15nmol/mL, 20nmol/mL, 30nmol/mL, 40nmol/mL, 50nmol/mL, 60nmol/mL, 70nmol/mL, 80nmol/mL, 90nmol/mL, and 100 nmol/mL) as measured with the serum bile acid test, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof when the patient's deoxycholate level is greater than 6nmol/mL (e.g., 6nmol/mL, 7nmol/mL, 8 nmol/mL, 9nmol/mL, 10nmol/mL, 15nmol/mL, 20nmol/mL, 30nmol/mL, 40nmol/mL, 50nmol/mL, 60nmol/mL, 70nmol/mL, 80nmol/mL, 90nmol/mL, and 100 nmol/mL) as measured with the serum bile acid test.
In some embodiments, when the patient's deoxycholic acid level is greater than 6nmol/mL (e.g., 6nmol/mL, 7nmol/mL, 8 nmol/mL, 9nmol/mL, 10nmol/mL, 15nmol/mL, 20nmol/mL, 30nmol/mL, 40nmol/mL, 50nmol/mL, 60nmol/mL, 70nmol/mL, 80nmol/mL, 90nmol/mL, and 100 nmol/mL) as measured with the serum bile acid test, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, when the patient's ursodeoxycholic acid level is greater than 2nmol/mL (e.g., 2nmol/mL, 3nmol/mL, 4nmol/mL, 5nmol/mL, 6nmol/mL, 7nmol/mL, 8 nmol/mL, 9nmol/mL, 10nmol/mL, 15nmol/mL, 20nmol/mL, 30nmol/mL, 40nmol/mL, 50nmol/mL, 60nmol/mL, 70nmol/mL, 80nmol/mL, 90nmol/mL, and 100 nmol/mL) as measured with the serum bile acid test, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof.
In some embodiments, when the patient's ursodeoxycholic acid level is greater than 5nmol/mL (e.g., 2nmol/mL, 3nmol/mL, 4nmol/mL, 5nmol/mL, 6nmol/mL, 7nmol/mL, 8 nmol/mL, 9nmol/mL, 10nmol/mL, 15nmol/mL, 20nmol/mL, 30nmol/mL, 40nmol/mL, 50nmol/mL, 60nmol/mL, 70nmol/mL, 80nmol/mL, 90nmol/mL, and 100 nmol/mL) as measured with the serum bile acid test, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
II liver function test
In some embodiments, when a parameter of the patient's LFT (e.g., ASP level or AST level) is greater than an age-adjusted specification as described herein, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
IIa, aspartate aminotransferase
In some embodiments, the progression of cholestasis or hyperbilirubinemia in the patient is monitored by measuring the patient's AST level in the LFT, and when the patient's AST level is greater than norm, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof when the patient's AST level is greater than 50U/L (e.g., 51U/L, 52U/L, 53U/L, 54U/L, 55U/L, 56U/L, 57U/L, 58U/L, 59U/L, 60U/L, 61U/L, 62U/L, 63U/L, 64U/L, 65U/L, 66U/L, 67U/L, 68U/L, 69U/L, 70U/L, 75U/L, 80U/L, 85U/L, 90U/L, 100U/L, 110U/L, 120U/L, 130U/L, 140U/L, 150U/L, 200U/L, 300U/L, 400U/L, and 500U/L).
In some embodiments, when the patient's AST level is greater than 50U/L (e.g., 51U/L, 52U/L, 53U/L, 54U/L, 55U/L, 56U/L, 57U/L, 58U/L, 59U/L, 60U/L, 61U/L, 62U/L, 63U/L, 64U/L, 65U/L, 66U/L, 67U/L, 68U/L, 69U/L, 70U/L, 75U/L, 80U/L, 85U/L, 90U/L, 100U/L, 110U/L, 120U/L, 130U/L, 140U/L, 150U/L, 200U/L, 300U/L, 400U/L, and 500U/L), the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
IIb alanine aminotransferase
In some embodiments, the progression of cholestasis or hyperbilirubinemia in a patient is monitored by measuring the ALT level of the patient in the LFT, and when the ALT level of the patient is greater than norm, the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, a patient is determined to exhibit cholestasis or one or more symptoms thereof when the patient's ALT level is greater than 50U/L (e.g., 51U/L, 52U/L, 53U/L, 54U/L, 55U/L, 56U/L, 57U/L, 58U/L, 59U/L, 60U/L, 61U/L, 62U/L, 63U/L, 64U/L, 65U/L, 66U/L, 67U/L, 68U/L, 69U/L, 70U/L, 75U/L, 80U/L, 85U/L, 90U/L, 100U/L, 110U/L, 120U/L, 130U/L, 140U/L, 150U/L, 200U/L, 300U/L, 400U/L, and 500U/L).
In some embodiments, when the patient's ALT level is greater than 50U/L (e.g., 51U/L, 52U/L, 53U/L, 54U/L, 55U/L, 56U/L, 57U/L, 58U/L, 59U/L, 60U/L, 61U/L, 62U/L, 63U/L, 64U/L, 65U/L, 66U/L, 67U/L, 68U/L, 69U/L, 70U/L, 75U/L, 80U/L, 85U/L, 90U/L, 100U/L, 110U/L, 120U/L, 130U/L, 140U/L, 150U/L, 200U/L, 300U/L, 400U/L and 500U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
Recommended clinical parameters for determining patients exhibiting cholestasis or symptoms thereof
I. Serum bile acid test
In some embodiments, when the patient exhibits a bile acid level greater than norm as measured with a serum bile acid test, the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient's total bile acid level is greater than 14 μmol/L as measured by the serum bile acid test (e.g., 15. Mu. Mol/L, 16. Mu. Mol/L, 17. Mu. Mol/L, 18. Mu. Mol/L, 19. Mu. Mol/L, 20. Mu. Mol/L, 21. Mu. Mol/L, 22. Mu. Mol/L, 23. Mu. Mol/L, 24. Mu. Mol/L, 25. Mu. Mol/L, 26. Mu. Mol/L, 27. Mu. Mol/L, 28. Mu. Mol/L, 29. Mu. Mol/L, 30. Mu. Mol/L, 31. Mu. Mol/L, 32. Mu. Mol/L, 33. Mu. Mol/L, 34. Mu. Mol/L, 35. Mu. Mol/L, 36. Mu. Mol/L, 37. Mu. Mol/L, 38. Mu. Mol/L, 39. Mu. Mol/L, 40. Mu. Mol/L, 41. Mu. Mol/L, 42. Mu. Mol/L, 43. Mu. Mol/L44. Mu. Mol/L, 45. Mu. Mol/L, 46. Mu. Mol/L, 47. Mu. Mol/L, 48. Mu. Mol/L, 49. Mu. Mol/L, 50. Mu. Mol/L, 51. Mu. Mol/L, 52. Mu. Mol/L, 53. Mu. Mol/L, 54. Mu. Mol/L, 55. Mu. Mol/L, 56. Mu. Mol/L, 57. Mu. Mol/L, 58. Mu. Mol/L, 59. Mu. Mol/L, 60. Mu. Mol/L, 61. Mu. Mol/L, 62. Mu. Mol/L, 63. Mu. Mol/L, 64. Mu. Mol/L, 65. Mu. Mol/L, 66. Mu. Mol/L, 67. Mu. Mol/L, 68. Mu. Mol/L, 69. Mu. Mol/L, 70. Mu. Mol/L, 71. Mu. Mol/L, 72. Mu. Mol/L, 73 μmol/L, 74 μmol/L, 75 μmol/L, 76 μmol/L, 77 μmol/L, 78 μmol/L, 79 μmol/L, 80 μmol/L, 81 μmol/L, 82 μmol/L, 83 μmol/L, 84 μmol/L, 85 μmol/L, 86 μmol/L, 87 μmol/L, 88 μmol/L, 89 μmol/L, 90 μmol/L, 91 μmol/L, 92 μmol/L, 93 μmol/L, 94 μmol/L, 95 μmol/L, 96 μmol/L, 97 μmol/L, 98 μmol/L, 99 μmol/L, and 100 μmol/L), determining that the patient exhibits cholestasis or one or more symptoms, and administering an anti-cholestasis agent to the patient.
II blood test
In some embodiments, when one or more parameters (e.g., GGT level, ASP level, AST level, ALT level, and bilirubin level) of a patient's blood test (e.g., LFT or bilirubin test) are greater than an age-adjusted specification as described herein, the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
IIa liver function test
In some embodiments, when one or more parameters of the patient's LFT (e.g., GGT levels, ASP levels, AST levels, and ALT levels) are greater than the age-adjusted specifications as described herein, the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
IIai gamma-glutamyl transferase
In some embodiments, when the patient exhibits GGT levels greater than the age-adjusted specification as measured by LFT, the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a neonate (e.g., 0-6 months), a young child (e.g., 6-12 months), or a child aged 1-5 years. In some embodiments, the patient is a neonate for 0-6 months. In some embodiments, the patient is a young child for 6-12 months. In some embodiments, the patient is a child aged 1-5 years.
In some embodiments, the patient is a neonate (e.g., 0-6 months), and when the patient's GGT level is outside of a normal range of about 12-122U/L (e.g., 12-122U/L, 13-122U/L, 14-122U/L, 15-122U/L, 16-122U/L, 17-122U/L, 18-122U/L, 19-122U/L, 20-122U/L, 25-122U/L, 30-122U/L, 40-122U/L, 50-122U/L, 60-122U/L, 70-122U/L, 80-122U/L, 90-122U/L, 100-122U/L, 110-122U/L, 120-122U/L, or 121-122U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a male neonate (e.g., 0-6 months), and the patient is determined to exhibit cholestasis or one or more symptoms thereof when the patient's GGT level is less than 12U/L (e.g., 11U/L, 10U/L, 9U/L, 8U/L, 7U/L, 6U/L, 5U/L, 4U/L, 3U/L, 2U/L, or 1U/L), and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a male neonate (e.g., 0-6 months), and the patient is determined to exhibit cholestasis or one or more symptoms thereof when the patient's GGT level is greater than 122U/L (e.g., 123U/L, 124U/L, 125U/L, 126U/L, 127U/L, 128U/L, 129U/L, 130U/L, 135U/L, 140U/L, 150U/L, 160U/L, 170U/L, 180U/L, 190U/L, and 200U/L), and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a male pediatric (e.g., 6-12 months), and when the patient's GGT level is in the normal range of 1-39U/L (e.g., 2-39U/L, 3-39U/L, 4-39U/L, 5-39U/L, 6-39U/L, 7-39U/L, 8-39U/L, 9-39U/L, 10-39U/L, 11-39U/L, 12-39U/L, 13-39U/L, 14-39U/L, 15-39U/L, 16-39U/L, 17-39U/L, 18-39U/L, 19-39U/L, 20-39U/L, 21-39U/L, 22-39U/L, 23-39U/L, 24-39U/L, 25-39U/L, 26-39U/L, 27-39U/L, 28-39U/L, 29-39U/L, 30-39U/L, 31-39U/L, 32-39U/L, 33-39U/L, 34-39U/L, 35-39U/L, 37-39U/L, or 37-39U/L when a plurality of bile is administered to a patient and/or a plurality of bile is indicated.
In some embodiments, the patient is a male pediatric (e.g., 6-12 months), and when the patient's GGT level is greater than 39U/L (e.g., 40U/L, 41U/L, 42U/L, 43U/L, 44U/L, 45U/L, 46U/L, 47U/L, 48U/L, 49U/L, 50U/L, 55U/L, 60U/L, 70U/L, 80U/L, 90U/L, 100U/L, 110U/L, 1120U/L, 130U/L, 140U/L, 150U/L, 160U/L, 170U/L, 180U/L, 190U/L, and 200U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a male child aged 1-5 years, and when the patient's GGT level is outside of the normal range of about 3-22U/L (e.g., about 3-22U/L, 4-22U/L, 5-22U/L, 6-22U/L, 7-22U/L, 8-22U/L, 9-22U/L, 10-22U/L, 11-22U/L, 12-22U/L, 13-22U/L, 14-22U/L, 15-22U/L, 16-22U/L, 17-22U/L, 18-22U/L, 19-22U/L, 20-22U/L, and 21-22U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a male child aged 1-5 years, and when the patient's GGT level is less than about 3U/L (e.g., 2U/L and 1U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a male child aged 1-5 years, and when the patient's GGT level is greater than 22U/L (e.g., 23U/L, 24U/L, 25U/L, 26U/L, 27U/L, 28U/L, 29U/L, 30U/L, 35U/L, 40U/L, 50U/L, 60U/L, 70U/L, 80U/L, 90U/L, 100U/L, 110U/L, 1120U/L, 130U/L, 140U/L, 150U/L, 160U/L, 170U/L, 180U/L, 190U/L, and 200U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a female neonate (e.g., 0-6 months), and when the patient's GGT level is outside of the normal range of about 15-132U/L (e.g., 15-132U/L, 16-132U/L, 17-132U/L, 18-132U/L, 19-132U/L, 20-132U/L, 25-132U/L, 30-132U/L, 40-132U/L, 50-132U/L, 60-132U/L, 70-132U/L, 80-132U/L, 90-132U/L, 100-132U/L, 110-132U/L, 120-132U/L, 130-132U/L, and 131-132U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a female neonate (e.g., 0-6 months), and the patient is determined to exhibit cholestasis or one or more symptoms thereof when the patient's GGT level is less than about 15U/L (e.g., 14U/L, 13U/L, 12U/L, 11U/L, 10U/L, 9U/L, 8U/L, 7U/L, 6U/L, 5U/L, 4U/L, 3U/L, 2U/L, or 1U/L), and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a female neonate (e.g., 0-6 months), and when the patient's GGT level is greater than 132U/L (e.g., 133U/L, 134U/L, 135U/L, 136U/L, 137U/L, 138U/L, 139U/L, 140U/L, 145U/L, 150U/L, 160U/L, 170U/L, 180U/L, 190U/L, and 200U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a female pediatric (e.g., 6-12 months), and when the patient's GGT level is in the normal range of 1-39U/L (e.g., 2-39U/L, 3-39U/L, 4-39U/L, 5-39U/L, 6-39U/L, 7-39U/L, 8-39U/L, 9-39U/L, 10-39U/L, 11-39U/L, 12-39U/L, 13-39U/L, 14-39U/L, 15-39U/L, 16-39U/L, 17-39U/L, 18-39U/L, 19-39U/L, 20-39U/L, 21-39U/L, 22-39U/L, 23-39U/L, 24-39U/L, 25-39U/L, 26-39U/L, 27-39U/L, 28-39U/L, 29-39U/L, 30-39U/L, 31-39U/L, 32-39U/L, 33-39U/L, 34-39U/L, 35-39U/L, 37-39U/L, or 37-39U/L when a plurality of bile is administered to a patient and/or a plurality of bile is indicated.
In some embodiments, the patient is a female pediatric (e.g., 6-12 months), and when the patient's GGT level is greater than 39U/L (e.g., 40U/L, 41U/L, 42U/L, 43U/L, 44U/L, 45U/L, 46U/L, 47U/L, 48U/L, 49U/L, 50U/L, 55U/L, 60U/L, 70U/L, 80U/L, 90U/L, 100U/L, 110U/L, 1120U/L, 130U/L, 140U/L, 150U/L, 160U/L, 170U/L, 180U/L, 190U/L, and 200U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a female child aged 1-5 years, and when the patient's GGT level is outside of the normal range of about 3-22U/L (e.g., about 3-22U/L, 4-22U/L, 5-22U/L, 6-22U/L, 7-22U/L, 8-22U/L, 9-22U/L, 10-22U/L, 11-22U/L, 12-22U/L, 13-22U/L, 14-22U/L, 15-22U/L, 16-22U/L, 17-22U/L, 18-22U/L, 19-22U/L, 20-22U/L, and 21-22U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a female child aged 1-5 years, and when the patient's GGT level is less than about 3U/L (e.g., 2U/L and 1U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the patient is a female child aged 1-5 years, and when the patient's GGT level is greater than 22U/L (e.g., 23U/L, 24U/L, 25U/L, 26U/L, 27U/L, 28U/L, 29U/L, 30U/L, 35U/L, 40U/L, 50U/L, 60U/L, 70U/L, 80U/L, 90U/L, 100U/L, 110U/L, 1120U/L, 130U/L, 140U/L, 150U/L, 160U/L, 170U/L, 180U/L, 190U/L, and 200U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
IIaii alkaline phosphatase
In some embodiments, when the patient exhibits ASP levels greater than the norm as measured by LFT, the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, when the patient's ASP level is outside of the normal range of about 50 to 300U/L (e.g., about 51 to 300U/L, about 52 to U/L, about 53 to 300U/L, about 54 to 300U/L, about 55 to 300U/L, about 56 to 300U/L, about 57 to 300U/L, about 58 to 300U/L, about 59 to 300U/L, about 60 to 300U/L, about 65 to 300U/L, about 70 to 300U/L, about 80 to 300U/L, about 90 to 300U/L, about 100 to 300U/L, about 125 to 300U/L, about 150 to 300U/L, about 175 to 300U/L, about 200 to 300U/L, about 225 to 300U/L, about 250 to 300U/L, or about 275 to 300U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, when the patient has an ASP level of less than about 50U/L (e.g., 50U/L, 49U/L, 48U/L, 47U/L, 46U/L, 45U/L, 44U/L, 43U/L, 42U/L, 41U/L, 40U/L, 39U/L, 38U/L, 37U/L, 36U/L, 35U/L, 34U/L, 33U/L, 32U/L, 31U/L, 30U/L, 29U/L, 28U/L, 27U/L, 26U/L, 25U/L, 24U/L, 23U/L, 22U/L, 21U/L, 20U/L, 19U/L, 18U/L, 17U/L, 16U/L, 15U/L, 14U/L, 13U/L, 12U/L, 11U/L, 10U/L, 9U/L, 8U, 7U/L, 6U/L, 4U/L and/L) and/or a bile is administered to the patient and/or the subject has a plurality of symptoms.
In some embodiments, when the patient's ASP level is greater than 300U/L (e.g., 300U/L, 301U/L, 302U/L, 303U/L, 304U/L, 305U/L, 306U/L, 307U/L, 308U/L, 309U/L, 310U/L, 311U/L, 312U/L, 313U/L, 314U/L, 315U/L, 316U/L, 317U/L, 318U/L, 319U/L, 320U/L, 321U/L, 322U/L, 323U/L, 324U/L, 325U/L, 330U/L, 340U/L, 350U/L, 400U/L, and 500U/L) the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
IIaiii aspartate aminotransferase
In some embodiments, when the patient exhibits AST levels greater than the norm as measured by LFT, the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, when the patient's AST level is greater than 50U/L (e.g., 51U/L, 52U/L, 53U/L, 54U/L, 55U/L, 56U/L, 57U/L, 58U/L, 59U/L, 60U/L, 61U/L, 62U/L, 63U/L, 64U/L, 65U/L, 66U/L, 67U/L, 68U/L, 69U/L, 70U/L, 75U/L, 80U/L, 85U/L, 90U/L, 100U/L, 110U/L, 120U/L, 130U/L, 140U/L, 150U/L, 200U/L, 300U/L, 400U/L and 500U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
IIaiv alanine aminotransferase
In some embodiments, when the patient exhibits ALT levels greater than the norm as measured by LFT, the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, when the patient's ALT level is greater than 50U/L (e.g., 51U/L, 52U/L, 53U/L, 54U/L, 55U/L, 56U/L, 57U/L, 58U/L, 59U/L, 60U/L, 61U/L, 62U/L, 63U/L, 64U/L, 65U/L, 66U/L, 67U/L, 68U/L, 69U/L, 70U/L, 75U/L, 80U/L, 85U/L, 90U/L, 100U/L, 110U/L, 120U/L, 130U/L, 140U/L, 150U/L, 200U/L, 300U/L, 400U/L and 500U/L), the patient is determined to exhibit cholestasis or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
Recommended clinical parameters for determining patients exhibiting hyperbilirubinemia or symptoms thereof
Bilirubin test
In some embodiments, when the patient exhibits bilirubin levels greater than normals, as measured in a blood test (e.g., bilirubin test), the patient is determined to exhibit hyperbilirubinemia or one or more symptoms thereof, and an anti-cholestasis agent is administered to the patient.
In some embodiments, the total bilirubin level of the patient is greater than 1.2mg/dL (e.g., 1.2mg/dL, 1.3mg/dL, 1.4mg/dL, 1.5mg/dL, 1.6mg/dL, 1.7mg/dL, 1.8mg/dL, 1.9mg/dL, 2mg/dL, 2.1mg/dL, 2.2mg/dL, 2.3mg/dL, 2.4mg/dL, 2.5mg/dL, 2.6mg/dL, 2.7mg/dL, 2.8mg/dL, 2.9mg/dL, 3mg/dL, 3.1mg/dL, 3.2mg/dL, 3.3.mg/dL, 3.4mg/dL, 3.5mg/dL, 3.6mg/dL 3.7mg/dL, 3.8mg/dL, 3.9mg/dL, 4mg/dL, 4.1mg/dL, 4.2mg/dL, 4.3mg/dL, 4.4mg/dL, 4.5mg/dL, 4.6mg/dL, 4.7mg/dL, 4.8mg/dL, 4.9mg/dL, 5mg/dL, 10mg/dL, 15mg/dL, 20mg/dL, 30mg/dL, 40mg/dL, 50mg/dL, 60mg/dL, 70mg/dL, 80mg/dL, 90mg/dL and 100 mg/dL), determining that the patient exhibits hyperbilirubinemia or one or more symptoms thereof, and administering an anti-cholestasis agent to the patient.
In some embodiments, when the patient's direct bilirubin level is greater than 0.2mg/dL (e.g., 0.2mg/dL, 0.3mg/dL, 0.4mg/dL, 0.5mg/dL, 0.6mg/dL, 0.7mg/dL, 0.8mg/dL, 0.9mg/dL, 1mg/dL, 1.1mg/dL, 1.2mg/dL, 1.3mg/dL, 1.4mg/dL, 1.5mg/dL, 1.6mg/dL, 1.7mg/dL, 1.8mg/dL, 1.9mg/dL, 2mg/dL, 2.1mg/dL, 2.2mg/dL, 2.3mg/dL, 2.4mg/dL, 2.5mg/dL, 2.6mg/dL, 2.7mg/dL, 2.8mg/dL, 2.9mg/dL, 3mg/dL, 3.1mg/dL, 1.8mg/dL, 1.9mg/dL, 2.4mg/dL, 2mg/dL, 2.1mg/dL, 2.3mg/dL, and 0.3mg/dL 3.2mg/dL, 3.3 mg/dL, 3.4mg/dL, 3.5mg/dL, 3.6mg/dL, 3.7mg/dL, 3.8mg/dL, 3.9mg/dL, 4mg/dL, 4.1mg/dL, 4.2mg/dL, 4.3mg/dL, 4.4mg/dL, 4.5mg/dL, 4.6mg/dL, 4.7mg/dL, 4.8mg/dL, 4.9mg/dL, 5mg/dL, 10mg/dL, 15mg/dL, 20mg/dL, 30mg/dL, 40mg/dL, 50mg/dL, 60mg/dL, 70mg/dL, 80mg/dL, 90mg/dL and 100 mg/dL), determining that the patient exhibits hyperbilirubinemia or one or more symptoms thereof, and administering an anti-cholestasis agent to the patient.
In some embodiments, when the patient exhibits a bilirubin level of greater than 1mg/dL in the bilirubin test (e.g., greater than 1mg/dL, 1.1mg/dL, 1.2mg/dL, 1.3mg/dL, 1.4mg/dL, 1.5mg/dL, 1.6mg/dL, 1.7mg/dL, 1.8mg/dL, 1.9mg/dL, 2mg/dL, 2.1mg/dL, 2.2mg/dL, 2.3mg/dL, 2.4mg/dL, 2.5mg/dL, 2.6mg/dL, 2.7mg/dL, 2.8mg/dL, 2.9mg/dL, 3mg/dL, 3.1mg/dL, 3.2mg/dL, 3.3 mg/dL, 3.4mg/dL, 3.5mg/dL 3.6mg/dL, 3.7mg/dL, 3.8mg/dL, 3.9mg/dL, 4mg/dL, 4.1mg/dL, 4.2mg/dL, 4.3mg/dL, 4.4mg/dL, 4.5mg/dL, 4.6mg/dL, 4.7mg/dL, 4.8mg/dL, 4.9mg/dL, 5mg/dL, 10mg/dL, 15mg/dL, 20mg/dL, 30mg/dL, 40mg/dL, 50mg/dL, 60mg/dL, 70mg/dL, 80mg/dL, 90mg/dL or 100 mg/dL), determining that the patient exhibits hyperbilirubinemia or one or more symptoms thereof, and administering an anti-cholestasis agent to the patient.
Examples
The following examples are put forth so as to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used and evaluated, and are intended to be merely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention.
Example 1 prevention of liver and gall disorders caused by Billebrand and Xiong Erchun as cholestasis syndrome
The objective of this study was to examine the potential side effects of birnesyl on human patients with X-linked myotubulomyopathy (XLMTM) and less than or equal to 5 years of age for up to five years after administration.
Materials and methods
Thirty patients were enrolled in the study. Twenty three patients with XLM and less than or equal to 5 years old were treated with 1.0X10 14 vg/kg (n=6) or 3.0x10 14 The dose of vg/kg (n=17) is administered with birefranyl (fig. 1). Seven controls were untreated.
Monitoring the general health of the patient daily; detailed clinical observations, functional improvement and adverse events caused by Treatment (TEAE) up to 27.9 months.
A summary of each group and monitoring duration is presented in table 2.
TABLE 2 study duration, at the level of the dose of Billerenyl
Results
All 23 subjects dosed in the study experienced TEAE, defined as Adverse Effects (AEs) that occurred after administration of birnesyl. AE of untreated control report during the study window was included as a comparison. Table 3 presents the most common TEAE reported in > 2 subjects. TEAE with a severity of > 3 levels in > 2 subjects included hyperbilirubinemia/increased bilirubin (n=4), cholestasis (n=2), increased alanine Aminotransferase (ALT) (n=2), increased aspartate Aminotransferase (AST) (n=2) and increased gamma-glutamyl transferase (GGT) (n=2). Grade 1 TEAE is defined as mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; no intervention is required. Grade 2 TEAE is defined as moderate; minimal, local or non-invasive intervention is required. Grade 3 TEAE is defined as severe or medically significant but not immediately life threatening; needs hospitalization or prolongs hospitalization time; disabilities. Grade 4 TEAE is defined as a life threatening outcome; emergency intervention is required, while grade 5 TEAE is defined as AE-related death.
Most common TEAE reported by 2 subjects, according to preference
Table 4 provides a summary of TEAEs that researchers participating in the study believe may be related to birnesyl.
Wherein, at 1.0X10 14 The TEAEs frequently reported in subjects treated at vg/kg dose levels included elevated aminotransferases (including ALT increase, AST increase, transaminase increase, liver function test abnormalities and liver function abnormalities) in 5 subjects (83.3%) and hyperbilirubinemia (including blood bilirubin increase) in 2 subjects (33.3%). At 1.0X10 14 Several TEAE are reported for vg/kg dose level. Of these, GGT was increased in one subject (grade 3), transaminase was increased in 1 subject (grade 4), and hyperbilirubinemia was seen in 1 subject (grade 3).
Wherein, at 3.0X10 14 The TEAEs frequently reported in subjects treated at vg/kg dose levels included elevated aminotransferases (including ALT increase, AST increase, transaminase increase, liver function test abnormality and liver enzyme increase) in 8 subjects (47.1%) and hyperbilirubinemia (including blood bilirubin increase) in 3 subjects (17.6%). At 3.0X10 14 Several TEAE are reported for vg/kg dose level. Wherein, grade 4 TEAE comprises hyperbilirubinemia in a subject; hyperbilirubinemia in a subject; AST increase in one subject, ALT increase in one subject, GGT increase in one subject, and liver function test abnormalities observed in one subject (grade 4).
Table 4. Gtoreq.2 subjects reported TEAE considered to be at least likely to be associated with Birella-base by systemic organ category and preference
Table 5 presents a summary of all treatment-induced SAE present in the dosed subjects.
9 subjects (at 1.0X10) 14 1 subject at vg/kg dose level and at 3.0X10 14 8 subjects at vg/kg dose level) were evaluated as at least likely to be associated with birnesyl. The investigator assessed twenty-five of the 10 subjects that the treatment-induced SAE were not related to birimuride. Most include respiratory problems as complications of the underlying XLM disease, including respiratory tract type infections (e.g., pneumonia or respiratory tract infections; 10 events in 6 subjects).
Hyperbilirubinemia and cholestasis events, as well as AST and ALT elevation, were determined as confirmed risk associated with birimyl after review of all available clinical safety data for subjects exposed to Yu Birui radium during the study.
TABLE 5 treatment-induced SAE in study, by systemic organ category and preference
At 3.0X10 14 Eight subjects administered birnesyl at a dose level of vg/kg experienced 26 SAE that were considered to be at least likely to be associated with birnesyl. Most of these 26 SAE are considered to be associated with severe cholestatic liver dysfunction. These Birella-based related SAEs are all briefly described below.
At 3.0X10 14 Five subjects administered birthwort at vg/kg dose level experienced a condition involving severe hepatobiliary events. Cholestatic SAE were reported in 1 subject, and the event was resolved and described briefly below.
One 6.8 year old subject (115-9001) underwent SAE with grade 3 cholestasis requiring hospitalization. The subject's medical history includes bile stasis and elevated total bilirubin. About 5 weeks after administration, the subject's direct bilirubin levels rise (grade 2), are treated with bear glycol and regress after 6 weeks. Approximately 11 weeks after dosing, subjects underwent cholestasis and decided to hospitalize the subjects 9 days after cholestasis was reported. Cholestasis subsides after about 12 weeks. Researchers believe that cholestasis may be associated with a birthwort infusion. The baseline cholestasis history of the subject supports the underlying disease as a causative factor. It should be noted that the patient did not show any other signs of disease than mild jaundice.
Conclusion(s)
At 1.0X10 14 At the vg/kg dose level, hepatobiliary SAE was not observed. At 1.0X10 14 At the vg/kg dose level, 2 out of 6 subjects reported non-critical hyperbilirubinemia events.
At 3.0X10 14 At the vg/kg dose level, SAE representing severe liver and gall dysfunction was observed in 4 subjects, one of which resulted in death. More specifically, among 3 subjects reporting significantly elevated bilirubin levels, cholestatic liver dysfunction resulted in 2 subjects experiencing fatal sepsis AE, and was presumed to result in a third subject experiencing fatal gastrointestinal bleeding. Each of the 3 subjects had a history of hyperbilirubinemia. The fourth subject reporting cholestatic SAE had a history of pretreatment for cholestasis and no clinically significant changes in liver and gall function, except for mild jaundice. At 3.0X10 14 At vg/kg dose levels, hyperbilirubinemia and cholestatic SAE are reported and considered as established risks associated with the use of bimesosyl.
Investigation of the liver dysfunction properties of xltm patients before and after bimesol administration indicated that intrahepatic cholestasis may be a central feature. Hyperbilirubinemia and cholestasis are reported in the natural history of the disease, but little is known about its pathophysiology (see, e.g., amburgy, kimberly, et al, "A natural history study of X-linked myotubular myopathy," Neurology 89.13 (2017): 1355-1364;Herman,Gail E, et al, "Medical complications in long-term survivors with X-linked myotubular myopathy," j.petiatr.134.2 (1999): 206-214). In our natural history study, 35 subjects had evaluable liver laboratory data (including 1 subject with final screening failure; the average study duration of the remaining 34 subjects was 13 months [ range, 0.5-32.9)]) And most subjectsALT level abnormality in at least 1 value (85.7% of patients (30/35) with an Upper Limit of Normal (ULN), AST level abnormality in 68.6% of patients (24/35) with an AST level abnormality in 54.3% of patients (19/35) with a GGT level abnormality in 31.4% of patients (11/35) with a total bilirubin abnormality, and direct bilirubin abnormality in 28.6% of patients (10/35) in the study, some received 1.0X10 14 vg/kg and 3.0X10 14 Subjects with vg/kg birthwort were noted to have hyperbilirubinemia at baseline or have a history consistent with cholestasis, and no liver SAE was reported after dosing. While potential XLM disease may lead to bile stasis and hyperbilirubinemia events in this population (see, e.g., herman, gail E., "J. Pediatr.134.2 (1999): 206-214), et al," Medical complications in long-term survivors with X-linked myotubular myopathic., "is believed to lead to bile stasis and hyperbilirubinemia events observed so far. Thus, bile stasis and hyperbilirubinemia are determined as risks of birthwort, and as described herein, the present invention establishes routine monitoring assessments for hepatobiliary assessment to monitor hepatobiliary changes.
Bile stasis and hyperbilirubinemia are considered established risks associated with birthwort. Thus, for subjects receiving birthwort, the use of bear diol as a prevention of possible cholestasis syndrome is suggested. Xiong Erchun (ursodeoxycholic acid) is an enterally administered hydrophilic bile acid that reduces the hydrophobic bile acid content of bile. Since hydrophilic bile acids are generally non-toxic to hepatocytes, while hydrophobic bile acids may be toxic to these same cells in direct contact, bear diols have been used to treat severe cholestasis syndromes such as progressive intrahepatic cholestasis in the family (see, e.g., "Bile acid therapy in pediatric hepatobiliary disease: the role of ursodeoxycholic acid." J.Pediatr. Gastroentol. Nutr.24.5 (1997): 573-589; strauss, et al "Management of hyperbilirubinemia and prevention of kernicterus in patients with Crigler-Najjar disease)," Eur J Pediatr 165.5 (2006): 306-319; suskind, et al "A child with Kabuki syndrome and primary sclerosing cholangitis successfully treated with ursodiol and cholestryamine." J.Pediatr. Gamentol. Nutr.43.4 (2006): 542-544). This procedure has been demonstrated to reduce the toxic effects of elevated serum bile acid levels in certain other intrahepatic cholestatic conditions. For example, transient hyperbilirubinemia is observed following bimatoyl therapy, and in some cases is responsive to bear diol therapy.
In the event of advanced hyperbilirubinemia, where bear glycol is refractory, additional measures such as nasal bile duct drainage (NBD) may be considered.
EXAMPLE 2 bilirubin laboratory trend after Billerenyl administration
The purpose of this longitudinal study was to examine the total and direct bilirubin levels of human patients with XLMTM and less than or equal to 5 years of age 48 weeks after the administration of birnesyl.
Materials and methods are described in example 1.
Results
35 subjects have at least 1 total bilirubin and an evaluable measurement of direct bilirubin.
FIG. 2 is a box-shaped plot of the number of observations of patients with multiple differences in total or direct bilirubin levels from ULN due to 1.0X10 in this study 14 vg/kg or 3.0X10 14 Dose level of vg/kg of bimesol. Regarding total bilirubin, 11 subjects (31.4%) have at least one outcome>ULN;5 subjects (14.3%) have at least 1 result ≡2×uln;3 subjects (8.6%) have at least 1 value ∈3×uln; and 2 subjects (5.7%) have at least 1 value ∈5×uln. Of 11 subjects with at least 1 elevated total bilirubin levels, 8 (73%) also showed normal values at other time points.
Regarding direct bilirubin, 10 subjects (28.6%) have at least 1 outcome > ULN;5 subjects (14.3%) have at least 1 result ≡2×uln;5 subjects (14.3%) have at least one value ∈3×uln; and 2 subjects (5.7%) have at least one value ∈5×ULN. Of 10 subjects with at least 1 elevated direct bilirubin levels, 7 (70%) also showed normal values at other time points.
Fig. 3 is a regression plot of the LOESS of the same total bilirubin data up to week 48.
Conclusion(s)
In summary, an increase in total bilirubinemia was observed in patients with XLMTM after administration of birthwort. And 1.0X10 14 3.0X10% compared to vg/kg dose level 14 The absolute elevation of vg/kg dose level from baseline is generally higher.
Example 3.X primary gene replacement therapy for myotubulomyopathy is specific for morganyl (ASPIRO): safety and efficacy of a 1/2/3 phase, multi-regional, random, open label trial
This example describes ASPIRO (NCT 03199469), a phase 1/2/3, random, open-label study of the safety and efficacy of single dose gene replacement therapy versus rayleigh for xltm patients, a rare, life threatening congenital myopathy caused by mutations in the MTM1 gene, resulting in severe muscle weakness and premature death.
Introduction to the invention
Birella is an AAV8 vector designed to deliver full-length human MTM1 complementary DNA (cDNA) to skeletal muscle under the control of a muscle-specific desmin promoter and enhancer. In the mouse and dog models of xltm, single administration of AAV vectors expressing the murine or canine version of MTM1 cDNA, respectively, resulted in reversal of disease phenotype and sustained therapeutic effects. ASPIRO clinical trial (NCT 03199469) assessed the safety and efficacy of single infusion of birefranyl in xltm children at both dose levels.
Materials and methods
Briefly, we report an open label ASPIRO random trial (NCT 03199469) in which participants entered the group and received a single intravenous dose of AAV vector of delivered human MTM1 versus rayleigh. By 1 month 2021, six participants received 1×10 14 vg/kg, and 17 participants received 3X 10 14 vg/kg, which was compared with 15 untreated (control) participants. In the subsequent phase of the trial, seven participants received 1X 10 14 vg/kg and 17 participants received 3X 10 14 vg/kg, which was compared to 14 untreated (control) participants. Efficacy was assessed as the number of daily ventilator support hours from baseline to week 48, maximum Inspiratory Pressure (MIP), philadelphia hospital neuromuscular disorder infant test (CHOP end) motor function score, and motor development assessed for each participant via motor development milestone assessment (based primarily on 10 developmental projects of bayey infant development scale III (Bayley III), assessing typical development such as unsupported sitting, standing and walking).
Other materials and methods are detailed in the following sections.
I. Study population
ASPIRO was an ongoing two-part, multi-regional, randomized, open-label trial, initiated in 2017, in which patients were randomized to receive either a disposable intravenous administration of birimuridyl or a delayed treatment control. Part 1 is the safety and dose escalation assessment. Part 2 (in progress) is the confirmation phase of the further study dose determined using part 1.
Prior to ASPIRO, 34 xltm patients were enrolled in the family inceps, which is a prospective lead-in (run-in) study (NCT 02704273) that provided information for the selection of clinically relevant endpoints to assess the therapeutic efficacy of ASPIRO. The males <4 years old who were genetically confirmed to be diagnosed as xltm and received mechanical ventilator support (invasive or non-invasive) entered the group incoptus and were followed up for 33 months.
In ASPIRO, the participants are genetically confirmed to be of the age of XLMTM<Boys of age 5 (average age: 20.4 months [ range 9.5, 49.7)]) It requires ventilator support and has no clinically significant potential liver disease>Alanine aminotransferase or aspartate aminotransferase 5x ULN, or shows liver purpura by imaging). Motor development was assessed as secondary efficacy endpoint in 23 participants of the birthwort treatment (n=6, low dose 1x 10 14 vg/kg; n=17, high dose 3x 10 14 vg/kg) and compared to 15 untreated controls (including 12 participants from incoptus, NCT 02704273). Specifically, untreated control participants (n=15) included those who entered the group inceptas but did not transition to ASPIROParticipants (n=12) and those directly into the group ASPIRO (whether with or without the involvement of incoptus) (n=3), but the control participants were fashionably untreated by 2021, 1 month, 29 day data cut-off. In the subsequent phase of the trial, another control participant (participant 40) was treated with 1X 10 14 Low dose of vg/kg.
Ia. randomization and treatment
In part 1, the participants entered one of two dose groups: group 1 ("low dose") received 1×10 14 The vector genome (vg) per kilogram (kg) body weight of the dose of the specific rayleigh, and group 2 ("high dose") received 3×10 14 Dose of specific Rayleigh in vg/kg.
The first (sentinel) participant in each group received biri-base; there were no safety issues 4 weeks after infusion, allowing three additional participants to be randomized (2:1) to immediately receive the same dose of treatment or delay treatment control, ultimately receiving the dose of treatment selected in part 2. According to the data and safety monitoring committee recommendations, group 1 was expanded to include three additional treated participants, with a total of six participants receiving this low dose. Group 2 was then started and ten participants in part 1 received high doses after expanding to include the other five participants.
Part 2 was initiated to confirm that it appears to be the maximum tolerated dose 3 x 10 determined in part 1 14 vg/kg. Ten participants were enrolled based on efficacy analysis at 80% of the 0.05 significance level at which a difference in ventilation demand reduction of at least 13 hours was detected, and age-matched two-person groups were randomly assigned (1:1) to immediate treatment or delayed treatment controls. Seven participants had been dosed at high doses in part 2 by month 1 of 2021. To date, a total of 17 participants received high doses.
II. Carrier
The birnesyl group is a non-replicating recombinant AAV8 vector that expresses non-codon optimized human MTM1 cDNA under the control of a muscle-specific human desmin promoter. The MTM1 expression cassette was constructed by cloning a synthetic DNA sequence complementary to the coding part (nucleotides 43-1864) of the wild type human MTM1 transcript (NCBI Ref. Seq NM-000252.3) downstream of the 1.05kb human desmin enhancer/promoter region. The second intron of the human beta-globulin gene (HBB) and polyadenylation sequence were inserted upstream and downstream, respectively, of the MTM1 synthetic cDNA to mediate RNA processing. The expression cassette is flanked by AAV2 Inverted Terminal Repeats (ITRs). Vectors were generated by double plasmid transfection into AAV8 capsids in HEK293 cells in bioreactor suspension culture during whole GMP.
III procedure
The birefrenyl is administered in a single dose by intravenous infusion. Participants began receiving praise Lai Su (1 mg/kg) 1 day prior to treatment to reduce potential T cell mediated liver inflammation that has been observed in previous AAV vector gene therapy trials. The first three participants received this dose daily for 4 weeks, followed by a gradual decrement of 4 weeks. This period was extended to 8 weeks, with the remaining participants undergoing a gradual decrease of 8 weeks in response to the observed increase in transaminase of one participant and troponin I of the other participant at 7 weeks after treatment.
Evaluation of
The primary efficacy outcome is the change in the number of ventilator support hours per day from baseline to week 48, defined as ventilator independence when participants reported that the ventilator was used for 0 hours/day. The participants' responses to gradual changes in ventilator settings and eventual loss of ventilator are supervised by local pneumologists who monitor measures of gas exchange (oxygen saturation, transcutaneous carbon dioxide levels and serum bicarbonate levels). Normal polysomnography, weight gain, development progression and a reassuring clinical examination are prerequisites for cessation of ventilation. Measurements of MIPs were obtained at the individual study sites and sent to a central reader to assess respiratory muscle strength.
Motor skills were assessed at individual study sites using CHOP interval (score ranging from 0 to 64 points, higher scores indicating better motor function; increments of 4 points were considered clinically significant), and motor skills were assessed for selected major motor milestones using Bayley III, CHOP interval, and related items of the motor function metric scale (MFM-32).
Open muscle biopsy samples were obtained from the left gastrocnemius muscle at baseline, from the right gastrocnemius muscle at week 24 post-treatment, and from the lateral femoral muscle at week 48, and subjected to histopathological analysis. Vector biodistribution was assessed by quantitative polymerase chain reaction (qPCR) and myotubulin RNA and protein expression were assessed by RNA sequencing and western blot methods, respectively. Immunological assessment included measurement of anti-AAV 8 neutralizing antibodies and anti-myotubulin antibodies according to the study protocol, and immunohistochemical staining of inflammatory markers in muscle biopsy samples.
AE starts recording from the time of informed consent and uses a supervision active medical dictionaryVersion 20.0 is encoded. SAE is defined according to international covariant conference standards.
IVa measurement of Maximum Inspiratory Pressure (MIP)
For patients requiring invasive ventilation support, MIP was evaluated by temporarily occluding the airway using a one-way valve attached to a sleeved tracheostomy tube. For a small number of patients requiring BiPAP or successful detachment from invasive ventilation support, the valve device is attached to a snug mask placed over the child's nose and mouth. Thus, the airflow is blocked in one direction (e.g., during an inhalation to evaluate the MIP) and unblocked in the other direction, allowing the patient to exhale to the remaining volume and thereby maximize the inhalation pressure. When a child makes an inspiratory effort during occlusion, the inspiratory muscle will develop pressure, which can be measured by a pressure transducer attached to the valve device. To ensure consistency and to maintain compliance with international guidelines, the obstruction is maintained for at least eight breaths and at least five sets of obstructions are performed. MIP is electronically determined as the maximum negative pressure generated during occlusion. All pressure tracking electronic data was uploaded to the on-line portal and read by the professional respiratory pathologist (fig. 4A-4B).
IVb determination of myotubulin expression
Expression of MTM1 in muscle biopsies was analyzed by semi-quantitative western blot method. Total protein extracts obtained from patient biopsies using a Fastprep tissue lyser were quantified by the Bradford assay and analyzed by SDS-PAGE (15 μg total protein/well). Proteins extracted from muscle biopsies of healthy individuals and MTM1 knockout mice were used as positive and negative controls on each gel, respectively. Recombinant SUMO-MTM1 fusion protein was added as an internal standard calibrator to healthy muscle extracts at concentrations of 0.01, 0.033, 0.11, 0.37, 1.22, 4.05, 13.53 and 45.05 ng/lane, respectively. Due to its large size (-83 kDa), SUMO-MTM1 is easily distinguishable from endogenous MTM1 (-70 kDa) on SDS-PAGE gel scans. For the western blot method, proteins were electrotransferred to nitrocellulose membranes and transfer was monitored by REVERT (Li-COR) total protein staining. After the decolorization and overnight blocking steps at 5 ℃ + -3deg.C, MTM1 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for loading normalization were detected by simultaneous incubation (1 hour at room temperature) with goat anti-human MTM1 (ABNOVA, catalog number: ABNOVAPAB 6061) and mouse anti-human GAPDH primary antibody (Millipore, catalog number: MAB 374) respectively, and with infrared fluorescent dye conjugated secondary antibodies (donkey anti-goat IRDye800CW, licor, catalog number: 926-32214 and goat anti-mouse IRDye680, licor, catalog number: 926-68070). The signals were captured and analyzed using the Odyssey system (LiCor). For the study samples, MTM1 expression was reported as fold expression relative to healthy control samples by REVERT normalization.
IVc determination of vector copy number
The birnesyl vector DNA was quantified as vector genome (vector copy number, VCN) in each diploid genome by TaqMan qPCR (Applied Biosystems, catalog No. 4440040) in genomic DNA extracted from muscle biopsies. For qPCR reactions, forward primer (MTM 1-3F:5' -CCCCAACTTCACCTTCCAG-3'; SEQ ID NO: 16) and reverse primer (MTM 1-3R:5' -ATTAGCCACACCAGCCAC-3'; SEQ ID NO: 17) were used for 50. Mu.L reaction volumes, 600nM and 300nM each of MTM1-3P probe (5 ' -6-FAM-TGCCCCATG/ZEN/TGCAAACTCACTTC-3' IBFQ-3'; SEQ ID NO: 18). The thermal cycle conditions were: 50℃for 2 minutes, 95℃for 10 minutes, then 40 cycles of 95℃for 15 seconds and 60℃for 30 seconds. The linearized pAAVAud-Des-hMTM1 plasmid was used as a quantification standard.
IVd assay for neutralizing antibodies against AAV8
anti-AAV 8 neutralizing antibody (Nab) titers in patient serum were determined by a cell-based assay that measures antibody-mediated inhibition of entry of AAV8 vector expressing a luciferase reporter gene (AAV 8-luc) in 293T cells. Briefly, 30,000 293T cells were seeded into 96-well plates and transduced with a 1:1 mixture of serial dilutions of AAV8-luc vector with a multiplicity of infection (MOI) of 10,000 and patient serum. Cells were incubated with the mixture for 1 hour, then etoposide (20 μm) was added, then incubated overnight. Cells were then lysed in buffer containing luciferase substrate (Steady-Glo, promega) and the luminescence read using a 96-well plate reader. Pre-tested anti-AAV 8 neutralizing activity negative serum was used as Negative Control (NC). The signal from the test sample wells was divided by the average signal from the NC wells for normalization. If the normalized signal of the sample is below a predetermined ratio, i.e., the critical point (0.78), the sample is considered positive against AAV8 neutralizing antibodies. The anti-AAV 8 NAb titer of the serum samples was calculated by linear interpolation of the two normalized signal values from the two dilutions on either side of the predetermined critical point 0.78 and their corresponding dilution factors.
IVe. Determination of anti-MTM 1 antibody titres
anti-MTM 1 antibody titers in patient serum were analyzed by electrochemiluminescence assay using a Meso Scale Discovery (MSD) platform (Meso Scale Diagnostics, rockville MD), followed by a stratification method, samples were first screened, and then signal specificity was confirmed by competition with unlabeled MTM1 (confirmation buffer). anti-MTM 1 antibody titers were measured in all confirmed positive samples. For anti-MTM 1 antibody assay, streptavidin-impregnated MSD plates were blocked with MSD wash buffer containing 5% bsa for approximately two hours at room temperature. The samples and controls were diluted appropriately in dilution buffer or validation buffer (2.22. Mu.g/mL MTM-1 in dilution buffer). mu.L of a Master Mix (Master Mix) solution containing biotinylated-MTM 1 and ruthenium-MTM 1 was added to the appropriate wells on the polypropylene (PP) plate. Fifty microliters of the diluted sample or control was added to the wells of the PP plate containing the labeled MTM1 mother liquor mixture. The plates were sealed and incubated at room temperature for about two hours to allow anti-MTM 1 antibodies (if present) in the samples to bridge the two labeled MTM1 species.
At the same time, streptavidin-MSD plates were blocked and washed with MSD wash buffer. 50 μl of sample or control from the master mix of PP plates was added to the streptavidin-MSD plates for capture of anti-MTM 1 antibodies via biotinylated MTM 1. The plates were sealed and incubated at room temperature for approximately one hour. After incubation, streptavidin-MSD plates were washed with MSD wash buffer. mu.L of surfactant-free 2 XMSD read buffer T was added to each well and the plate read using a MSD Sector Imager (S600) plate reader. The presence of anti-MTM 1 antibodies is determined by comparing the signal to a statistically derived threshold (i.e., the assay threshold).
To determine anti-MTM 1 antibody titers in confirmed positive samples (fig. 5B), each sample was serially diluted and the set of dilutions tested in a manner substantially similar to the screening assay. Two-fold serial dilutions of each sample were prepared in 10% human serum pool (NC) in dilution buffer and assayed in duplicate until the signal fell below the critical point. The dilution factor above which the normalized signal was first below the titration critical point (1.32 sample/NC signal, titration critical point) was multiplied by the dilution factor to determine the final titer value.
IVf. RNA sequencing analysis
Vector-derived MTM1 mRNA expression levels were measured by RNA sequencing. Total RNA was extracted from frozen muscle biopsies and quality and quantity were assessed by Nanodrop (Thermo Fisher Scientific, waltham, mass.), qubit (Thermo Fisher) and TapeStation (Agilent, santa Clara, calif.) prior to sequencing library preparation. ERCC (external RNA control alliance, national Institute of Standards and Technology, gaithersburg, MD). RNA incorporation was used according to the manufacturer's instructions. Sequencing libraries were prepared using a standard Illumina strand-specific protocol with poly-a selection and unique double index barcodes for sample multiplexing. Samples were multiplexed and sequenced together in two lanes of Illumina (San Diego, CA) HiSeq 4000 (2 x 150 bp), with ten lanes of raw data in total. Sequencing reads trim the adaptor sequence and align with the human genome supplemented with the transgene sequence. Quality control and analysis of RNA-seq data was performed using an internally developed bioinformatics pipeline. Read count normalization, downstream analysis and mapping were performed using R version 3.5.1.
As described in table 6, each allele is classified based on mutations that result in potentially ineffective mutations that result in little or no stable protein and mutations that the muscle may express stable intact or internally deleted proteins (e.g., may have residual activity). Loss of function (LOF) alleles include all predicted genetically null mutations. Partial loss of function (PLOF) variants include single in-frame exon repeats, three base pair in-frame deletions, in-frame insertions, small in-frame insertions deletions, and missense variants. In-frame and out-of-frame exon deletions (IFED) include larger deletions predicted to encode stable but internally deleted proteins that may lack the entire functional domain and epitope.
TABLE 6 genotype data and potential mutation effects
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* MTM1 mutation status and predicted effects are from e.g. Graham et al Arch Dis Child 2019, 9, 4; 10.1136/archdischild-2019-31791.
dbSNP ID: a database of single nucleotide polymorphisms; HGMD ID-human gene mutation database
V. statistical method
The results report was 29 days 1 month by 2021. The number of daily ventilation hours, CHOP interval scores and MIP changes over time from baseline were calculated and compared between the low and high dose groups and the control group using a repeated measure anova model with participants as the randomized effect and weekly treatment interactions as the fixed effect. Changes from baseline are reported as Least Squares Mean (LSM) and Standard Error (SE). The probability of the treatment group reaching a milestone is estimated as the relative risk and associated 95% confidence interval [ CI ] compared to the control group, with continuity correction used to avoid division by zero. Ventilator independent time and movement milestone realization time were analyzed using the kaplan-mel and Wilcoxon test. A 95% confidence interval was calculated for the median event occurrence time analysis. SAS v9.4 was used for all analyses.
Results
Participants (participants)
By month 1 of 2021, 23 participants received biriranyl: six low doses and 17 high doses (fig. 6). No control participants (n=15) received biriresinol by month 1 of 2021. In the subsequent phase of the trial, another control participant (participant 40) received a low dose of birthwort.
The participants at baseline were similar in characteristics for the treatment and control groups (see table 7 below). At the time of treatment administration, the average age of the low dose group was 20.4 months (range: 9.5, 49.7), the average age of the high dose group was 39.4 months (range: 6.8, 72.7), and the average age of the control participants at the time of group entry was 19.6 months (range: 5.9, 39.3). In all three groups, baseline mean invasive ventilation was used for 22 hours per day, and mean MIP values were 80cmH above the normal range lower limit for children of the same age 2 O is four standard deviations lower. In 3 to 6 month-old healthy children, the average baseline CHOP score was about 50% lower than expected. Only three participants (one for each group) were able to sit unassisted for 30 seconds at baseline. Genotype data is provided in table 6.
Respiratory function
The number of ventilator support hours per day was significantly reduced from baseline to week 48 in both dose groups, but not in the control group (P <0.0001, fig. 7A-7B). In the low dose group, a decrease from 20.5.+ -. 2.0 hours to 1.3.+ -. 2.0 hours (LSM change analyzed using repeated measure variance model analysis, -19.2 hours) was supported, in the high dose group, from 23.6.+ -. 1.2 hours to 7.7.+ -. 1.5 hours (LSM change-15.9 hours), and in the control group, from 20.2.+ -. 1.3 hours to 21.5.+ -. 1.4 hours (LSM change-0.3 hours). The treated participants had a significantly greater percentage reduction in ventilator dependent hours per day (P < 0.0001) relative to baseline (figures 7A to 7B) than the control participants. Between 16 and 72 weeks after treatment, fifteen treated participants (all six low doses and nine high doses) achieved ventilator independence; however, a low dose participant subsequently requires intermittent ventilation support, in part because of potential scoliosis, a common xlm complications. Median event occurrence time was 50.7 weeks (95% ci,41.9 to 71.1) among ventilator independent treated participants. No ventilator independent reduction was achieved for the control patient.
From baseline to week 48, the measure of respiratory muscle strength of the two dose groups, MIP, increased significantly compared to the control (P<0.0001, fig. 7C to 7D). MIP was 30.0.+ -. 6.9cmH from LSM (. + -. SE) in low dose cohort 2 O was increased to 73.8.+ -. 8.5cmH 2 O (LSM Change 43.8 cmH) 2 O) from 24.3.+ -. 4.1cmH in the high dose cohort 2 O was increased to 71.5.+ -. 5.4cmH 2 O (LSM Change 47.2 cmH) 2 O), and from 35.4±4.4cmH in control group participants 2 O was reduced to 29.7.+ -. 5.6cmH 2 O (LSM Change-5.7 cmH) 2 O)。
Exercise function
In the participants receiving either dose, the CHOP score increased significantly from baseline to week 48 compared to the control group (P <0.0001, fig. 8A to 8B and 4C). The variation in LSM (±se, analyzed using the repeated measures anova model) was 18.8 in the low dose group (from 37.7±3.6 to 56.5±3.6), 19.6 in the high dose group (from 30.7±2.1 to 54.4±3.3), and 4.8 in the control (from 33.0±2.3 to 36.4±3.1). Significant improvement occurred as early as 4 weeks after treatment; by week 4, 78% (18/23) of the treated participants achieved a clinically significant 4 point or higher increase in CHOP score. The treated participants reached a higher percentage of the base movement milestones between baseline and last observation than the control participants (table 8 below). At the data cutoff, all six (100%) low dose participants and 13/17 (77%) high dose participants were able to sit unassisted for at least 30 seconds, while the control group was 5/15 (33%) participants. Five (83%) low-dose participants were able to stand on their own compared to 2/17 (12%) high-dose participants and no control participants. Five/six (83%) low-dose participants and 1/17 (6%) high-dose participants could start unsupported walking on average 21.1 months (range: 16.4-29.8) after dosing compared to no control group participants. The motor function results of the individual participants are shown in fig. 9A to 9B.
Muscle biopsy results
Dose-dependent changes in VCN and mRNA and MTM1 protein expression were observed 24 and 48 weeks after treatment (fig. 10A-10B). All participants had pre-treatment muscle biopsies characterized by xltm, including muscular fiber dystrophy, central organelle aggregation, and increased fiber fractions with nuclei placed inside. Muscle biopsy samples obtained 24 weeks after low dose group treatment showed improved organelle (mitochondrial) tissue with minimal impact on muscle fiber size or percentage of fibers with nuclei inside. Muscle biopsies 48 weeks after treatment continued to show proper organelle localization and similar levels of internal nucleation, but increased myofiber size relative to baseline. By week 24, a greater increase in fiber size was observed in some patients in the high dose group compared to the low dose group, indicating that the histopathological abnormalities in some patients at high doses decrease more rapidly. Post-treatment biopsy samples from four participants contained varying degrees of inflammation (figures 11 to 12) and mixed lymphocyte infiltration; the extent found in a given participant did not correlate well with evidence of muscle injury in clinical evaluations or laboratory tests (e.g., some patients with elevated creatine phosphokinase did not show lymphocyte infiltration while some patients with lymphocyte infiltration did not show elevated creatine phosphokinase at biopsy) (fig. 5A).
Survival and safety
The kaplan-mel survival analysis of the first stage of the trial is shown in fig. 13. At this stage, there were no deaths in the low dose group, three deaths in the high dose group, and three deaths in the control group (supposedly shock associated with purpura secondary to liver hemorrhage, aspiration pneumonia with acute respiratory failure, and chronic bronchopneumonia with acute onset with evidence of cardiac dysfunction due to chronic pulmonary disease). Of the three participants who received high doses and died, suspected potential causes of death were severe cholestatic liver injury with decompensated liver disease. The direct death reported by researchers was due to: (1) sepsis (participant 06); (2) Liver disease, severe immune dysfunction and pseudomonas sepsis (participant 09); and (3) circulatory failure due to gastrointestinal bleeding (participant 12). All three participants had persistent cholestatic hepatobiliary SAE with decompensated liver disease at death. At the time of administration, the ages of the three participants were 4.8 years (17.3 kg), 5.6 years (15.8 kg) and 6.1 years (25.8 kg), respectively. Beginning 3-4 weeks after treatment, all three showed significant increases in direct and total bilirubin values (eventually reaching peaks 28-92 times ULN and 34-54 times ULN, respectively), followed by increases in ALT, AST and GGT values (reaching peaks 7-22 times ULN, 7-23 times ULN and 4-11 times ULN, respectively). All three then experienced progression to severe decompensated liver disease characterized by ascites, extensive liver fibrosis and poor liver synthesis. Three participants had evidence of pre-existing (e.g., pre-treatment) cholestasis at the time of group entry, but met the test eligibility criteria, i.e., there was no clinically significant liver disease, such as by >As defined by imaging evidence of 5x ULN ALT or AST or liver purpura. At the setting of high total dose AAV8, these three fatal events are thought to be clinically associated with severe, cholestatic, decompensated liver disease; these participants were the heaviest participants and therefore received the highest total dose of birnesyl (4.8x10 15 -7.7×10 15 Total vg, no SAE-like was observed in the low-dose group or in the high-dose group in the lighter-weight participants, although more than half of ASPIRO participants had pre-existing hepatobiliary disease (including intermittent transaminasesElevated, hyperbilirubinemia, and/or past cholestasis or jaundice). Although a 9.4kg participant in the high dose group reported cholestatic hepatitis approximately one year after dosing, the event was not complicated by progression to fibrotic, decompensated liver disease. Participants who did not receive low doses experienced hepatobiliary SAE, although four of the six participants had evidence of pre-existing hepatobiliary disease, three of which had a history prior to administration consistent with bile stasis and/or documented laboratory hyperbilirubinemia. In the high dose group, in addition to three deceased participants, three other participants also experienced hepatobiliary SAE, including cholestasis, hepatitis and transaminase elevation. Participant 01, dosed at 6.8 years old, had a body weight of about 21kg and had a peak direct and total bilirubin values of 10x ULN and 32x ULN during the 10-17 week period after receiving birthwort, after which the bilirubin values decreased and SAE resolved without liver sequelae. Participants 39 and 38 received high doses at the age of 0.6 and 1.5 years, respectively, and showed abrupt increases in ALT values (19 x and 20x ULN) and AST values (23 x and 6x ULN) at 1 week and 23 weeks after treatment, with normal bilirubin values followed by regression. Subsequently, after only one year of treatment, participants 38 had seen a similar degree of repeated elevation of ALT and AST, as well as direct and total bilirubin elevation. Diagnostic liver biopsies are consistent with intrahepatic cholestasis and elevated serum bile acid levels. In the last report, ALT and total bilirubin levels have been normalized, while AST and direct bilirubin have tended to be normal, but have been slightly elevated. Among all study participants with liver-related SAE, serological, cytological, complement, cytokine, routine laboratory and histopathological evaluations did not indicate that SAE is immune response driven, although there is insufficient data to draw clear conclusions.
In the subsequent phase of the trial, 24 participants received biriranyl: seven low doses and 17 high doses. One of the low dose groups died (participant 40), three of the high dose groups died (as described above), and three of the control groups died. As with the three high dose deaths, participant 40 showed evidence of cholestasis prior to dosing and increased liver function testing within 1-4 weeks after dosing. Participants experienced progression to severe decompensated liver disease characterized by ascites, extensive liver fibrosis and poor liver synthesis. Direct causes of death are reported as sepsis. Histopathological evaluation at necropsy of all four patients, as well as biopsies performed before the birth of subject 12, were consistent with severe and rapidly progressive cholestatic liver failure, including giant cells and intracellular and intratubular bile aggregation, and there were indications that the expression of the key bile transporter BSEP in the liver of these patients was reduced at least for the first few months after treatment. Liver biopsies taken on participant 12 prior to the 85 th day of post-dosing fatal severe adverse events showed hepatocyte degeneration and giant cell formation, intracellular and extracellular bile aggregation, biliary proliferation and minimal inflammation consistent with the response to hepatocyte injury (fig. 14). Liver biopsies of participant 06 obtained from post mortem samples showed hepatocyte degeneration, necrosis, giant cell formation, intracellular and extracellular bile aggregation, biliary proliferation and severe fibrosis (fig. 15). A summary of the four deceased participants is shown in table 9. Of the seven participants in the low dose group, one participant did not report liver laboratory abnormalities as adverse events or severe adverse events, six reported liver-related adverse events, one participant reported non-fatal liver-related severe adverse events, and one participant had fatal liver-gall severe adverse events. Of the 17 participants in the high dose group, four participants did not report liver laboratory abnormalities as adverse events or severe adverse events, 13 participants reported liver-related adverse events, four participants reported non-fatal liver-related severe adverse events, and three participants had fatal liver-gall severe adverse events. The number of liver-related adverse events for all 24 treated participants is summarized in table 10.
Among all the treated participants, the most common adverse events reported were respiratory tract infections, increased creatine phosphokinase and fever. Two high dose participants, one low dose participant and no control were elevated in troponin I. One participant (patient 23 and patient 05) of each dose group had the expected null MTM1 mutation that was not expected to produce myotubulin, but none of them showed the highest anti-myotubulin antibody titres observed in the study, was considered to have a possible myocarditis case, and the investigator chose to treat both participants with pulsed methyl pra Lai Su and sirolimus (sirolimus) with the additional administration of mycophenolate mofetil (mycophenolate mofetil) and intravenous immunoglobulin to one participant. It is reported that myocarditis has resolved (within about 4 months and 10 months each) in two participants, and that continuous echocardiography continues to show normal myocardial function, but one participant continues to take sirolimus after resolution. Six patients receiving high doses (five mild intensities, one moderate intensity) reported adverse events that occurred within two weeks prior to dosing and were considered to be at least likely to be treatment-related transient, asymptomatic thrombocytopenia. Among five patients, regression was reported without treatment, while the sixth patient received a single dose of methylprednisolone Lai Su, followed by regression. Flow cytometry analysis of samples taken during the first month of dosing showed non-specific binding to glycoproteins (GpIIb/IIIa, gpIb/IX, gpIV, HLA class I, gpIa/IIa) in different platelet populations.
SAE reported by 1 participant is summarized in Table 11 below. In the low dose group, 19 SAE were reported among four participants. Four of these events occurred in participant 05, were considered likely to be associated with treatment, and were considered to be associated with suspected clinical myocarditis. In the high dose group, 45 cases of SAE appeared in 12 participants. Of these, 29 out of nine participants were considered likely to be relevant to treatment. In the control group, 41 SAE were observed among 13 participants, including many respiratory infections and diseases not observed among the treated participants (table 11 below).
Detectable anti-AAV 8 neutralizing antibodies were present in all treated participants. After dosing, responses to myotubulin peptide pool stimulation in the IFNg-ELISpot assay were recorded in five participants (01, 02, 05, 08, and 23), all of whom had predicted LOF or IFED mutations (fig. 13A). Four participants had only a negative assay response after dosing, and 14 participants had no assessable post-dosing data. Two reactive participants (23 and 05) reported SAE for myocarditis and both underwent immunosuppressive treatment, including using T cell modulation therapy under the assumption of an anti-transgenic cytotoxic T cell response. Among the remaining three participants who recorded responsiveness, the signal appeared to be transient and resolved without treatment. Of the 23 treated participants 19 appeared to have detectable anti-MTM 1 antibodies after treatment (fig. 10A to 10B and 13B), and the presence of antibodies was not correlated with differences found in clinical outcome or muscle biopsies.
TABLE 7 demographic and clinical characteristics at baseline
Na=inapplicable.
* The age of the untreated control group was the age of the incoptus informed consent.
See genotype data and potential mutation effects of Table 6
The score ranges from 0 to 64, with higher scores indicating better function.
Including bi-level positive airway pressure or continuous positive airway pressure.
TABLE 8 implementation of a Birella base post-movement milestone
Ne=unestimable.
* The milestone achieved is based on a Bayley-III assessment (Bayley item 26: unsupported sitting: 30 seconds; bayley item 35: standing on its own; bayley item 40: free standing; bayley item 42: free-standing).
If the milestones in Bayley-III are not achieved, MFM-32 (item 9: sitting on the floor; item 11: standing from sitting; item 25: standing) and/or CHOP INTEND (item 12: head control).
1x10 14 Relative risk of vg/kg control
3x10 14 Relative risk of vg/kg control
# 1x10 14 One patient in vg/kg dose group and 3x10 14 One patient in the vg/kg dose group may be sitting unsupported at baseline.
TABLE 9 liver function parameter increase and liver disease sign after administration of deceased participants
ALT = alanine aminotransferase
Ast=aspartate aminotransferase
GGT = gamma-glutamyl transferase
Lft=liver function test parameter
SAE = severe adverse event
ULN = upper normal limit
TABLE 10 number of liver related adverse events in treated subjects
AE = adverse event
SAE = severe adverse event
Serious adverse events due to treatment occurred in 1 or more participants
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* Platelet count<150x10 9 /L
The 3 cholestatic patients in the high dose group were 3 patients who died.
Discussion of the invention
We report here significant improvements in ventilation status, motor function and major motor milestones in the clinical trial of xltm gene therapy versus rella-ji. This represents the first effective treatment of this disease and an important milestone for successful systemic gene therapy for congenital myopathies.
From existing natural history data, xltm patients receiving long-term ventilation are highly unlikely to fall out of the ventilator. In a prospective study of 33 ventilated xltm individuals for one year, no patient was able to achieve ventilator independence or significantly reduced ventilator usage time. Thus, ventilator independence by some of the treated participants represents an extremely rare condition in the natural course of the disease. These improvements occur in children from 10 months to 6.8 years of age, indicating that ventilator independence is obtained even in chronic and invasive ventilated years of patients. Since respiratory complications are a major cause of mortality in xltm children, ventilator independence may improve survival and overall quality of life by reducing the risk of aspiration pneumonia and hospitalization, as well as reliance on caregivers.
Although respiratory parameters of the treated participants were greatly improved, untreated patients were not spontaneously improved, which was also observed in natural history studies. We caution not to compare changes in ventilator support between low and high dose participants because the former has a longer follow-up time and the latter has gradually been out of ventilation using a more conservative algorithm (manuscript in preparation). Likewise, MIPs of low dose participants improved significantly faster than those of high dose participants. It is important to note that once the patient has achieved ventilator independence and reached 80cmH in two separate assessments 2 MIP of O, the MIP test is stopped to minimize the test burden, which is laborious and painful for children, households and researchers. The MIP measurements were smaller in the low dose group because all six low dose participants achieved ventilator independence (one participant restored non-invasive ventilation due to potential scoliosis). The CHOP score of treated participants increased rapidly relative to baseline, with some participants reaching the upper scale limit (64 points), while in natural history studies, there was little or no improvement in these scores for untreated control participants or patients. Powerful therapeutic effects were also observed in older participants with xltm, who had longer disease course and accumulated more xltm-related medical complications. These children have achieved and subsequently maintained critical motor milestones, which were unprecedented in xltm patients with this extensive disease burden, including one of five and seventeen high-dose participants in six low-dose participants walking independently in the last assessment (one using braces).
The improvement in muscle pathology for the treated participants paralleled their clinical improvement. It should be noted that despite the observed clinical improvement, the increase in the proportion of myofibers with the kernel (which is a defined pathological feature of xltm) is not altered by the treatment. Further research is needed to determine if a change in nuclear internalization is likely to occur after the window of post-treatment biopsy samples are collected. Furthermore, although exogenous MTM1 expression varies greatly, the treated participants showed clinically significant improvements, including ventilator independent and independent walking. We speculate that as an enzymatic phosphatase, relatively low levels of transgene expression in muscle fibers may be sufficient to achieve significant histopathological and influential functional improvement.
Death of three participants after high dose birthwort administration and one participant after low dose birthwort caused one to recheck for hepatobiliary disease in the natural history of xltm and considered the potential interaction of AAV-mediated therapy in this case. The total direct bilirubin level of all four participants increased significantly above baseline 3-4 weeks after treatment, progressing to severe decompensated liver dysfunction characterized by ascites, extensive liver fibrosis and reduced liver synthesis function, which is thought to lead to fatal events. Three high dose deceased participants who experienced hepatobiliary SAE characterized by significant hyperbilirubinemia had different mutation types (table 6), but shared significant clinical features: as older (and thus heavier) participants, they received the highest total vector genome dose (4.8x10 15 -7.7×10 15 vg) and has clinical evidence that may be consistent with cholestasis prior to administration of bimesol, including intermittent hyperbilirubinemia, cholestatic hepatitis, and ultrasound-displayed echo enhancement of the liver. Half of the higher body weight in the high dose participants (all received>4.5×10 15 vg), three participants without evidence of past cholestasis did not experience hepatobiliary SAE. At the receiving end<4.5×10 15 Of the eight lighter weight participants of vg, three had a past history consistent with cholestasis, and only one (participant 38) had a hepatobiliary SAE. His symptomatic onset was delayed (reference time to brimani administration) compared to the participants with fatal liver outcome, and two liver biopsies were free of fibrotic lesionsInjury, and does not progress to decompensated disease. Thus, the change in this situation may be more reflective of the underlying XLM pathology. In the low dose group (maximum dose 8.1X10) 14 vg), one of the seven participants reported post-treatment hepatobiliary SAE.
When ASPIRO studies began, the primary liver disease associated with xltm was known to be liver purpura, a rare, well-described, life-threatening vascular condition characterized by the presence of multiple randomly distributed blood-filled voids throughout the liver. In addition, non-specific cholestasis tendencies have also been described in a few xltm patients, mainly reported as jaundice, cholelithiasis and pruritus, but their nature, extent and pathophysiology are not well characterized and, unlike purpura, are not known to be associated with morbidity or mortality in this population. In INCEPTUS, 24% of the participants had a history of hepatobiliary disease at the time of group entry, and total bilirubin was elevated at least once for 12 participants (35%) during the study, with levels >5 XULN for both cases. Furthermore, the recently recorded clinical, laboratory and histopathological results of five untreated xltm patients are associated with intrahepatic cholestasis, which is often characterized by recurrent episodes, including the subsequent risk of decompensated liver failure, further illustrating that cholestasis is an important part of the natural history of xltm. Despite the frequency of liver laboratory abnormalities, xltm patients do not routinely undergo diagnostic liver biopsies due to the low frequency of symptomatic disease and the risk of life threatening bleeding.
Before death of three high-dose participants, it was decided to continue the high dose (3×10) during the confirmation phase of ASPIRO 14 vg/kg). This decision was based on no significant differences in respiratory and neuromuscular results between the two dose groups, no dose-limiting toxicity at either dose level, and 24-week muscle biopsy evaluation indicated more rapid histopathological improvement, dose-dependent transduction, transcription and protein expression at high doses. After death of three high-dose participants, the remaining participants of ASPIRO were receiving low doses (1 x 10 14 vg/kg) and will receive increased liver monitoring and be known to be beneficial for chronic or recurrent cholestasis caused by other causesProphylactic or reactive therapy of children.
Overall, the percentage of participants with SAE in the treated and control groups were similar. Three control participants died from similar causes as observed in the natural history of the disease. Given that control participants are on average younger than the treated participants, they may suffer from a more severe disease (i.e., increased health may be associated with living to a greater age). However, the treated and control participants share a similar degree of baseline ventilator dependence. Most adverse events in the treated participants, except for the deaths associated with liver and gall disease, were consistent with those reported by patients receiving other AAV-based gene therapy products, including transient thrombocytopenia and elevated troponin. Given the flow cytometry results, the rapid kinetics of thrombocytopenia regression, and the large platelets in blood smears, the compensation may be biphasic, first from the spleen pool, and then through the bone marrow to produce platelets.
For this first human clinical trial of pediatric disease with extremely high mortality, an open label trial design with delayed treatment control is considered appropriate because double-blind, placebo-controlled trials require pseudomuscle biopsies, double-simulated drug administration, use of placebo with a praise Lai Su for up to 16 weeks and a dense visit schedule, often requiring extensive trips. Most participants were relatively young and relied on invasive ventilation, reflecting the vast unmet medical need in xltm. Clinical studies in older xltm patients are needed to assess the potential impact of bimatose on potential reversibility, particularly in terms of muscle stiffness/joint contracture and diaphragmatic and respiratory progression in this population. The mechanism of action of birnesyl is not expected to be age-dependent and xltm is typically not characterized by progressive loss of muscle mass due to fibrous fat substitution. Two of the biggest aged participants were nearly 7 years of dosing: one (6.1 years of administration) died from the liver and gall SAE and one (6.8 years of administration and 24 hours of invasive ventilation per day) achieved a 30 second unassisted sitting and ventilator independence. With administration of 1X 10 14 vg/kg related risk, benefitThe equilibrium is worth further investigation. Nevertheless, the data of ASPIRO trials to date support clinical efficacy, safety and histopathological improvements of the bimeso-therapy and underscores the potential of this therapy to provide a revolutionary clinical improvement for this rare, severe and fatal pediatric neuromuscular disease.
Conclusion(s)
In xltm patients, a rapid increase in muscle strength and acquisition of motor development milestones was observed following bimatose treatment compared to untreated controls. In particular, motor function is significantly improved, including the ability of some patients to obtain unassisted walking. Furthermore, we have observed that there is a significant reduction in ventilator dependence over Rarenyl, resulting in ventilator independence in some patients. Taken together, these results demonstrate that a boy <5 years old with xlm administered a single dose of birnesyl can improve muscle strength and achieve exercise milestones and respiratory function.
Example 4 treatment of X-linked myotubular myopathy in human patients by administration of a pseudoAAV 2/8 vector comprising a nucleic acid sequence encoding a myotubulin 1 gene operably linked to a desmin promoter and an anti-cholestasis agent
Using the compositions and methods of the present disclosure, a pseudotyped AAV2/8 vector (e.g., birthwort) comprising a nucleic acid sequence encoding a myotubulin 1 (MTM 1) gene operably linked to a desmin promoter may be administered to a patient suffering from xltm (e.g., five years old or less), e.g., at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less); and an anti-cholestasis agent (e.g., xiong Erchun), e.g., at one or more doses of about 5 mg/kg/dose to about 20 mg/kg/dose and by comprising 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
After administration of a viral vector comprising a transgene encoding MTM1 (e.g., birnesyl) to a patient, the patient exhibits a change in the number of hours of mechanical ventilatory support over time from baseline. For example, the number of hours that a patient exhibits mechanical ventilatory support varies over time from baseline about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to the patient. After administration of a viral vector (e.g., birimyl) comprising a transgene encoding MTM1 to a patient, the patient exhibits bilirubin levels greater than 1mg/dL (e.g., 2mg/dL, 3mg/dL, 4mg/dL, or 5 mg/dL) in a bilirubin test performed about 3 weeks after administration of the viral vector to the patient.
Example 5 treatment of X-linked myotubulomyopathy in human patients by administration of Bireosyl and an anti-cholestasis agent
Using the compositions and methods of the present disclosure, a patient suffering from xltm (e.g., five years old or less) may be administered birnesyl. For example, at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less); and anti-cholestasis agents (e.g., xiong Erchun). For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
After administration of the birnesyl to the patient, the patient achieves a functionally independent sitting for at least 30 seconds. For example, the patient achieves functional independent sitting about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of birnesyl to the patient.
Example 6 treatment of X-linked myotubular myopathy in human patients by administration of a pseudoAAV 2/8 vector comprising a nucleic acid sequence encoding a myotubulin 1 gene operably linked to a desmin promoter and bear diol
Using the compositions and methods of the present disclosure, a pseudotyped AAV2/8 vector (e.g., birthwort) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter can be administered to a patient suffering from xltm (e.g., five years old or less). For example, at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less); bear diol. For example, at 5 mg/kg/dose to about 20 mg/kg/dose of one or moreIndividual doses and by containing 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
Upon administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to a patient, the patient exhibits a reduction in the required mechanical ventilator support to about 16 hours per day or less. For example, the patient exhibits a desired ventilator support reduction about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to the patient.
EXAMPLE 7 treatment of X-linked myotubulomyopathy in human patients by administration of Billenyl and bear diol
Using the compositions and methods of the present disclosure, a patient suffering from xltm (e.g., five years old or less) may be administered birnesyl. For example, at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less); bear diol. For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
After administration of birnesyl to a patient, the patient exhibits a change in CHOP interval from baseline. For example, the patient exhibits a change in CHOP period from baseline about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of the bimesol to the patient.
Example 8 treatment of cholestasis or hyperbilirubinemia in a human patient suffering from X-linked myotubular myopathy by administration of a pseudoAAV 2/8 vector comprising a nucleic acid sequence encoding a myotubulin 1 gene operably linked to a desmin promoter
Using the compositions and methods of the present disclosure, a pseudotyped AAV2/8 vector (e.g., birthwort) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter may be administered to a patient (e.g., five years old or less) having xltm who has previously been administered an anti-cholestasis agent. For example, at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less); bear diol. For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
Upon administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to a patient, the patient exhibits a reduction in the required mechanical ventilator support to about 16 hours per day or less. For example, the patient exhibits a desired ventilator support reduction about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to the patient.
Example 9 treatment of X-linked myotubular myopathy in human patients by administration of a pseudoAAV 2/8 vector comprising a nucleic acid sequence encoding a myotubulin 1 gene operably linked to a desmin promoter
Using the compositions and methods of the present disclosure, a pseudoaav 2/8 vector (e.g., birimyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter may be administered to a patient suffering from xltm to less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 Amount of vg/kg or less). Thereafter, the patient's development of cholestasis and/or hyperbilirubinemia may be monitored, and if the patient is determined to exhibit cholestasis or hyperbilirubinemia or one or more symptoms thereof, an anti-cholestasis agent (e.g., xiong Erchun) is administered to the patient. For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
Upon administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to a patient, the patient exhibits a change in maximum inspiratory pressure from baseline. For example, the patient exhibits a change in maximum inspiratory pressure from baseline about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to the patient.
Example 10 treatment of X-linked myotubulomyopathy in human patients by administration of Birerun base
Using the compositions and methods of the present disclosure, a patient suffering from xltm can be administered birefresh to less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 Amount of vg/kg or less). Thereafter, the patient's development of cholestasis and/or hyperbilirubinemia may be monitored, and if the patient is determined to exhibit cholestasis or hyperbilirubinemia or one or more symptoms thereof, an anti-cholestasis agent (e.g., xiong Erchun) is administered to the patient. For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
After administration of birnesyl to a patient, the patient exhibits a change in maximum inspiratory pressure from baseline. For example, the patient exhibits a change in maximum inspiratory pressure from baseline about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of the bivalve to the patient.
Example 11 treatment of X-linked myotubular myopathy in human patients five years or less by administration of a pseudoAAV 2/8 vector comprising a nucleic acid sequence encoding a myotubulin 1 gene operably linked to a desmin promoter
Using the compositions and methods of the present disclosure, a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter may be administered to a patient having xltm less than about five years old. For example, at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less). Thereafter, the patient's progression of cholestasis may be monitored, and if the patient is determined to exhibit cholestasis or one or more symptoms thereof, an anti-cholestasis agent (e.g., xiong Erchun) is administered to the patient. For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
Upon administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to a patient, the patient exhibits a change from baseline in a quantitative analysis of myotubulin expression in a muscle biopsy. For example, the patient exhibits a change from baseline in quantitative analysis of myotubulin expression in a muscle biopsy about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to the patient. After administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to a patient, the patient exhibits a reduction in stiffness and/or joint contracture about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to the patient.
Example 12 treatment of X-linked myotubular myopathy in five year old or less human patients by administration of Birella
Using the compositions and methods of the present disclosure, patients less than about five years old with XLMTM may be administered birefresh. For example, at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less). Thereafter, the patient's progression of cholestasis may be monitored, and if the patient is determined to exhibit cholestasis or one or more symptoms thereof, an anti-cholestasis agent (e.g., xiong Erchun) is administered to the patient. For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
After administration of birnesyl to a patient, the patient exhibits a change from baseline in the quantitative analysis of myotubulin expression in muscle biopsies. For example, the patient exhibits a change from baseline in a quantitative analysis of myotubulin expression in a muscle biopsy about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of bimesosyl to the patient. For example, the quantitative analysis of myotubulin expression in a muscle biopsy persists for at least 48 weeks from baseline after administration of the viral vector to the patient. After administration of the birthwort to the patient, the patient exhibits diaphragmatic and/or respiratory muscle progression about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of the birthwort to the patient.
Example 13 treatment of X-linked myotubular myopathy in human patients by administration of a pseudoAAV 2/8 vector comprising a nucleic acid sequence encoding a myotubulin 1 gene operably linked to a desmin promoter and an anti-cholestasis agent
Using the compositions and methods of the present disclosure, a pseudoaav 2/8 vector (e.g., birimyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter may be administered to a patient suffering from xltm to less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 Amount of vg/kg or less). Thereafter, the patient is determined to exhibit cholestasis or hyperbilirubinemia or one or more symptoms thereof, and the patient is presented withAn anti-cholestasis agent (e.g., xiong Erchun) is administered. For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
Upon administration of a pseudotyped AAV2/8 vector comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to a patient, the patient exhibits a change in maximum inspiratory pressure from baseline. For example, the patient exhibits a change in maximum inspiratory pressure from baseline about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to the patient.
Example 14 treatment of X-linked myotubulomyopathy in human patients by administration of Bireosyl and an anti-cholestasis agent
Using the compositions and methods of the present disclosure, a patient suffering from xltm can be administered birefresh to less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 Amount of vg/kg or less). Thereafter, the patient is determined to exhibit cholestasis or hyperbilirubinemia or one or more symptoms thereof, and an anti-cholestasis agent (e.g., xiong Erchun) is administered to the patient. For example, in one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or5 mg/kg/day to about 40 mg/kg/day.
After administration of birnesyl to a patient, the patient exhibits a change in maximum inspiratory pressure from baseline. For example, the patient exhibits a change in maximum inspiratory pressure from baseline about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of the bivalve to the patient.
Example 15 treatment of X-linked myotubular myopathy in human patients five years old or less by administration of a pseudoAAV 2/8 vector comprising a nucleic acid sequence encoding a myotubulin 1 gene operably linked to a desmin promoter and an anti-cholestasis agent
Using the compositions and methods of the present disclosure, a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter may be administered to a patient having xltm less than about five years old. For example, at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less). Thereafter, the patient is determined to exhibit cholestasis or hyperbilirubinemia or one or more symptoms thereof, and an anti-cholestasis agent (e.g., xiong Erchun) is administered to the patient. For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
Upon administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to a patient, the patient exhibits a change from baseline in a quantitative analysis of myotubulin expression in a muscle biopsy. For example, the patient exhibits a change from baseline in quantitative analysis of myotubulin expression in a muscle biopsy about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to the patient. For example, the quantitative analysis of myotubulin expression in a muscle biopsy persists for at least 48 weeks from baseline after administration of the viral vector to the patient.
Example 16 treatment of X-linked myotubulomyopathy in five year old or less human patients by administration of Birerun base and an anti-cholestasis agent
Using the compositions and methods of the present disclosure, patients less than about five years old with XLMTM may be administered birefresh. For example, at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less). Thereafter, the patient is determined to exhibit cholestasis or hyperbilirubinemia or one or more symptoms thereof, and an anti-cholestasis agent (e.g., xiong Erchun) is administered to the patient. For example, in one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by comprising unit dosage forms of 250mg or 500mg and/or 5mg +.kg/day to about 40 mg/kg/day.
After administration of birnesyl to a patient, the patient exhibits a change from baseline in the quantitative analysis of myotubulin expression in muscle biopsies. For example, the patient exhibits a change from baseline in a quantitative analysis of myotubulin expression in a muscle biopsy about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of bimesosyl to the patient. For example, the quantitative analysis of myotubulin expression in a muscle biopsy persists for at least 48 weeks from baseline after administration of the viral vector to the patient.
EXAMPLE 17 treatment or prevention of cholestasis or hyperbilirubinemia in human patients suffering from X-linked myotubulomyopathy by administration of an anti-cholestasis agent
Using the compositions and methods of the present disclosure, the compositions and methods can be used to advance at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less) a patient with xltm administered an anti-cholestatic agent (e.g., xiong Erchun) comprising a pseudotyped AAV2/8 vector (e.g., birnesyl) operably linked to a nucleic acid sequence encoding the MTM1 gene of the desmin promoter. For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
After administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to a patient, the patient exhibits a change in the number of hours of mechanical ventilatory support over time relative to baseline. For example, the number of hours that a patient exhibits mechanical ventilatory support varies over time from baseline about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to the patient.
Example 18 treatment or prevention of cholestasis or hyperbilirubinemia in a human patient suffering from X-linked myotubulomyopathy by administration of an anti-cholestasis agent
Using the compositions and methods of the present disclosure, the compositions and methods can be used to advance at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less) of a patient with xltm administered a cholestasis agent (e.g., xiong Erchun) than is administered with galenical. For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
After administering to a patient a pseudotyped AAV2/8 vector (e.g., birimyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter, the patient achieves functional independence for at least 30 seconds. For example, the patient achieves functional independent seating about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to the patient.
Example 19 treatment or prevention of cholestasis or hyperbilirubinemia in a human patient suffering from X-linked myotubular myopathy by administration of bear diol
Using the compositions and methods of the present disclosure, the compositions and methods can be used to advance at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less) is administered Xiong Erchun to a patient suffering from xltm comprising a pseudotyped AAV2/8 vector (e.g., birnesyl) operably linked to a nucleic acid sequence encoding the MTM1 gene of the desmin promoter. For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
Upon administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to a patient, the patient exhibits a reduction in the required mechanical ventilator support to about 16 hours per day or less. For example, the patient exhibits a desired ventilator support reduction about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to the patient.
Example 20 treatment or prevention of cholestasis or hyperbilirubinemia in a human patient suffering from X-linked myotubular myopathy by administration of bear diol
Using the compositions and methods of the present disclosure, the compositions and methods can be used to advance at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less) of a patient suffering from xltm who is administered pranluki Xiong Erchun. For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
Example 21 treatment or prevention of cholestasis or hyperbilirubinemia in a five year old or less human patient suffering from X-linked myotubulomyopathy by administration of an anti-cholestasis agent
Using the compositions and methods of the present disclosure, a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter was previously administered to patients five years old or less suffering from xltm. For example, at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less), an anti-cholestasis agent (e.g., xiong Erchun) is administered to the patient. For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
After administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to a patient, the patient exhibits a change in the number of hours of mechanical ventilatory support over time relative to baseline. For example, the number of hours that a patient exhibits mechanical ventilatory support varies over time from baseline about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to the patient.
Example 22 treatment or prevention of cholestasis or hyperbilirubinemia in a person five years old or less and suffering from X-linked myotubulomyopathy by administration of an anti-cholestasis agent
Using the compositions and methods of the present disclosure, patients five years old or less suffering from XLMTM were previously administered birefresh. For example, at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less), an anti-cholestasis agent (e.g., xiong Erchun) is administered to the patient. For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
After administering to a patient a pseudotyped AAV2/8 vector (e.g., birimyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter, the patient achieves functional independence for at least 30 seconds. For example, the patient achieves functional independent seating about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to the patient.
Example 23 treatment or prevention of cholestasis or hyperbilirubinemia in a five year old or less human patient suffering from X-linked myotubulomyopathy by administration of bear diol
Using the compositions and methods of the present disclosure, a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter was previously administered to patients five years old or less suffering from xltm. For example, at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less), and Xiong Erchun to the patient. For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
Upon administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to a patient, the patient exhibits a reduction in the required mechanical ventilator support to about 16 hours per day or less. For example, the patient exhibits a desired ventilator support reduction about 24 weeks (e.g., about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks) after administration of a pseudotyped AAV2/8 vector (e.g., birnesyl) comprising a nucleic acid sequence encoding an MTM1 gene operably linked to a desmin promoter to the patient.
Example 24 treatment or prevention of cholestasis or hyperbilirubinemia in a five year old or less human patient suffering from X-linked myotubulomyopathy by administration of bear diol
Using the compositions and methods of the present disclosure, patients five years old or less suffering from XLMTM were previously administered birefresh. For example, at less than about 3x 10 14 A dose of vg/kg (e.g., at less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less), and Xiong Erchun to the patient. For example, at one or more doses of 5 mg/kg/dose to about 20 mg/kg/dose and by including 250mg or 500mg of unit dosage form and/or 5 mg/kg/day to about 40 mg/kg/day.
Other embodiments
In addition to the portions outlined above, the compositions and methods of the present disclosure are also included in the embodiments listed below:
[1] a method of treating an xltm in a human patient in need thereof, the method comprising administering to the patient (i) a therapeutically effective amount of a transgene encoding MTM1 and (ii) an anti-cholestasis agent, wherein the anti-cholestasis agent is administered to the patient at a dose of one or more (e.g., one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) starting within about six weeks (e.g., about six weeks prior to administration or about six weeks after administration) of the transgene to the patient.
[2] A method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm, the method comprising administering to the patient (i) a therapeutically effective amount of a transgene encoding MTM1 and (ii) an anti-cholestasis agent, wherein the anti-cholestasis agent is administered to the patient at one or more doses beginning within about six weeks of administration of a viral vector to the patient.
[3] A method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm, the method comprising administering to the patient (i) a therapeutically effective amount of a transgene encoding MTM1 and (ii) an anti-cholestasis agent, wherein the anti-cholestasis agent is administered to the patient at one or more doses beginning within about six weeks of administration of a viral vector to the patient.
[4] The method of any one of embodiments 1 to 3, wherein the transgene encoding MTM1 is administered to the patient by transduction with a viral vector comprising a transgene encoding MTM 1.
[5] The method of any one of embodiments 1-4, wherein the anti-cholestasis agent is administered to the patient at a dose of one or more (e.g., one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) starting within about five weeks of administration of the transgene or viral vector to the patient (e.g., about five weeks prior to administration or about five weeks after administration).
[6] The method of embodiment 5, wherein the anti-cholestasis agent is administered to the patient in one or more (e.g., one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) doses beginning within about four weeks of administration of the transgenic or viral vector to the patient (e.g., about four weeks before administration or about four weeks after administration).
[7] The method of embodiment 5, wherein the anti-cholestasis agent is administered to the patient in one or more (e.g., one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) doses beginning within about three weeks of administration of the transgene or viral vector to the patient (e.g., about three weeks prior to administration or about three weeks after administration).
[8] The method of embodiment 5, wherein the anti-cholestasis agent is administered to the patient in one or more (e.g., one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) doses beginning within about two weeks of administration of the transgene or viral vector to the patient (e.g., about two weeks prior to administration or about two weeks after administration).
[9] The method of embodiment 5, wherein the anti-cholestasis agent is administered to the patient in one or more (e.g., one or more, two or more, three or more, four or more, five or more, seven or more, eight or more, nine or more, or ten or more) doses beginning within about one week (e.g., about one week before administration or about one week after administration, about six days before administration or about six days after administration, about five days before administration or about four days after administration, about three days before administration or about three days after administration, about two days before administration or about two days after administration or about one day before administration or about one day after administration) of the transgenic or viral vector to the patient.
[10] The method of embodiment 5, wherein the anti-cholestasis agent is administered to the patient at one or more (e.g., one or more, two or more, three or more, four or more, five or more, eight or more, or seven or more) doses beginning on the same day (e.g., 24 th, 23 th, 22 th, 21 th, 20 th, 19 th, 18 th, 17 th, 16 th, 15 th, 14 th, 13 th, 12 th, 11 th, 10 th, 9 th, 8 th, 7 th, 6 th, 5 th, 4 th, 3 rd, 2 nd, 1 th, 60 th, 59 th, 58 th, 57 th, 56 th, 55 th, 50 th, 40 th, 30 th, 20 th, 10 th, or the same minute) as the transgenic or viral vector is administered to the patient.
[11] A method of treating xltm in a human patient in need thereof and who has previously been administered an anti-cholestasis agent, the method comprising administering to the patient a therapeutically effective amount of a transgene encoding MTM 1.
[12] A method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm and previously administered an anti-cholestasis agent, the method comprising administering to the patient a therapeutically effective amount of a transgene encoding MTM 1.
[13] A method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm and previously administered an anti-cholestasis agent, the method comprising administering to the patient a therapeutically effective amount of a transgene encoding MTM 1.
[14] The method of any one of embodiments 11 to 13, wherein the transgene encoding MTM1 is administered by transduction of the patient with a viral vector comprising a transgene encoding MTM 1.
[15]The method of any one of embodiments 4 to 10 or 14, wherein the viral vector is present at less than about 3x 10 14 An amount of vg/kg (e.g., less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[16]The method of embodiment 15, wherein the viral vector is present at less than about 2.5x10 14 An amount of vg/kg (e.g., less than about 2.5x10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[17]The method of embodiment 16, wherein the viral vector is present at less than about 2x10 14 An amount of vg/kg (e.g., less than about 2x10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[18]The method of embodiment 16, wherein the viral vector is present at less than about 1.5x10 14 An amount of vg/kg (e.g., less than about 1.5x10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[19]The method of embodiment 16, wherein the viral vector is present at less than about 1.4x10 14 An amount of vg/kg (e.g., less than about 1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[20]The method of any one of embodiments 4 to 10 or 14, wherein the viral vector is present at about 3x 10 13 vg/kg to about 2.3X10 14 The amount of vg/kg (e.g., 3X 10 13 vg/kg to about 2.3X10 14 vg/kg、3.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、4x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.1x10 13 vg/kg to about 2.3X10 14 vg/kg、4.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、5x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、6x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、7x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、8x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、9x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.6x 10 13 vg/kg to about 2.3x10 14 vg/kg、9.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、1x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.1x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.2x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.3x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.4x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.5x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.6x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.7x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.8x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.9x 10 14 vg/kg to about 2.3X10 14 vg/kg、2x 10 14 vg/kg to about 2.3X10 14 vg/kg、2.1x 10 14 vg/kg to about 2.3X10 14 vg/kg or 2.2X10 14 vg/kg to about 2.3X10 14 vg/kg) to the patient.
[21]The method of embodiment 20, wherein the viral vector is present at about 8x10 13 vg/kg to about 1.8x10 14 The amount of vg/kg (e.g., 8X10 13 vg/kg to about 1.8x10 14 vg/kg、8.1x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.2x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.3x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.4x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.5x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.6x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.7x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.8x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.9x 10 13 vg/kg to about 1.8x10 14 vg/kg、9x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.1x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.2x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.3x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.4x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.5x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.6x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.7x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.8x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.9x 10 13 vg/kg to about 1.8x10 14 vg/kg、1x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.1x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.2x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.3x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.4x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.5x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.6x 10 14 vg/kg to about 1.8x10 14 vg/kg or 1.7X10 14 vg/kg to about 1.8x10 14 vg/kg) to the patient.
[22]The method of embodiment 20, wherein the viral vector is present at about 1x 10 14 vg/kg to about 1.6X10 14 The amount of vg/kg (e.g., 1X 10 14 vg/kg to about 1.6X10 14 vg/kg、1.1x 10 14 vg/kg to about 1.6X10 14 vg/kg、1.2x 10 14 vg/kg to about 1.6X10 14 vg/kg、1.3x 10 14 vg/kg to about 1.6X10 14 vg/kg、1.4x 10 14 vg/kg to about 1.6X10 14 vg/kg、1.5x 10 14 vg/kg to about 1.6X10 14 vg/kg、1.6x 10 14 vg/kg to about 1.6X10 14 vg/kg or about 1.7X10 14 vg/kg to about 1.6X10 14 vg/kg) to the patient.
[23]The method of embodiment 20, wherein the viral vector is present at 1.1X10 14 vg/kg to about 1.5x10 14 The amount of vg/kg (e.g., 1.1X10) 14 vg/kg to about 1.5x10 14 vg/kg、1.2x 10 14 vg/kg to about 1.5x10 14 vg/kg、1.3x 10 14 vg/kg to about 1.5x10 14 vg/kg or 1.4X10 14 vg/kg to about 1.5x10 14 vg/kg) to the patient.
[24]The method of embodiment 20, wherein the viral vector is present at about 1.2x10 14 vg/kg to about 1.4x10 14 Amount of vg/kg (exampleE.g., 1.2X10 14 vg/kg to about 1.4x10 14 vg/kg or 1.3X10 14 vg/kg to about 1.4x10 14 vg/kg) to the patient.
[25]The method of any one of embodiments 4 to 10 or 14 to 24, wherein the viral vector is present at about 1.3x 10 14 An amount of vg/kg is administered to the patient.
[26] The method of any one of embodiments 1-25, wherein the patient is five years old or less (e.g., 5 years old or less, 4 years old or less, 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[27] The method of embodiment 26, wherein the patient is four years old or less (e.g., 4 years old or less, 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[28] The method of embodiment 27, wherein the patient is three years old or less (e.g., 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[29] The method of embodiment 27, wherein the patient is two years old or less (e.g., 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[30] The method of embodiment 27, wherein the patient is one year old or less (e.g., 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[31] The method of embodiment 27, wherein the patient is six months or less (e.g., 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) at the time of administration of the transgene or viral vector.
[32] The method of any one of embodiments 1-25, wherein the patient is about 1 month to about 5 years old (e.g., about 1 month to about 5 years old, about 2 months to about 5 years old, about 3 months to about 5 years old, about 4 months to about 5 years old, about 5 months to about 5 years old, about 6 months to about 5 years old, about 1 year to about 5 years old, about 2 years to about 5 years old, about 3 years to about 5 years old, or about 4 years to about 5 years old) at the time of administration of the transgenic or viral vector.
[33] The method of any one of embodiments 1 to 32, further comprising monitoring the patient for development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof.
[34] The method of embodiment 33, wherein the progression of cholestasis, hyperbilirubinemia, or one or more symptoms thereof in the patient is monitored by evaluating a parameter of a blood sample obtained from the patient, wherein finding the parameter above a reference level determines the patient as having cholestasis, hyperbilirubinemia, or one or more symptoms thereof.
[35] The method of embodiment 34, wherein the parameter comprises the level of serum bile acid in the blood sample.
[36] The method of embodiment 35, wherein the serum bile acid is cholic acid, chenodeoxycholic acid, deoxycholic acid, or ursodeoxycholic acid.
[37] The method of embodiment 34, wherein the parameter comprises one or more results of a liver function test.
[38] The method of embodiment 37, wherein the parameter comprises the level of aspartate aminotransferase or alanine aminotransferase in the blood sample.
[39] A method of treating xltm in a human patient in need thereof, the method comprising:
(a) Administering to the patient a transgene encoding MTM1,
(b) Monitoring the patient for the development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof,
(c) An anti-cholestasis agent is administered to the patient.
[40] A method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm, the method comprising:
(a) At less than about 3x 10 14 The amount of vg/kg to the patient,
(b) Monitoring the patient for the development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof,
(c) An anti-cholestasis agent is administered to the patient.
[41] A method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm, the method comprising:
a) At less than about 3x 10 14 The amount of vg/kg to the patient,
(b) Monitoring the patient for the development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof,
(c) An anti-cholestasis agent is administered to the patient.
[42] The method of any one of embodiments 39-41, wherein the transgene encoding MTM1 is administered by transduction of the patient with a viral vector comprising a transgene encoding MTM 1.
[43] A method of treating xltm in a human patient in need thereof, the method comprising:
(a) Administering to the patient a transgene encoding MTM1,
(b) Determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and
(c) An anti-cholestasis agent is administered to the patient.
[44] A method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm, the method comprising:
(a) At less than about 3x 10 14 The amount of vg/kg to the patient,
(b) Determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more thereof
Symptoms of
(c) An anti-cholestasis agent is administered to the patient.
[45] A method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm, the method comprising:
(a) At less than about 3x 10 14 The amount of vg/kg to the patient,
(b) Determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and
(c) An anti-cholestasis agent is administered to the patient.
[46] The method of any one of embodiments 42 or 44-45, wherein the transgene encoding MTM1 is administered by transduction of the patient with a viral vector comprising a transgene encoding MTM 1.
[47]The method of embodiment 42 or 46, wherein the viral vector is present at less than about 3x10 14 An amount of vg/kg (e.g., less than about 3x10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[48]The method of embodiment 47, wherein the viral vector is present at less than about 2.5x10 14 An amount of vg/kg (e.g., less than about 2.5x10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[49]The method of embodiment 47, wherein the viral vector is present at less than about 2x10 14 An amount of vg/kg (e.g., less than about 2x10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[50]The method of embodiment 47, wherein the viral vector is present at less than about 1.5x10 14 An amount of vg/kg (e.g., less than about 1.5x10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[51]The method of embodiment 47, wherein the viral vector is present at less than about 1.4x10 14 An amount of vg/kg (e.g., less than about 1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[52]The method of embodiment 42 or 46, wherein the viral vector is present at about 3x10 13 vg/kg to about 2.3X10 14 The amount of vg/kg (e.g., 3X10 13 vg/kg to about 2.3x10 14 vg/kg、3.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、4x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、5x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、6x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、7x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、8x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、9x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、1x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.1x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.2x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.3x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.4x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.5x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.6x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.7x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.8x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.9x 10 14 vg/kg to about 2.3X10 14 vg/kg、2x 10 14 vg/kg to about 2.3X10 14 vg/kg、2.1x 10 14 vg/kg to about 2.3X10 14 vg/kg or 2.2X10 14 vg/kg to about 2.3X10 14 vg/kg) to the patient.
[53]The method of embodiment 52, wherein the viral vector is present at about 8x10 13 vg/kg to about 1.8x10 14 The amount of vg/kg (e.g., 8X10 13 vg/kg to about 1.8x10 14 vg/kg、8.1x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.2x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.3x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.4x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.5x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.6x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.7x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.8x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.9x 10 13 vg/kg to about 1.8x10 14 vg/kg、9x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.1x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.2x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.3x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.4x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.5x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.6x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.7x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.8x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.9x 10 13 vg/kg to about 1.8x10 14 vg/kg、1x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.1x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.2x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.3x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.4x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.5x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.6x 10 14 vg/kg to about 1.8x10 14 vg/kg or 1.7X10 14 vg/kg to about 1.8x10 14 vg/kg) to the patient.
[54]The method of embodiment 52, wherein the viral vector is present at about 1x 10 14 vg/kg to about 1.6X10 14 The amount of vg/kg (e.g., 1X 10 14 vg/kg to about 1.6X10 14 vg/kg、1.1x 10 14 vg/kg to about 1.6X10 14 vg/kg、1.2x 10 14 vg/kg to about 1.6X10 14 vg/kg、1.3x 10 14 vg/kg to about 1.6X10 14 vg/kg、1.4x 10 14 vg/kg to about 1.6X10 14 vg/kg、1.5x 10 14 vg/kg to about 1.6X10 14 vg/kg、1.6x 10 14 vg/kg to about 1.6X10 14 vg/kg or about 1.7X10 14 vg/kg to about 1.6X10 14 vg/kg) to the patient.
[55]The method of embodiment 52, wherein the viral vector is present at 1.1X10 14 vg/kg to about 1.5x10 14 The amount of vg/kg (e.g., 1.1X10) 14 vg/kg to about 1.5x10 14 vg/kg、1.2x 10 14 vg/kg to about 1.5x10 14 vg/kg、1.3x 10 14 vg/kg to about 1.5x10 14 vg/kg or 1.4X10 14 vg/kg to about 1.5x10 14 vg/kg) to the patient.
[56]The method of embodiment 52, wherein the viral vector is present at about 1.2x10 14 vg/kg to about 1.4x10 14 The amount of vg/kg (e.g., 1.2X10 14 vg/kg to about 1.4x10 14 vg/kg or 1.3X10 14 vg/kg to about 1.4x10 14 vg/kg) to the patient.
[57]The method of any one of embodiments 42 or 46 to 56, wherein the viral vector is present at about 1.3x10 14 An amount of vg/kg is administered to the patient.
[58] The method of any one of embodiments 39-57, wherein the patient is five years old or less (e.g., 5 years old or less, 4 years old or less, 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[59] The method of embodiment 58, wherein the patient is four years old or less (e.g., 4 years old or less, 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[60] The method of embodiment 59, wherein the patient is three years old or less (e.g., 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[61] The method of embodiment 59, wherein the patient is two years old or less (e.g., 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[62] The method of embodiment 59, wherein the patient is one year old or less (e.g., 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[63] The method of embodiment 59, wherein the patient is six months or less (e.g., 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) at the time of administration of the transgene or viral vector.
[64] The method of any one of embodiments 39-57, wherein the patient is about 1 month to about 5 years old (e.g., about 1 month to about 5 years old, about 2 months to about 5 years old, about 3 months to about 5 years old, about 4 months to about 5 years old, about 5 months to about 5 years old, about 6 months to about 5 years old, about 1 year to about 5 years old, about 2 years to about 5 years old, about 3 years to about 5 years old, or about 4 years to about 5 years old) at the time of administration of the transgenic or viral vector.
[65] A method of treating an xltm in a human patient in need thereof, the patient being five years old or less (e.g., 5 years old or less, 4 years old or less, 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less), the method comprising:
(a) Administering to the patient a therapeutically effective amount of a transgene encoding MTM1,
(b) Monitoring the patient for the development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof,
(c) An anti-cholestasis agent is administered to the patient.
[66] A method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm, the method comprising:
(a) Administering to the patient a therapeutically effective amount of a transgene encoding MTM1,
(b) Monitoring the patient for the development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof,
(c) An anti-cholestasis agent is administered to the patient.
[67] A method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm, the method comprising:
(a) Administering to the patient a therapeutically effective amount of a transgene encoding MTM1,
(b) Monitoring the patient for the development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof,
(c) An anti-cholestasis agent is administered to the patient.
[68] The method of any one of embodiments 65-67, wherein the transgene encoding MTM1 is administered by transduction of the patient with a viral vector comprising a transgene encoding MTM 1.
[69] A method of treating an xltm in a human patient in need thereof, the patient being five years old or less (e.g., 5 years old or less, 4 years old or less, 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less), the method comprising:
(a) Administering to the patient a therapeutically effective amount of a transgene encoding MTM1,
(b) Determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and
(c) An anti-cholestasis agent is administered to the patient.
[70] A method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm, the method comprising:
(a) Administering to the patient a therapeutically effective amount of a transgene encoding MTM1,
(b) Determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and
(c) An anti-cholestasis agent is administered to the patient.
[71] A method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm, the method comprising:
(a) Administering to the patient a therapeutically effective amount of a transgene encoding MTM1,
(b) Determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and
(c) An anti-cholestasis agent is administered to the patient.
[72] The method of any one of embodiments 69 to 71 wherein the transgene encoding MTM1 is administered by transduction of the patient with a viral vector comprising a transgene encoding MTM 1.
[73] The method of any one of embodiments 65-72, wherein the patient is four years old or less (e.g., 4 years old or less, 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[74] The method of embodiment 73, wherein the patient is three years old or less (e.g., 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[75] The method of embodiment 73, wherein the patient is two years old or less (e.g., 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[76] The method of embodiment 73, wherein the patient is one year old or less (e.g., 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[77] The method of embodiment 73, wherein the patient is six months or less (e.g., 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) at the time of administration of the transgene or viral vector.
[78] The method of any one of embodiments 65-72, wherein the patient is about 1 month to about 5 years old (e.g., about 1 month to about 5 years old, about 2 months to about 5 years old, about 3 months to about 5 years old, about 4 months to about 5 years old, about 5 months to about 5 years old, about 6 months to about 5 years old, about 1 year to about 5 years old, about 2 years to about 5 years old, about 3 years to about 5 years old, or about 4 years to about 5 years old) at the time of administration of the transgenic or viral vector.
[79]The method of embodiments 68 or 72-78, wherein the viral vector is present at less than about 3x 10 14 An amount of vg/kg (e.g., less than about 3x10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[80]The method of embodiment 79, wherein the viral vector is present at less than about 3x10 14 An amount of vg/kg (e.g., less than about 3x10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[81]The method of embodiment 80, wherein the viral vector is present at less than about 2x10 14 An amount of vg/kg (e.g., less than about 2x10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[82]The method of embodiment 80, wherein the viral vector is present at less than about 1.5x10 14 An amount of vg/kg (e.g., less than about 1.5x10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[83]The method of embodiment 80, wherein the viral vector is present at less than about 1.4x10 14 An amount of vg/kg (e.g., less than about 1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[84]The method of any one of embodiments 68 or 72 to 78, wherein the viral vector is at about 3x10 13 vg/kg to about 2.3X10 14 The amount of vg/kg (e.g., 3X10 13 vg/kg to about 2.3X10 14 vg/kg、3.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、4x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.1x10 13 vg/kg to about 2.3X10 14 vg/kg、4.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、5x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、6x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、7x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、8x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、9x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、1x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.1x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.2x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.3x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.4x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.5x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.6x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.7x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.8x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.9x 10 14 vg/kg to about 2.3X10 14 vg/kg、2x 10 14 vg/kg to about 2.3X10 14 vg/kg、2.1x 10 14 vg/kg to about 2.3X10 14 vg/kg or 2.2X10 14 vg/kg to about 2.3X10 14 vg/kg) to the patient.
[85]The method of embodiment 84, wherein the viral vector is present at about 8x10 13 vg/kg to about 1.8x10 14 The amount of vg/kg (e.g., 8X10 13 vg/kg to about 1.8x10 14 vg/kg、8.1x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.2x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.3x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.4x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.5x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.6x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.7x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.8x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.9x 10 13 vg/kg to about 1.8x10 14 vg/kg、9x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.1x 10 13 vg/kg to about1.8x10 14 vg/kg、9.2x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.3x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.4x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.5x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.6x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.7x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.8x 10 13 vg/kg to about 1.8x10 14 vg/kg、9.9x 10 13 vg/kg to about 1.8x10 14 vg/kg、1x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.1x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.2x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.3x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.4x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.5x 10 14 vg/kg to about 1.8x10 14 vg/kg、1.6x 10 14 vg/kg to about 1.8x10 14 vg/kg or 1.7X10 14 vg/kg to about 1.8x10 14 vg/kg) to the patient.
[86]The method of embodiment 84, wherein the viral vector is present at about 1x 10 14 vg/kg to about 1.6X10 14 The amount of vg/kg (e.g., 1X 10 14 vg/kg to about 1.6X10 14 vg/kg、1.1x 10 14 vg/kg to about 1.6X10 14 vg/kg、1.2x 10 14 vg/kg to about 1.6X10 14 vg/kg、1.3x 10 14 vg/kg to about 1.6X10 14 vg/kg、1.4x 10 14 vg/kg to about 1.6X10 14 vg/kg、1.5x 10 14 vg/kg to about 1.6X10 14 vg/kg、1.6x 10 14 vg/kg to about 1.6X10 14 vg/kg or about 1.7X10 14 vg/kg to about 1.6X10 14 vg/kg) to the patient.
[87]The method of embodiment 84, wherein the viral vector is present at 1.1x10 14 vg/kg to about 1.5x10 14 The amount of vg/kg (e.g., 1.1X10) 14 vg/kg to about 1.5x10 14 vg/kg、1.2x 10 14 vg/kg to about 1.5x10 14 vg/kg、1.3x 10 14 vg/kg to about 1.5x10 14 vg/kg or 1.4X10 14 vg/kg to about 1.5x10 14 vg/kg) to the patient.
[88]The method of embodiment 84, wherein the viral vector is present at about 1.2x10 14 vg/kg to about 1.4x10 14 The amount of vg/kg (e.g., 1.2X10 14 vg/kg to about 1.4x10 14 vg/kg or 1.3X10 14 vg/kg to about 1.4x10 14 vg/kg) to the patient.
[89]The method of any one of embodiments 68 or 72 to 84, wherein the viral vector is present at about 1.3x10 14 An amount of vg/kg is administered to the patient.
[90] A method of treating or preventing cholestasis or hyperbilirubinemia in a human patient suffering from xltm and having previously been administered a transgene encoding MTM1, the method comprising administering an anti-cholestasis agent to the patient.
[91]A method of treating or preventing cholestasis or hyperbilirubinemia in a human patient having xltm and having previously been administered a viral vector comprising a transgene encoding MTM1 in an amount of less than about 3x 10 14 vg/kg (e.g., the amount of the viral vector is less than about 3x 10 14 vg/kg、2.9x 10 14 vg/kg、2.8x 10 14 vg/kg、2.7x 10 14 vg/kg、2.6x 10 14 vg/kg、2.5x 10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 vg/kg or less), comprising administering an anti-cholestasis agent to the patient.
[92]The method of embodiment 91, wherein the viral vector is present at less than about 2.5x10 14 The amount of vg/kg (e.g.,less than about 2.5x10 14 vg/kg、2.4x 10 14 vg/kg、2.3x 10 14 vg/kg、2.2x 10 14 vg/kg、2.1x 10 14 vg/kg、2x 10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[93]The method of embodiment 92, wherein the viral vector is present at less than about 2x10 14 An amount of vg/kg (e.g., less than about 2x10 14 vg/kg、1.9x 10 14 vg/kg、1.8x 10 14 vg/kg、1.7x 10 14 vg/kg、1.6x 10 14 vg/kg、1.5x 10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[94]The method of embodiment 92, wherein the viral vector is present at less than about 1.5x10 14 An amount of vg/kg (e.g., less than about 1.5x10 14 vg/kg、1.4x 10 14 vg/kg、1.3x 10 14 vg/kg、1.2x 10 14 vg/kg、1.1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[95]The method of embodiment 92, wherein the viral vector is present at less than about 1.4x10 14 The amount of vg/kg (e.g. smallAt about 1x 10 14 vg/kg、1x 10 14 vg/kg、1x 10 13 vg/kg、1x 10 12 vg/kg、1x 10 11 vg/kg、1x 10 10 vg/kg、1x 10 9 vg/kg、1x 10 8 An amount of vg/kg or less) to the patient.
[96]The method of embodiment 91, wherein the viral vector is present at about 3x 10 13 vg/kg to about 2.3X10 14 The amount of vg/kg (e.g., 3X10 13 vg/kg to about 2.3X10 14 vg/kg、3.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、3.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、4x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.1x 10 13 vg/kg to about 2.3x10 14 vg/kg、4.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、4.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、5x 10 13 vg/kg to about 2.3x10 14 vg/kg、5.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、5.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、6x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、6.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、7x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、7.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、8x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.2x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、8.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、9x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.1x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.2x 10 13 vg/kg to about2.3x 10 14 vg/kg、9.3x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.4x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.5x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.6x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.7x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.8x 10 13 vg/kg to about 2.3X10 14 vg/kg、9.9x 10 13 vg/kg to about 2.3X10 14 vg/kg、1x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.1x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.2x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.3x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.4x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.5x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.6x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.7x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.8x 10 14 vg/kg to about 2.3X10 14 vg/kg、1.9x 10 14 vg/kg to about 2.3X10 14 vg/kg、2x 10 14 vg/kg to about 2.3X10 14 vg/kg、2.1x 10 14 vg/kg to about 2.3X10 14 vg/kg or 2.2X10 14 vg/kg to about 2.3X10 14 vg/kg) to the patient.
[97]The method of embodiment 96, wherein the viral vector is present at about 8x10 13 vg/kg to about 1.8x10 14 The amount of vg/kg (e.g., 8X10 13 vg/kg to about 1.8x10 14 vg/kg、8.1x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.2x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.3x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.4x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.5x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.6x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.7x 10 13 vg/kg to about 1.8x10 14 vg/kg、8.8x10 13 vg/kg to about 1.8x10 14 vg/kg、8.9x10 13 vg/kg to about 1.8x10 14 vg/kg、9x10 13 vg/kg to about 1.8x10 14 vg/kg、9.1x10 13 vg/kg to about 1.8x10 14 vg/kg、9.2x10 13 vg/kg to about 1.8x10 14 vg/kg、9.3x10 13 vg/kg to about 1.8x10 14 vg/kg、9.4x10 13 vg/kg to about 1.8x10 14 vg/kg、9.5x10 13 vg/kg to about 1.8x10 14 vg/kg、9.6x10 13 vg/kg to about 1.8x10 14 vg/kg、9.7x10 13 vg/kg to about 1.8x10 14 vg/kg、9.8x10 13 vg/kg to about 1.8x10 14 vg/kg、9.9x10 13 vg/kg to about 1.8x10 14 vg/kg、1x10 14 vg/kg to about 1.8x10 14 vg/kg、1.1x10 14 vg/kg to about 1.8x10 14 vg/kg、1.2x10 14 vg/kg to about 1.8x10 14 vg/kg、1.3x10 14 vg/kg to about 1.8x10 14 vg/kg、1.4x10 14 vg/kg to about 1.8x10 14 vg/kg、1.5x10 14 vg/kg to about 1.8x10 14 vg/kg、1.6x10 14 vg/kg to about 1.8x10 14 vg/kg or 1.7x10 14 vg/kg to about 1.8x10 14 vg/kg) to the patient.
[98]The method of embodiment 96, wherein the viral vector is present at about 1x10 14 vg/kg to about 1.6x10 14 The amount of vg/kg (e.g., 1X10 14 vg/kg to about 1.6x10 14 vg/kg、1.1x10 14 vg/kg to about 1.6x10 14 vg/kg、1.2x10 14 vg/kg to about 1.6x10 14 vg/kg、1.3x10 14 vg/kg to about 1.6x10 14 vg/kg、1.4x10 14 vg/kg to about 1.6x10 14 vg/kg、1.5x10 14 vg/kg to about 1.6x10 14 vg/kg、1.6x10 14 vg/kg to about 1.6x10 14 vg/kg or about 1.7x10 14 vg/kg to about 1.6x10 14 vg/kg) to the patient.
[99]The method of embodiment 96, wherein the viral vector is present at 1.1x10 14 vg/kg to about 1.5x10 14 The amount of vg/kg (e.g., 1.1x10 14 vg/kg to about 1.5x10 14 vg/kg、1.2x10 14 vg/kg to about 1.5x10 14 vg/kg、1.3x10 14 vg/kg to about 1.5x10 14 vg/kg or 1.4x10 14 vg/kg to about 1.5x10 14 vg/kg) to said patientIs used.
[100]The method of embodiment 96, wherein the viral vector is present at about 1.2x10 14 vg/kg to about 1.4x10 14 The amount of vg/kg (e.g., 1.2x10 14 vg/kg to about 1.4x10 14 vg/kg or 1.3x10 14 vg/kg to about 1.4x10 14 vg/kg) to the patient.
[101]The method of any one of embodiments 91 to 100, wherein the viral vector is present at about 1.3x10 14 An amount of vg/kg is administered to the patient.
[102] The method of any one of embodiments 91-101, wherein the patient is five years old or less (e.g., 5 years old or less, 4 years old or less, 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[103] The method of embodiment 102, wherein the patient is four years old or less (e.g., 4 years old or less, 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[104] The method of embodiment 103, wherein the patient is three years old or less (e.g., 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[105] The method of embodiment 103, wherein the patient is two years old or less (e.g., 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[106] The method of embodiment 103, wherein the patient is one year old or less (e.g., 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[107] The method of embodiment 103, wherein the patient is six months or less (e.g., 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) at the time of administration of the transgene or viral vector.
[108] The method of any one of embodiments 90-101, wherein the patient is about 1 month to about 5 years old (e.g., about 1 month to about 5 years old, about 2 months to about 5 years old, about 3 months to about 5 years old, about 4 months to about 5 years old, about 5 months to about 5 years old, about 6 months to about 5 years old, about 1 year to about 5 years old, about 2 years to about 5 years old, about 3 years to about 5 years old, or about 4 years to about 5 years old) at the time of administration of the transgenic or viral vector.
[109] A method of treating or preventing cholestasis or hyperbilirubinemia in a human patient having xltm, having previously been administered a transgene encoding MTM1, and five years old or less (e.g., 5 years old or less, 4 years old or less, 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgene is administered, the method comprising administering an anti-cholestasis agent to the patient.
[110] A method of treating or preventing cholestasis or hyperbilirubinemia in a human patient having xltm, having previously been administered a viral vector comprising a transgene encoding MTM1, and five years old or less (e.g., 5 years old or less, 4 years old or less, 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the viral vector is administered, the method comprising administering an anti-cholestasis agent to the patient.
[111] The method of embodiment 109 or 110, wherein the patient is four years old or less (e.g., 4 years old or less, 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[112] The method of embodiment 111, wherein the patient is three years old or less (e.g., 3 years old or less, 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[113] The method of embodiment 111, wherein the patient is two years old or less (e.g., 2 years old or less, 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[114] The method of embodiment 111, wherein the patient is one year old or less (e.g., 1 year old or less, 12 months or less, 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) when the transgenic or viral vector is administered.
[115] The method of embodiment 111, wherein the patient is six months or less (e.g., 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less) at the time of administration of the transgene or viral vector.
[116] The method of embodiment 109 or 110, wherein the patient is about 1 month to about 5 years old (e.g., about 1 month to about 5 years old, about 2 months to about 5 years old, about 3 months to about 5 years old, about 4 months to about 5 years old, about 5 months to about 5 years old, about 6 months to about 5 years old, about 1 year to about 5 years old, about 2 years to about 5 years old, about 3 years to about 5 years old, or about 4 years to about 5 years old) at the time of administration of the transgenic or viral vector.
[117]The method of any one of embodiments 110 to 116, wherein the viral vector is present at less than about 3x10 14 An amount of vg/kg (e.g., less than about 3x10 14 vg/kg、2.9x10 14 vg/kg、2.8x10 14 vg/kg、2.7x10 14 vg/kg、2.6x10 14 vg/kg、2.5x10 14 vg/kg、2.4x10 14 vg/kg、2.3x10 14 vg/kg、2.2x10 14 vg/kg、2.1x10 14 vg/kg、2x10 14 vg/kg、1.9x10 14 vg/kg、1.8x10 14 vg/kg、1.7x10 14 vg/kg、1.6x10 14 vg/kg、1.5x10 14 vg/kg、1.4x10 14 vg/kg、1.3x10 14 vg/kg、1.2x10 14 vg/kg、1.1x10 14 vg/kg、1x10 14 vg/kg、1x10 14 vg/kg、1x10 13 vg/kg、1x10 12 vg/kg、1x10 11 vg/kg、1x10 10 vg/kg、1x10 9 vg/kg、1x10 8 An amount of vg/kg or less) to the patient.
[118]The method of embodiment 117, wherein the viral vector is present at less than about 2.5x10 14 An amount of vg/kg (e.g., less than about 2.5x10 14 vg/kg、2.4x10 14 vg/kg、2.3x10 14 vg/kg、2.2x10 14 vg/kg、2.1x10 14 vg/kg、2x10 14 vg/kg、1.9x10 14 vg/kg、1.8x10 14 vg/kg、1.7x10 14 vg/kg、1.6x10 14 vg/kg、1.5x10 14 vg/kg、1.4x10 14 vg/kg、1.3x10 14 vg/kg、1.2x10 14 vg/kg、1.1x10 14 vg/kg、1x10 14 vg/kg、1x10 14 vg/kg、1x10 13 vg/kg、1x10 12 vg/kg、1x10 11 vg/kg、1x10 10 vg/kg、1x10 9 vg/kg、1x10 8 An amount of vg/kg or less) to the patient.
[119]The method of embodiment 118, wherein the viral vector is present at less than about 2x10 14 An amount of vg/kg (e.g., less than about 2x10 14 vg/kg、1.9x10 14 vg/kg、1.8x10 14 vg/kg、1.7x10 14 vg/kg、1.6x10 14 vg/kg、1.5x10 14 vg/kg、1.4x10 14 vg/kg、1.3x10 14 vg/kg、1.2x10 14 vg/kg、1.1x10 14 vg/kg、1x10 14 vg/kg、1x10 14 vg/kg、1x10 13 vg/kg、1x10 12 vg/kg、1x10 11 vg/kg、1x10 10 vg/kg、1x10 9 vg/kg、1x10 8 An amount of vg/kg or less) to the patient.
[120]The method of embodiment 118, wherein the viral vector is present at less than about 1.5x10 14 An amount of vg/kg (e.g., less than about 1.5x10 14 vg/kg、1.4x10 14 vg/kg、1.3x10 14 vg/kg、1.2x10 14 vg/kg、1.1x10 14 vg/kg、1x10 14 vg/kg、1x10 14 vg/kg、1x10 13 vg/kg、1x10 12 vg/kg、1x10 11 vg/kg、1x10 10 vg/kg、1x10 9 vg/kg、1x10 8 An amount of vg/kg or less) to the patient.
[121]The method of embodiment 118, wherein the viral vector is present at less than about 1.4x10 14 An amount of vg/kg (e.g., less than about 1x10 14 vg/kg、1x10 14 vg/kg、1x10 13 vg/kg、1x10 12 vg/kg、1x10 11 vg/kg、1x10 10 vg/kg、1x10 9 vg/kg、1x10 8 An amount of vg/kg or less) to the patient.
[122]The method of any one of embodiments 110 to 116, wherein the viral vector is present at about 3x10 13 vg/kg to about 2.3x10 14 The amount of vg/kg (e.g., 3X10 13 vg/kg to about 2.3x10 14 vg/kg、3.1x10 13 vg/kg to about 2.3x10 14 vg/kg、3.2x10 13 vg/kg to about 2.3x10 14 vg/kg、3.3x10 13 vg/kg to about 2.3x10 14 vg/kg、3.4x10 13 vg/kg to about 2.3x10 14 vg/kg、3.5x10 13 vg/kg to about 2.3x10 14 vg/kg、3.6x10 13 vg/kg to about 2.3x10 14 vg/kg、3.7x10 13 vg/kg to about 2.3x10 14 vg/kg、3.8x10 13 vg/kg to about 2.3x10 14 vg/kg、3.9x10 13 vg/kg to about 2.3x10 14 vg/kg、4x10 13 vg/kg to about 2.3x10 14 vg/kg、4.1x10 13 vg/kg to about 2.3x10 14 vg/kg、4.2x10 13 vg/kg to about 2.3x10 14 vg/kg、4.3x10 13 vg/kg to about 2.3x10 14 vg/kg、4.4x10 13 vg/kg to about 2.3x10 14 vg/kg、4.5x10 13 vg/kg to about 2.3x10 14 vg/kg、4.6x10 13 vg/kg to about 2.3x10 14 vg/kg、4.7x10 13 vg/kg to about 2.3x10 14 vg/kg、4.8x10 13 vg/kg to about 2.3x10 14 vg/kg、4.9x10 13 vg/kg to about 2.3x10 14 vg/kg、5x10 13 vg/kg to about 2.3x10 14 vg/kg、5.1x10 13 vg/kg to about 2.3x10 14 vg/kg、5.2x10 13 vg/kg to about 2.3x10 14 vg/kg、5.3x10 13 vg/kg to about 2.3x10 14 vg/kg、5.4x10 13 vg/kg to about 2.3x10 14 vg/kg、5.5x10 13 vg/kg to about 2.3x10 14 vg/kg、5.6x10 13 vg/kg to about 2.3x10 14 vg/kg、5.7x10 13 vg/kg to about 2.3x10 14 vg/kg、5.8x10 13 vg/kg to about 2.3x10 14 vg/kg、5.9x10 13 vg/kg to about 2.3x10 14 vg/kg、6x10 13 vg/kg to about 2.3x10 14 vg/kg、6.1x10 13 vg/kg to about 2.3x10 14 vg/kg、6.2x10 13 vg/kg to about 2.3x10 14 vg/kg、6.3x10 13 vg/kg to about 2.3x10 14 vg/kg、6.4x10 13 vg/kg to about 2.3x10 14 vg/kg、6.5x10 13 vg/kg to about 2.3x10 14 vg/kg、6.6x10 13 vg/kg to about 2.3x10 14 vg/kg、6.7x10 13 vg/kg to about 2.3x10 14 vg/kg、6.8x10 13 vg/kg to about 2.3x10 14 vg/kg、6.9x10 13 vg/kg to about 2.3x10 14 vg/kg、7x10 13 vg/kg to about 2.3x10 14 vg/kg、7.1x10 13 vg/kg to about 2.3x10 14 vg/kg、7.2x10 13 vg/kg to about 2.3x10 14 vg/kg、7.3x10 13 vg/kg to about 2.3x10 14 vg/kg、7.4x10 13 vg/kg to about 2.3x10 14 vg/kg、7.5x10 13 vg/kg to about 2.3x10 14 vg/kg、7.6x10 13 vg/kg to about 2.3x10 14 vg/kg、7.7x10 13 vg/kg to about 2.3x10 14 vg/kg、7.8x10 13 vg/kg to about 2.3x10 14 vg/kg、7.9x10 13 vg/kg to about 2.3x10 14 vg/kg、8x10 13 vg/kg to about 2.3x10 14 vg/kg、8.1x10 13 vg/kg to about 2.3x10 14 vg/kg、8.2x10 13 vg/kg to about 2.3x10 14 vg/kg、8.3x10 13 vg/kg to about 2.3x10 14 vg/kg、8.4x10 13 vg/kg to about 2.3x10 14 vg/kg、8.5x10 13 vg/kg to about 2.3x10 14 vg/kg、8.6x10 13 vg/kg to about 2.3x10 14 vg/kg、8.7x10 13 vg/kg to about 2.3x10 14 vg/kg、8.8x10 13 vg/kg to about 2.3x10 14 vg/kg、8.9x10 13 vg/kg to about 2.3x10 14 vg/kg、9x10 13 vg/kg to about 2.3x10 14 vg/kg、9.1x10 13 vg/kg to about 2.3x10 14 vg/kg、9.2x10 13 vg/kg to about 2.3x10 14 vg/kg、9.3x10 13 vg/kg to about 2.3x10 14 vg/kg、9.4x10 13 vg/kg to about 2.3x10 14 vg/kg、9.5x10 13 vg/kg to about 2.3x10 14 vg/kg、9.6x10 13 vg/kg to about 2.3x10 14 vg/kg、9.7x10 13 vg/kg to about 2.3x10 14 vg/kg、9.8x10 13 vg/kg to about 2.3x10 14 vg/kg、9.9x10 13 vg/kg to about 2.3x10 14 vg/kg、1x10 14 vg/kg to about 2.3x10 14 vg/kg、1.1x10 14 vg/kg to about 2.3x10 14 vg/kg、1.2x10 14 vg/kg to about 2.3x10 14 vg/kg、1.3x10 14 vg/kg to about 2.3x10 14 vg/kg、1.4x10 14 vg/kg to about 2.3x10 14 vg/kg、1.5x10 14 vg/kg to about 2.3x10 14 vg/kg、1.6x10 14 vg/kg to about 2.3x10 14 vg/kg、1.7x10 14 vg/kg to about 2.3x10 14 vg/kg、1.8x10 14 vg/kg to about 2.3x10 14 vg/kg、1.9x10 14 vg/kg to about 2.3x10 14 vg/kg、2x10 14 vg/kg to about 2.3x10 14 vg/kg、2.1x10 14 vg/kg to about 2.3x10 14 vg/kg or 2.2x10 14 vg/kg to about 2.3x10 14 vg/kg) to the patient.
[123]The method of embodiment 122, wherein the viral vector is present at about 8x10 13 vg/kg to about 1.8x10 14 Amount of vg/kg (e.g., 8x10 13 vg/kg to about 1.8x10 14 vg/kg、8.1x10 13 vg/kg to about 1.8x10 14 vg/kg、8.2x10 13 vg/kg to about 1.8x10 14 vg/kg、8.3x10 13 vg/kg to about 1.8x10 14 vg/kg、8.4x10 13 vg/kg to about 1.8x10 14 vg/kg、8.5x10 13 vg/kg to about 1.8x10 14 vg/kg、8.6x10 13 vg/kg to about 1.8x10 14 vg/kg、8.7x10 13 vg/kg to about 1.8x10 14 vg/kg、8.8x10 13 vg/kg to about 1.8x10 14 vg/kg、8.9x10 13 vg/kg to about 1.8x10 14 vg/kg、9x10 13 vg/kg to about 1.8x10 14 vg/kg、9.1x10 13 vg/kg to about 1.8x10 14 vg/kg、9.2x10 13 vg/kg to about 1.8x10 14 vg/kg、9.3x10 13 vg/kg to about 1.8x10 14 vg/kg、9.4x10 13 vg/kg toAbout 1.8x10 14 vg/kg、9.5x10 13 vg/kg to about 1.8x10 14 vg/kg、9.6x10 13 vg/kg to about 1.8x10 14 vg/kg、9.7x10 13 vg/kg to about 1.8x10 14 vg/kg、9.8x10 13 vg/kg to about 1.8x10 14 vg/kg、9.9x10 13 vg/kg to about 1.8x10 14 vg/kg、1x10 14 vg/kg to about 1.8x10 14 vg/kg、1.1x10 14 vg/kg to about 1.8x10 14 vg/kg、1.2x10 14 vg/kg to about 1.8x10 14 vg/kg、1.3x10 14 vg/kg to about 1.8x10 14 vg/kg、1.4x10 14 vg/kg to about 1.8x10 14 vg/kg、1.5x10 14 vg/kg to about 1.8x10 14 vg/kg、1.6x10 14 vg/kg to about 1.8x10 14 vg/kg or 1.7x10 14 vg/kg to about 1.8x10 14 vg/kg) to the patient.
[124]The method of embodiment 122, wherein the viral vector is present at about 1x10 14 vg/kg to about 1.6x10 14 The amount of vg/kg (e.g., 1X10 14 vg/kg to about 1.6x10 14 vg/kg、1.1x10 14 vg/kg to about 1.6x10 14 vg/kg、1.2x10 14 vg/kg to about 1.6x10 14 vg/kg、1.3x10 14 vg/kg to about 1.6x10 14 vg/kg、1.4x10 14 vg/kg to about 1.6x10 14 vg/kg、1.5x10 14 vg/kg to about 1.6x10 14 vg/kg、1.6x10 14 vg/kg to about 1.6x10 14 vg/kg or about 1.7x10 14 vg/kg to about 1.6x10 14 vg/kg) to the patient.
[125]The method of embodiment 122, wherein the viral vector is present at 1.1x10 14 vg/kg to about 1.5x10 14 The amount of vg/kg (e.g., 1.1x10 14 vg/kg to about 1.5x10 14 vg/kg、1.2x10 14 vg/kg to about 1.5x10 14 vg/kg、1.3x10 14 vg/kg to about 1.5x10 14 vg/kg or 1.4x10 14 vg/kg to about 1.5x10 14 vg/kg) to the patient.
[126]The method of embodiment 122, wherein the viral vector is present at about 1.2x10 14 vg/kg to about 1.4x10 14 The amount of vg/kg (e.g., 1.2x10 14 vg/kg to about 1.4x10 14 vg/kg or 1.3x10 14 vg/kg to about 1.4x10 14 vg/kg) to the patient.
[127]The method of any one of embodiments 110 to 126, wherein the viral vector is present at about 1.3x10 14 The amount of vg/kg is administered to the patient.
[128] The method of any one of embodiments 1-108 and 117-127, wherein the transgene or viral vector is administered to the patient in a single dose comprising the amount.
[129] The method of any one of embodiments 1-108 and 117-127, wherein the transgene or viral vector is administered to the patient in two or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) doses that together comprise the amount.
[130] The method of any one of embodiments 1-108 and 117-127, wherein the transgene or viral vector is administered to the patient in two or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) doses each individually comprising the amount.
[131] The method of embodiment 129 or 130, wherein the two or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) doses are separated from each other by one year or more (e.g., one year or more, two years or more, three years or more, four years or more, or five years or more).
[132] The method of embodiments 129 and 130, wherein the two or more doses are administered to the patient within about 12 months of each other (e.g., within about 12 months, within about 11 months, within about 10 months, within about 9 months, within about 8 months, within about 7 months, within about 6 months, within about 5 months, within about 4 months, within about 3 months, within about 2 months, or within about 1 month).
[133] The method of embodiments 4-10, 14-38, 42, 46-64, 68, 72-89, 91-108, or 110-132, wherein the viral vector is selected from the group consisting of adeno-associated virus (AAV), adenovirus, lentivirus, retrovirus, poxvirus, baculovirus, herpes simplex virus, vaccinia virus, and synthetic virus.
[134] The method of embodiment 133, wherein the viral vector is AAV.
[135] The method of embodiment 134, wherein the AAV is AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh10, or AAVrh74 serotype.
[136] The method of embodiment 134, wherein the viral vector is a pseudotyped AAV.
[137] The method of embodiment 136, wherein the pseudotyped AAV is AAV2/8 or AAV2/9.
[138] The method of embodiment 137, wherein the pseudotyped AAV is AAV2/8.
[139] The method of any one of embodiments 1 to 138, wherein the transgene encoding MTM1 is operably linked to a muscle-specific promoter.
[140] The method of embodiment 139, wherein the muscle-specific promoter is a desmin promoter, a muscle creatine kinase promoter, a myosin light chain promoter, a myosin heavy chain promoter, a cardiac troponin C promoter, a troponin I promoter, a myoD gene family promoter, an actin alpha promoter, an actin beta promoter, an actin gamma promoter, or a promoter within intron 1 of pair-like homeodomain 3 in the eye.
[141] The method of embodiment 140, wherein the muscle-specific promoter is a desmin promoter.
[142] The method of any one of embodiments 4 to 10, 14 to 38, 42, 46 to 64, 68, 72 to 89, 91 to 108, or 110 to 141, wherein the viral vector is birnesyl.
[143] The method of any one of embodiments 4-10, 14-38, 42, 46-64, 68, 72-89, 91-108, or 110-142, wherein the viral vector is administered to the patient by intravenous, intramuscular, intradermal, or subcutaneous administration.
[144] The method of any one of embodiments 1 to 143, wherein the anti-cholestasis agent is selected from the group consisting of: bile acids, farnesol X Receptor (FXR) ligands, fibroblast growth factor 19 (FGF-19) mimics, takeda-G protein receptor 5 (TGR 5) agonists, peroxisome proliferator-activated receptor (PPAR) agonists, PPAR-alpha agonists, PPAR-delta agonists, dual PPAR-alpha and PPAR-delta agonists, apical sodium-dependent bile acid transporter (ASBT) inhibitors, immunomodulatory drugs, anti-fibrotic therapies, and nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitors.
[145] The method of embodiment 144, wherein the FXR ligand is obeticholic acid.
[146] The method of embodiment 144, wherein the FXR ligand is cilofaxolol.
[147] The method of embodiment 144, wherein the FXR ligand is t Luo Fasuo.
[148] The method of embodiment 144, wherein the FXR ligand is tretinoin.
[149] The method of embodiment 144, wherein the FXR ligand is EDP-305.
[150] The method of embodiment 144, wherein the FGF-19 mimetic is aldafidamin.
[151] The method of embodiment 144 wherein the TGR5 agonist is INT-777.
[152] The method of embodiment 144, wherein the TGR5 agonist is INT-767.
[153] The method of embodiment 144, wherein the PPAR agonist is bezafibrate.
[154] The method of embodiment 144, wherein the PPAR agonist is selrad pa.
[155] The method of embodiment 144, wherein the PPAR agonist is alabeno.
[156] The method of embodiment 144, wherein the PPAR-alpha agonist is fenofibrate.
[157] The method of embodiment 144, wherein the PPAR-delta agonist is seladelpha.
[158] The method of embodiment 144, wherein the dual PPAR-alpha and PPAR-delta agonist is alafeinuo.
[159] The method of embodiment 144, wherein the ASBT inhibitor is aldvitamin xibat.
[160] The method of embodiment 144, wherein the ASBT inhibitor is maraglixibat.
[161] The method of embodiment 144, wherein the ASBT inhibitor is Li Naixi bat.
[162] The method of embodiment 144, wherein the immunomodulatory drug is rituximab.
[163] The method of embodiment 144, wherein the immunomodulatory drug is abamectin.
[164] The method of embodiment 144, wherein the immunomodulatory drug is you-tec-mab.
[165] The method of embodiment 144, wherein the immunomodulatory drug is infliximab.
[166] The method of embodiment 144, wherein the immunomodulatory drug is baratinib.
[167] The method of embodiment 144, wherein the immunomodulatory drug is FFP-104.
[168] The method of embodiment 144, wherein the anti-fibrotic therapy is a vitamin D receptor agonist.
[169] The method of embodiment 144, wherein the anti-fibrotic therapy is Xin Tuozhu mab.
[170] The method of embodiment 144, wherein the NOX inhibitor is celecoxib.
[171] The method of embodiment 144, wherein the bile acid is ursodeoxycholic acid (e.g., xiong Erchun) or a pharmaceutically acceptable salt thereof.
[172] The method of embodiment 144, wherein the bile acid is norursodeoxycholic acid or a pharmaceutically acceptable salt thereof.
[173] The method of embodiment 171, wherein the bile acid is bear glycol.
[174] The method of embodiments 144, 171, or 173, wherein said bile acid is administered to said patient in a single dose.
[175] The method of embodiments 144, 171, or 173, wherein said bile acid is administered to said patient in a plurality of doses.
[176] The method of embodiment 174 or 175, wherein the bile acid is administered to the patient in an amount of about 5 mg/kg/dose to about 20 mg/kg/dose (e.g., 5 mg/kg/dose to about 20 mg/kg/dose, 6 mg/kg/dose to about 20 mg/kg/dose, 7 mg/kg/dose to about 20 mg/kg/dose, 8 mg/kg/dose to about 20 mg/kg/dose, 9 mg/kg/dose to about 20 mg/kg/dose, 10 mg/kg/dose to about 20 mg/kg/dose, 11 mg/kg/dose to about 20 mg/kg/dose, 12 mg/kg/dose to about 20 mg/kg/dose, 13 mg/kg/dose to about 20 mg/kg/dose, 14 mg/kg/dose to about 20 mg/kg/dose, 15 mg/kg/dose to about 20 mg/kg/dose, 16 mg/kg/dose to about 20 mg/kg/dose, 17 mg/kg/dose to about 20 mg/kg/dose, 18 mg/kg/dose to about 20 mg/dose, or about 19 mg/kg/dose).
[177] The method of embodiment 176, wherein the bile acid is administered to the patient in an amount of about 6 mg/kg/dose to about 19 mg/dose (e.g., 6 mg/kg/dose to about 19 mg/dose, 7 mg/kg/dose to about 19 mg/kg/dose, 8 mg/kg/dose to about 19 mg/kg/dose, 9 mg/kg/dose to about 19 mg/kg/dose, 10 mg/kg/dose to about 19 mg/kg/dose, 11 mg/kg/dose to about 19 mg/kg/dose, 12 mg/kg/dose to about 19 mg/kg/dose, 13 mg/kg/dose to about 19 mg/kg/dose, 14 mg/kg/dose to about 19 mg/kg/dose, 15 mg/kg/dose to about 19 mg/kg/dose, 16 mg/kg/dose to about 19 mg/kg/dose, 17 mg/kg/dose to about 19 mg/kg/dose, or 18 mg/kg/dose to about 19 mg/kg/dose).
[178] The method of embodiment 176, wherein the bile acid is administered to the patient in an amount of about 7 mg/kg/dose to about 18 mg/dose (e.g., 7 mg/kg/dose to about 18 mg/kg/dose, 8 mg/kg/dose to about 18 mg/kg/dose, 9 mg/kg/dose to about 18 mg/kg/dose, 10 mg/kg/dose to about 18 mg/kg/dose, 11 mg/kg/dose to about 18 mg/kg/dose, 12 mg/kg/dose to about 18 mg/kg/dose, 13 mg/kg/dose to about 18 mg/kg/dose, 14 mg/kg/dose to about 18 mg/kg/dose, 15 mg/kg/dose to about 18 mg/kg/dose, 16 mg/kg/dose to about 18 mg/kg/dose, or 17 mg/kg/dose to about 18 mg/kg/dose).
[179] The method of embodiment 176, wherein the bile acid is administered to the patient in an amount of about 8 mg/kg/dose to about 17 mg/kg/dose (e.g., 8 mg/kg/dose to about 17 mg/kg/dose, 9 mg/kg/dose to about 17 mg/kg/dose, 10 mg/kg/dose to about 17 mg/kg/dose, 11 mg/kg/dose to about 17 mg/kg/dose, 12 mg/kg/dose to about 17 mg/kg/dose, 13 mg/kg/dose to about 17 mg/kg/dose, 14 mg/kg/dose to about 17 mg/kg/dose, 15 mg/kg/dose to about 17 mg/kg/dose, or 16 mg/kg/dose to about 17 mg/kg/dose).
[180] The method of embodiment 176, wherein the bile acid is administered to the patient in an amount of about 10 mg/kg/dose to about 15 mg/kg/dose (e.g., 10 mg/kg/dose to about 15 mg/kg/dose, 11 mg/kg/dose to about 15 mg/kg/dose, 12 mg/kg/dose to about 15 mg/kg/dose, 13 mg/kg/dose to about 15 mg/kg/dose, or 14 mg/kg/dose to about 15 mg/kg/dose).
[181] The method of embodiment 176, wherein said bile acid is administered to said patient in an amount of about 12 mg/kg/dose to about 13 mg/kg/dose.
[182] The method of embodiment 176, wherein the bile acid is administered to the patient in an amount of about 5 mg/kg/dose to about 11 mg/kg/dose (e.g., 5 mg/kg/dose to about 11 mg/kg/dose, 6 mg/kg/dose to about 11 mg/kg/dose, 7 mg/kg/dose to about 11 mg/kg/dose, 8 mg/kg/dose to about 11 mg/kg/dose, 9 mg/kg/dose to about 11 mg/kg/dose, or 10 mg/kg/dose to about 11 mg/kg/dose).
[183] The method of embodiment 182, wherein the bile acid is administered to the patient in an amount of about 6 mg/kg/dose to about 10 mg/kg/dose (e.g., 6 mg/kg/dose to about 10 mg/kg/dose, 7 mg/kg/dose to about 10 mg/kg/dose, 8 mg/kg/dose to about 10 mg/kg/dose, or 9 mg/kg/dose to about 10 mg/kg/dose).
[184] The method of embodiment 182, wherein the bile acid is administered to the patient in an amount of about 7 mg/kg/dose to about 9 mg/kg/dose (e.g., 7 mg/kg/dose to about 7 mg/kg/dose or 8 mg/kg/dose to about 9 mg/kg/dose).
[185] The method of embodiment 182, wherein the bile acid is administered to the patient in one or more (e.g., one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) doses per day, week, or month.
[186] The method of embodiment 185, wherein the bile acid is administered to the patient in one or more (e.g., one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more) doses per day.
[187] The method of embodiment 186, wherein said bile acid is administered to said patient at a dose of one per day.
[188] The method of embodiment 186, wherein said bile acid is administered to said patient in two doses per day.
[189] The method of embodiment 186, wherein said bile acid is administered to said patient at three doses per day.
[190] The method of embodiment 186, wherein said bile acid is administered to said patient at four doses per day.
[191] The method of embodiment 186, wherein said bile acid is administered to said patient in five doses per day.
[192] The method of any one of embodiments 144 to 191, wherein the bile acid is present in an amount of about 5 mg/kg/day to about 40 mg/kg/day (e.g., 5 mg/kg/day to about 40 mg/kg/day, 5.1 mg/kg/day to about 40 mg/kg/day, 5.2 mg/kg/day to about 40 mg/kg/day, 5.3 mg/kg/day to about 40 mg/kg/day, 5.4 mg/kg/day to about 40 mg/kg/day, 5.5 mg/day to about 40 mg/kg/day, 6 mg/kg/day to about 40 mg/kg/day, 6.5 mg/kg/day to about 40 mg/kg/day, 7 mg/kg/day to about 40 mg/kg/day, 8 mg/kg/day to about 40 mg/day, 9 mg/day to about 40 mg/day, 5.4 mg/kg/day to about 40 mg/day, 5.5 mg/kg/day to about 40 mg/day, 11 mg/day, about 11 mg/day to about 40 mg/kg/day, 14 mg/kg/day to about 40 mg/kg/day, 15 mg/kg/day to about 40 mg/kg/day, 16 mg/kg/day to about 40 mg/kg/day, 17 mg/kg/day to about 40 mg/kg/day, 18 mg/kg/day to about 40 mg/kg/day, an amount of 19 mg/kg/day to about 40 mg/kg/day, 20 mg/kg/day to about 40 mg/kg/day, 25 mg/kg/day to about 40 mg/kg/day, 30 mg/kg/day to about 40 mg/kg/day, 35 mg/kg/day to about 40 mg/kg/day, or 40 mg/kg/day to about 40 mg/kg/day) is administered to the patient.
[193] The method of embodiment 192, wherein the bile acid is administered in an amount of about 6 mg/kg/day to about 39 mg/kg/day (e.g., 6 mg/kg/day to about 39 mg/kg/day, 6.5 mg/kg/day to about 39 mg/kg/day, 7 mg/kg/day to about 39 mg/kg/day, 8 mg/kg/day to about 39 mg/kg/day, 9 mg/kg/day to about 39 mg/day, 10 mg/kg/day to about 39 mg/kg/day, 11 mg/day to about 39 mg/kg/day, 12 mg/kg/day to about 39 mg/kg/day, 13 mg/kg/day to about 39 mg/day, 14 mg/kg/day to about 39 mg/kg/day, 15 mg/kg/day to about 39 mg/day, 16 mg/kg/day to about 39 mg/kg/day, 17 mg/kg/day to about 39 mg/day, 18 mg/day to about 39 mg/day, 12 mg/kg/day to about 39 mg/day, 39 mg/day to about 39 mg/day, 14 mg/kg/day to about 39 mg/day, 15 mg/day to about 39 mg/day, about 39 mg/day to about 39 mg/day, 15 mg/kg/day to about 39 mg/day, about 39 mg/day to about 39 mg/day to about 39 kg/day.
[194] The method of embodiment 192, wherein the bile acid is administered in an amount of about 8 mg/kg/day to about 37 mg/kg/day (e.g., 8 mg/kg/day to about 37 mg/kg/day, 9 mg/kg/day to about 37 mg/kg/day, 10 mg/kg/day to about 37 mg/kg/day, 11 mg/kg/day to 37 mg/kg/day, 12 mg/kg/day to about 37 mg/kg/day, 13 mg/kg/day to about 37 mg/kg/day, 14 mg/kg/day to about 37 mg/kg/day, 15 mg/kg/day to about 37 mg/kg/day, 16 mg/kg/day to about 37 mg/kg/day, 17 mg/kg/day to about 37 mg/kg/day, 18 mg/kg/day to about 37 mg/kg/day, 19 mg/kg/day to about 37 mg/kg/day, 20 mg/kg/day to about 37 mg/kg/day, 25 mg/kg/day to about 37 mg/kg/day, 15 mg/kg/day to about 37 mg/day, or about 37 mg/kg/day to about 35 mg/day to the patient.
[195] The method of embodiment 192, wherein the bile acid is administered to the patient in an amount of about 13 mg/kg/day to about 32 mg/kg/day (e.g., 13 mg/kg/day to about 32 mg/kg/day, 14 mg/kg/day to about 32 mg/kg/day, 15 mg/kg/day to about 32 mg/kg/day, 16 mg/kg/day to about 32 mg/kg/day, 17 mg/kg/day to about 32 mg/kg/day, 18 mg/kg/day to about 32 mg/kg/day, 19 mg/kg/day to about 32 mg/kg/day, 20 mg/kg/day to about 32 mg/kg/day, 25 mg/kg/day to about 32 mg/kg/day, or 30 mg/kg/day to about 32 mg/kg/day).
[196] The method of embodiment 192, wherein the bile acid is administered to the patient in an amount of about 20 mg/kg/day to about 25 mg/kg/day (e.g., 20 mg/kg/day to about 25 mg/kg/day, 21 mg/kg/day to about 25 mg/kg/day, 22 mg/kg/day to about 25 mg/kg/day, 23 mg/kg/day to about 25 mg/kg/day, or 24 mg/kg/day to about 25 mg/kg/day).
[197] The method of embodiment 192, wherein the bile acid is administered to the patient in an amount of about 17 mg/kg/day to about 23 mg/kg/day (e.g., 17 mg/kg/day to about 23 mg/kg/day, 18 mg/kg/day to about 23 mg/kg/day, 19 mg/kg/day to about 23 mg/kg/day, 20 mg/kg/day to about 23 mg/kg/day, 21 mg/kg/day to about 23 mg/kg/day, or 22 mg/kg/day to about 23 mg/kg/day).
[198] The method of embodiment 192, wherein the bile acid is administered to the patient in an amount of about 18 mg/kg/day to about 22 mg/kg/day (e.g., 18 mg/kg/day to about 22 mg/kg/day, 19 mg/kg/day to about 22 mg/kg/day, 20 mg/kg/day to about 22 mg/kg/day, or 21 mg/kg/day to about 22 mg/kg/day).
[199] The method of embodiment 192, wherein the bile acid is administered to the patient in an amount of about 19 mg/kg/day to about 21 mg/kg/day (e.g., 19 mg/kg/day to about 21 mg/kg/day or 20 mg/kg/day to about 21 mg/kg/day).
[200] The method of any one of embodiments 144 to 199, wherein the bile acid is administered to the patient in an amount of 20 mg/kg/day.
[201] The method of any one of embodiments 144 to 200, wherein the bile acid is administered to the patient by a unit dosage form comprising 250mg of the bile acid.
[202] The method of any one of embodiments 144 to 200, wherein the bile acid is administered to the patient by a unit dosage form comprising 500mg of the bile acid.
[203] The method of any one of embodiments 144 to 202, wherein the bile is administered to the patient by enteral administration.
[204] The method of any one of embodiments 1-203, wherein the patient has no history of cholestasis or hyperbilirubinemia.
[205] The method of embodiment 204, wherein the patient does not have any history of potential liver disease.
[206] The method of any one of embodiments 1-205, wherein the patient is greater than or equal to 35 weeks of gestational age at birth and is or has been in the age of feet (e.g., adjusted age of feet) to about 5 years (e.g., 1 day to about 5 years, 2 days to about 5 years, 3 days to about 5 years, 4 days to about 5 years, 5 days to about 5 years, 6 days to about 5 years, 7 days to about 5 years, 8 days to about 5 years, 9 days to about 5 years, 10 days to about 5 years, 11 days to about 5 years, 12 days to about 5 years, 13 days to about 5 years, 14 days to about 5 years, 15 days to about 5 years, 16 days to about 5 years, 17 days to about 5 years, 18 days to about 5 years, 19 days to about 5 years, 20 days to about 5 years, 25 days to about 5 years, one month to about 5 years, two months to about 5 years, 3 days to about 5 years, 4 days to about 5 years, 1 month to about 5 years, and about 5 years).
[207] The method of any one of embodiments 1-206, wherein the patient is male.
[208] The method of any of embodiments 1-207, wherein the patient is in need of mechanical ventilation support.
[209] The method of embodiment 208, wherein mechanical ventilation support comprises invasive mechanical ventilation support.
[210] The method of embodiment 208, wherein mechanical ventilation support comprises non-invasive mechanical ventilation support.
[211] The method of any one of embodiments 1-210, wherein the patient exhibits a change in the number of hours of mechanical ventilation support over time from baseline after administration of the transgene or the viral vector to the patient.
[212] The method of embodiment 211, wherein the patient exhibits a change in the number of hours of mechanical ventilation support over time from baseline about 24 weeks after administration of the transgene or viral vector to the patient.
[213] The method of embodiment 212, wherein the patient exhibits a change in the number of hours of mechanical ventilation support from baseline over time about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
[214] The method of any one of embodiments 1-212, wherein after administering the transgene or the viral vector to the patient, the patient achieves functional independent sitting about 24 weeks after administering the transgene or viral vector to the patient.
[215] The method of embodiment 214, wherein after administration of the transgene or the viral vector to the patient, the patient achieves functional independent sitting about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
[216] The method of any one of embodiments 1-215, wherein the patient exhibits a reduction in required mechanical ventilator support to about 16 hours per day or less following administration of the transgene or the viral vector to the patient.
[217] The method of embodiment 216, wherein the patient exhibits a reduction in the required mechanical ventilator support about 24 weeks after administration of the transgene or viral vector to the patient.
[218] The method of embodiment 217, wherein after administering the transgene or the viral vector to the patient, the patient exhibits a reduction in required mechanical ventilator support about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administering the viral vector to the patient.
[219] The method of any one of embodiments 1-218, wherein the patient exhibits a change in CHOP period from baseline after administration of the transgene or the viral vector to the patient.
[220] The method of embodiment 219, wherein the patient exhibits a change in CHOP period from baseline about 24 weeks after administration of the transgenic or viral vector to the patient.
[221] The method of embodiment 220, wherein after administration of the transgene or the viral vector to the patient, the patient exhibits a change in CHOP interval from baseline about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
[222] The method of any one of embodiments 1-221, wherein the patient exhibits a change in Maximum Inspiratory Pressure (MIP) from baseline upon administration of the transgene or the viral vector to the patient.
[223] The method of embodiment 222, wherein the patient exhibits a change in MIP from baseline about 24 weeks after administration of the transgene or viral vector to the patient.
[224] The method of embodiment 223, wherein after administration of the transgene or the viral vector to the patient, the patient exhibits a change in MIP from baseline about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
[225] The method of any one of embodiments 1-224, wherein the patient exhibits a change from baseline in a quantitative analysis of myotubulin expression in a muscle biopsy following administration of the transgene or the viral vector to the patient.
[226] The method of embodiment 225, wherein the patient exhibits a change from baseline in a quantitative analysis of myotubulin expression in a muscle biopsy about 24 weeks after administration of the transgene or viral vector to the patient.
[227] The method of embodiment 226, wherein after administering the transgene or the viral vector to the patient, the patient exhibits a change from baseline in a quantitative analysis of myotubulin expression in a muscle biopsy about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administering the viral vector to the patient.
[228] The method of embodiment 226 or 227, wherein the quantitative analysis of myo-tubulin expression in the muscle biopsy continues for at least 48 weeks from baseline after administration of the viral vector to the patient.
[229] The method of any one of embodiments 1-228, wherein the patient exhibits a reduction in stiffness and/or joint contracture after administration of the transgene or the viral vector to the patient, optionally wherein the patient exhibits a reduction in stiffness and/or joint contracture about 24 weeks after administration of the viral vector to the patient, optionally wherein the patient exhibits a reduction in stiffness and/or joint contracture about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
[230] The method of any one of embodiments 1-229, wherein the patient exhibits diaphragmatic and/or respiratory muscle progression after administration of the transgene or the viral vector to the patient, optionally wherein the patient exhibits diaphragmatic and/or respiratory muscle progression about 24 weeks after administration of the viral vector to the patient, optionally wherein the patient exhibits diaphragmatic and/or respiratory muscle progression about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
[231] The method of any one of embodiments 33 to 226, wherein the patient exhibits a therapeutic effect by finding that the patient exhibits a therapeutic effect of greater than 14 μmol/L (e.g., greater than 14 μmol/L, 15 μmol/L, 16 μmol/L, 17 μmol/L, 18 μmol/L, 19 μmol/L, 20 μmol/L, 21 μmol/L, 22 μmol/L, 23 μmol/L, 24 μmol/L, 25 μmol/L, 26 μmol/L, 27 μmol/L, 28 μmol/L, 29 μmol/L, 30 μmol/L, 31 μmol/L, 32 μmol/L, 33 μmol/L, 34 μmol/L, 35 μmol/L, 36 μmol/L, 37 μmol/L, 38 μmol/L, 39 μmol/L, 40 μmol/L, 41 μmol/L, 42 μmol/L43. Mu. Mol/L, 44. Mu. Mol/L, 45. Mu. Mol/L, 46. Mu. Mol/L, 47. Mu. Mol/L, 48. Mu. Mol/L, 49. Mu. Mol/L, 50. Mu. Mol/L, 51. Mu. Mol/L, 52. Mu. Mol/L, 53. Mu. Mol/L, 54. Mu. Mol/L, 55. Mu. Mol/L, 56. Mu. Mol/L, 57. Mu. Mol/L, 58. Mu. Mol/L, 59. Mu. Mol/L, 60. Mu. Mol/L, 61. Mu. Mol/L, 62. Mu. Mol/L, 63. Mu. Mol/L, 64. Mu. Mol/L, 65. Mu. Mol/L, 66. Mu. Mol/L, 67. Mu. Mol/L, 68. Mu. Mol/L, 69. Mu. Mol/L, 70. Mu. Mol/L, 71. Mu. Mol/L, serum total bile acid levels of 72 μmol/L, 73 μmol/L, 74 μmol/L, 75 μmol/L, 76 μmol/L, 77 μmol/L, 78 μmol/L, 79 μmol/L, 80 μmol/L, 81 μmol/L, 82 μmol/L, 83 μmol/L, 84 μmol/L, 85 μmol/L, 86 μmol/L, 87 μmol/L, 88 μmol/L, 89 μmol/L, 90 μmol/L, 91 μmol/L, 92 μmol/L, 93 μmol/L, 94 μmol/L, 95 μmol/L, 96 μmol/L, 97 μmol/L, 98 μmol/L, 99 μmol/L or 100 μmol/L) determine that the patient exhibits cholestasis or one or more symptoms thereof.
[232] The method of any one of embodiments 33 to 231, wherein the patient is determined to exhibit cholestasis or one or more symptoms thereof by finding that the patient exhibits an increase or decrease in one or more parameters in a blood test relative to a reference level.
[233] The method of embodiment 232, wherein the blood test is a liver function test.
[234] The method of embodiment 232 or 233, wherein the one or more parameters comprise the level of gamma-glutamyl transferase, alkaline phosphatase, aspartate aminotransferase, and/or alanine aminotransferase.
[235] The method of any one of embodiments 33-234, wherein the patient has been identified as exhibiting a bilirubin test of greater than 1mg/dL (e.g., greater than 1mg/dL, 1.1mg/dL, 1.2mg/dL, 1.3mg/dL, 1.4mg/dL, 1.5mg/dL, 1.6mg/dL, 1.7mg/dL, 1.8mg/dL, 1.9mg/dL, 2mg/dL, 2.1mg/dL, 2.2mg/dL, 2.3mg/dL, 2.4mg/dL, 2.5mg/dL, 2.6mg/dL, 2.7mg/dL, 2.8mg/dL, 2.9mg/dL, 3mg/dL, 3.1mg/dL, 3.2mg/dL, 3.3 mg/dL, 3.4mg/dL, 3.5mg/dL a bilirubin level of 3.6mg/dL, 3.7mg/dL, 3.8mg/dL, 3.9mg/dL, 4mg/dL, 4.1mg/dL, 4.2mg/dL, 4.3mg/dL, 4.4mg/dL, 4.5mg/dL, 4.6mg/dL, 4.7mg/dL, 4.8mg/dL, 4.9mg/dL, 5mg/dL, 10mg/dL, 15mg/dL, 20mg/dL, 30mg/dL, 40mg/dL, 50mg/dL, 60mg/dL, 70mg/dL, 80mg/dL, 90mg/dL or 100 mg/dL), determining that the patient exhibits hyperbilirubinemia or one or more symptoms thereof.
[236] The method of embodiment 235, wherein a bilirubin level of greater than 1mg/dL in the bilirubin test occurs about 3 weeks after administration of the transgene or the viral vector to the patient.
[237] The method of embodiment 235 or 236, wherein the bilirubin level comprises a direct bilirubin level or a total bilirubin level.
[238] The method of any one of embodiments 33 to 237, wherein the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof by finding that the patient exhibits an increase in a parameter in a blood test relative to a reference level.
[239] The method of embodiment 238, wherein the parameter comprises the level of serum bile acid.
[240] The method of embodiment 239, wherein the serum bile acid is cholic acid, chenodeoxycholic acid, deoxycholic acid, or ursodeoxycholic acid.
[241] The method of embodiment 238, wherein the blood test is a liver function test.
[242] The method of embodiment 241, wherein the parameter comprises the level of aspartate aminotransferase or alanine aminotransferase.
[243] A kit comprising a transgene encoding MTM1 and a package insert, wherein the package insert directs a user of the kit to administer the transgene to a patient having xltm according to the method of any one of embodiments 1 to 3, 11 to 13, 39 to 41, 43 to 45, 65 to 67, and 69 to 71.
[244] A kit comprising a viral vector comprising a transgene encoding MTM1 and a package insert, wherein the package insert directs a user of the kit to administer the viral vector to a patient having xltm according to the method of any one of embodiments 1 to 89 and 128 to 243.
[245] A kit comprising an anti-cholestasis agent and a package insert, wherein the package insert directs a user of the kit to administer the anti-cholestasis agent to a patient according to the method of any one of embodiments 90 to 127 to treat or prevent cholestasis or hyperbilirubinemia.
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.
While the invention has been described in connection with specific embodiments thereof, it will be understood that the invention is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.
Other embodiments are within the claims.

Claims (118)

1. A method of treating X-linked myotubulomyopathy (xltm) in a human patient in need thereof, the method comprising administering to the patient (i) a therapeutically effective amount of a viral vector comprising a transgene encoding myotubulin 1 (MTM 1) and (ii) an anti-cholestasis agent, wherein the anti-cholestasis agent is administered to the patient in one or more doses beginning within about six weeks of administration of the viral vector to the patient.
2. A method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm, the method comprising administering to the patient (i) a therapeutically effective amount of a viral vector comprising a transgene encoding MTM1 and (ii) an anti-cholestasis agent, wherein the anti-cholestasis agent is administered to the patient in one or more doses beginning within about six weeks of administration of the viral vector to the patient.
3. A method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm, the method comprising administering to the patient (i) a therapeutically effective amount of a viral vector comprising a transgene encoding MTM1 and (ii) an anti-cholestasis agent, wherein the anti-cholestasis agent is administered to the patient in one or more doses beginning within about six weeks of administration of the viral vector to the patient.
4. The method of any one of claims 1 to 3, wherein the anti-cholestasis agent is administered to the patient in one or more doses beginning within about five weeks of administration of the viral vector to the patient, optionally wherein the anti-cholestasis agent is administered to the patient in one or more doses beginning within about four weeks, about three weeks, about two weeks, or about one week of administration of the viral vector to the patient.
5. The method of claim 4, wherein the anti-cholestasis agent is administered to the patient in one or more doses beginning on the same day as the viral vector is administered to the patient.
6. A method of treating xltm in a human patient in need thereof and who has previously been administered an anti-cholestasis agent, the method comprising administering to the patient a therapeutically effective amount of a viral vector comprising a transgene encoding MTM 1.
7. A method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm and previously administered an anti-cholestasis agent, the method comprising administering to the patient a therapeutically effective amount of a viral vector comprising a transgene encoding MTM 1.
8. A method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm and previously administered an anti-cholestasis agent, the method comprising administering to the patient a therapeutically effective amount of a viral vector comprising a transgene encoding MTM 1.
9. The method of any one of claims 1 to 8, wherein the diseaseToxic carrier at less than about 3x 10 14 An amount of vg/kg is administered to the patient.
10. The method of claim 9, wherein the viral vector is present at less than about 2.5x10 14 Administering to said patient an amount of vg/kg, optionally wherein said viral vector is administered in an amount of less than about 2x 10 14 vg/kg, less than about 1.5x10 14 vg/kg or less than about 1.4x10 14 An amount of vg/kg is administered to the patient.
11. The method of any one of claims 1 to 10, wherein the viral vector is present at about 3x 10 13 vg/kg to about 2.3X10 14 Administering to said patient an amount of vg/kg, optionally wherein said viral vector is administered at about 8x 10 13 vg/kg to about 1.8x10 14 vg/kg, about 1X10 14 vg/kg to about 1.6X10 14 vg/kg, about 1.1X10 14 vg/kg to about 1.5x10 14 vg/kg or about 1.2x10 14 vg/kg to about 1.4x10 14 An amount of vg/kg is administered to the patient.
12. The method of any one of claims 1 to 11, wherein the viral vector is present at about 1.3x 10 14 An amount of vg/kg is administered to the patient.
13. The method of any one of claims 1 to 12, wherein the patient is five years old or less at the time of administration of the viral vector.
14. The method of claim 13, wherein the patient is four years old or less when the viral vector is administered, optionally wherein the patient is three years old or less, two years old or less, one year old or less, or six months or less.
15. The method of any one of claims 1 to 12, wherein the patient is about 1 month to about 5 years of age at the time of administration of the viral vector.
16. The method of any one of claims 1 to 15, further comprising monitoring the patient for development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof.
17. The method of claim 16, wherein the progression of cholestasis, hyperbilirubinemia, or one or more symptoms thereof in the patient is monitored by evaluating a parameter of a blood sample obtained from the patient, wherein finding the parameter above a reference level determines the patient as having cholestasis, hyperbilirubinemia, or one or more symptoms thereof.
18. The method of claim 17, wherein the parameter comprises a level of serum bile acid in the blood sample.
19. The method of claim 18, wherein the serum bile acid is cholic acid, chenodeoxycholic acid, deoxycholic acid, or ursodeoxycholic acid.
20. The method of claim 17, wherein the parameters comprise one or more results of a liver function test.
21. The method of claim 20, wherein the parameter comprises a level of aspartate aminotransferase or alanine aminotransferase in the blood sample.
22. A method of treating xltm in a human patient in need thereof, the method comprising:
(a) At less than about 3x 10 14 The amount of vg/kg administering to the patient a viral vector comprising a transgene encoding MTM1,
(b) Monitoring the patient for the development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof,
(c) An anti-cholestasis agent is administered to the patient.
23. A method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm, the method comprising:
(a) At less than about 3x 10 14 The amount of vg/kg administering to the patient a viral vector comprising a transgene encoding MTM1,
(b) Monitoring the patient for the development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof,
(c) An anti-cholestasis agent is administered to the patient.
24. A method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm, the method comprising:
a) At less than about 3x 10 14 The amount of vg/kg administering to the patient a viral vector comprising a transgene encoding MTM1,
(b) Monitoring the patient for the development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof,
(c) An anti-cholestasis agent is administered to the patient.
25. A method of treating xltm in a human patient in need thereof, the method comprising:
(a) At less than about 3x 10 14 The amount of vg/kg administering to the patient a viral vector comprising a transgene encoding MTM1,
(b) Determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and
(c) An anti-cholestasis agent is administered to the patient.
26. A method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm, the method comprising:
(a)at less than about 3x 10 14 The amount of vg/kg administering to the patient a viral vector comprising a transgene encoding MTM1,
(b) Determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and
(c) An anti-cholestasis agent is administered to the patient.
27. A method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm, the method comprising:
(a) At less than about 3x 10 14 The amount of vg/kg administering to the patient a viral vector comprising a transgene encoding MTM1,
(b) Determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and
(c) An anti-cholestasis agent is administered to the patient.
28. The method of any one of claims 22-27, wherein the viral vector is present at less than about 2.5x 10 14 Administering to said patient an amount of vg/kg, optionally wherein said viral vector is administered in an amount of less than about 2x 10 14 vg/kg, less than about 1.5x10 14 vg/kg or less than about 1.4x10 14 An amount of vg/kg is administered to the patient.
29. The method of any one of claims 22-27, wherein the viral vector is at about 3x 10 13 vg/kg to about 2.3X10 14 Administering to said patient an amount of vg/kg, optionally wherein said viral vector is administered at about 8x 10 13 vg/kg to about 1.8x10 14 vg/kg, about 1X10 14 vg/kg to about 1.6X10 14 vg/kg, about 1.1X10 14 vg/kg to about 1.5x10 14 vg/kg or about 1.2x10 14 vg/kg to about 1.4x10 14 An amount of vg/kg is administered to the patient.
30. The method of any one of claims 22-29, wherein the viral vector is at about 1.3x 10 14 The amount of vg/kgThe patient is administered.
31. The method of any one of claims 22-30, wherein the patient is five years old or less at the time of administration of the viral vector.
32. The method of claim 24, wherein the patient is four years old or less when the viral vector is administered, optionally wherein the patient is three years old or less, two years old or less, one year old or less, or six months or less.
33. The method of any one of claims 22-30, wherein the patient is about 1 month to about 5 years of age at the time of administration of the viral vector.
34. A method of treating xltm in a human patient in need thereof five years old or less, the method comprising:
(a) Administering to the patient a therapeutically effective amount of a viral vector comprising a transgene encoding MTM1,
(b) Monitoring the patient for the development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof,
(c) An anti-cholestasis agent is administered to the patient.
35. A method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm, the method comprising:
(a) Administering to the patient a therapeutically effective amount of a viral vector comprising a transgene encoding MTM1,
(b) Monitoring the patient for the development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof,
(c) An anti-cholestasis agent is administered to the patient.
36. A method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm, the method comprising:
(a) Administering to the patient a therapeutically effective amount of a viral vector comprising a transgene encoding MTM1,
(b) Monitoring the patient for the development of cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and if the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof,
(c) An anti-cholestasis agent is administered to the patient.
37. A method of treating xltm in a human patient in need thereof five years old or less, the method comprising:
(a) Administering to the patient a therapeutically effective amount of a viral vector comprising a transgene encoding MTM1,
(b) Determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and
(c) An anti-cholestasis agent is administered to the patient.
38. A method of reducing stiffness and/or joint contracture in a human patient diagnosed with xltm, the method comprising:
(a) Administering to the patient a therapeutically effective amount of a viral vector comprising a transgene encoding MTM1,
(b) Determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and
(c) An anti-cholestasis agent is administered to the patient.
39. A method of increasing diaphragmatic and/or respiratory muscle progression in a human patient diagnosed with xltm, the method comprising:
(a) Administering to the patient a therapeutically effective amount of a viral vector comprising a transgene encoding MTM1,
(b) Determining that the patient exhibits cholestasis, hyperbilirubinemia, or one or more symptoms thereof, and
(c) An anti-cholestasis agent is administered to the patient.
40. The method of any one of claims 34-39, wherein the patient is four years old or less when the viral vector is administered, optionally wherein the patient is three years old or less, two years old or less, one year old or less, or six months or less.
41. The method of any one of claims 34-39, wherein the patient is about 1 month to about 5 years of age at the time of administration of the viral vector.
42. The method of any one of claims 34-41, wherein the viral vector is present at less than about 3x 10 14 An amount of vg/kg is administered to the patient.
43. The method of claim 42, wherein the viral vector is present at less than about 2.5x10 14 Administering to said patient an amount of vg/kg, optionally wherein said viral vector is administered in an amount of less than about 2x 10 14 vg/kg, less than about 1.5x10 14 vg/kg or less than about 1.4x10 14 An amount of vg/kg is administered to the patient.
44. The method of any one of claims 34 to 41, wherein the viral vector is present at about 3x 10 13 vg/kg to about 2.3X10 14 Administering to said patient an amount of vg/kg, optionally wherein said viral vector is administered at about 8x 10 13 vg/kg to about 1.8x10 14 vg/kg, about 1X10 14 vg/kg to about 1.6X10 14 vg/kg, about 1.1X10 14 vg/kg to about 1.5x10 14 vg/kg or about 1.2x10 14 vg/kg to about 1.4x10 14 An amount of vg/kg is administered to the patient.
45. The method of any one of claims 34 to 44, wherein the viral vector is present at about 1.3x 10 14 An amount of vg/kg is administered to the patient.
46. A method of treating or preventing cholestasis or hyperbilirubinemia in a human patient having xltm and having previously been at less than about 3x 10 14 A viral vector comprising a transgene encoding MTM1 is administered in an amount of vg/kg, the method comprising administering an anti-cholestasis agent to the patient.
47. The method of claim 46, wherein the viral vector is present at less than about 2.5x10 14 Administering to said patient an amount of vg/kg, optionally wherein said viral vector is administered in an amount of less than about 2x 10 14 vg/kg, less than about 1.5x10 14 vg/kg or less than about 1.4x10 14 An amount of vg/kg is administered to the patient.
48. The method of claim 46, wherein the viral vector is present at about 3X 10 13 vg/kg to about 2.3X10 14 Administering to said patient an amount of vg/kg, optionally wherein said viral vector is administered at about 8x 10 13 vg/kg to about 1.8x10 14 vg/kg, about 1X 10 14 vg/kg to about 1.6X10 14 vg/kg, about 1.1X10 14 vg/kg to about 1.5x10 14 vg/kg or about 1.2x10 14 vg/kg to about 1.4x10 14 An amount of vg/kg is administered to the patient.
49. The method of any one of claims 46 to 48, wherein the viral vector is present at about 1.3x 10 14 An amount of vg/kg is administered to the patient.
50. The method of any one of claims 46-49, wherein the patient is five years old or less when the viral vector is administered.
51. The method of claim 50, wherein the patient is four years old or less when the viral vector is administered, optionally wherein the patient is three years old or less, two years old or less, one year old or less, or six months or less.
52. The method of any one of claims 46-49, wherein the patient is about 1 month to about 5 years of age at the time of administration of the viral vector.
53. A method of treating or preventing cholestasis or hyperbilirubinemia in a human patient having xltm, having previously been administered a viral vector comprising a transgene encoding MTM1, and five years old or less when the viral vector is administered, comprising administering an anti-cholestasis agent to the patient.
54. The method of claim 53, wherein the patient is four years old or less when the viral vector is administered, optionally wherein the patient is three years old or less, two years old or less, one year old or less, or six months or less.
55. The method of claim 53, wherein the patient is about 1 month to about 5 years of age at the time of administration of the viral vector.
56. The method of any one of claims 53-55, wherein the viral vector is present at less than about 3x 10 14 An amount of vg/kg is administered to the patient.
57. The method of claim 56, wherein said viral vector is present at less than about 2.5x10 14 Administering to said patient an amount of vg/kg, optionally wherein said viral vector is administered in an amount of less than about 2x 10 14 vg/kg, less than about 1.5x10 14 vg/kg or less than about 1.4x10 14 An amount of vg/kg is administered to the patient.
58. The method of any one of claims 53-55, wherein the viral vector is at about 3x 10 13 vg/kg to about 2.3X10 14 Administering to said patient an amount of vg/kg, optionally wherein said viral vector is administered at about 8x 10 13 vg/kg to about 1.8x10 14 vg/kg, about 1X10 14 vg/kg to about 1.6X10 14 vg/kg, about 1.1X10 14 vg/kg to about 1.5x10 14 vg/kg or about 1.2x10 14 vg/kg to about 1.4x10 14 An amount of vg/kg is administered to the patient.
59. The method of any one of claims 53-58, wherein said viral vector is present at about 1.3x 10 14 An amount of vg/kg is administered to the patient.
60. The method of any one of claims 1-52 and 56-59, wherein said viral vector is administered to said patient in a single dose comprising said amount.
61. The method of any one of claims 1-52 and 56-59, wherein said viral vector is administered to said patient in two or more doses that together comprise said amount.
62. The method of any one of claims 1-52 and 56-59, wherein said viral vector is administered to said patient in two or more doses each individually comprising said amount.
63. The method of claim 61 or 62, wherein the two or more doses are separated from each other by one year or more.
64. The method of claim 61 or 62, wherein the two or more doses are administered to the patient within about 12 months of each other.
65. The method of any one of claims 1 to 64, wherein the viral vector is selected from the group consisting of adeno-associated virus (AAV), adenovirus, lentivirus, retrovirus, poxvirus, baculovirus, herpes simplex virus, vaccinia virus, and synthetic virus.
66. The method of claim 65, wherein the viral vector is AAV.
67. The method of claim 66, wherein the AAV is AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh10, or AAVrh74 serotype.
68. The method of claim 66, wherein the viral vector is a pseudotyped AAV.
69. The method of claim 68, wherein the pseudotyped AAV is AAV2/8 or AAV2/9, optionally wherein the pseudotyped AAV is AAV2/8.
70. The method of any one of claims 1 to 69, wherein the transgene encoding MTM1 is operably linked to a muscle-specific promoter.
71. The method of claim 70, wherein the muscle-specific promoter is a desmin promoter, a muscle creatine kinase promoter, a myosin light chain promoter, a myosin heavy chain promoter, a cardiac troponin C promoter, a troponin I promoter, a myoD gene family promoter, an actin alpha promoter, an actin beta promoter, an actin gamma promoter, or a promoter within intron 1 of pair-like homeodomain 3 in the eye.
72. The method of claim 71, wherein the muscle-specific promoter is a desmin promoter.
73. The method of any one of claims 1 to 72, wherein the viral vector is birnesyl.
74. The method of any one of claims 1-73, wherein the viral vector is administered to the patient by intravenous, intramuscular, intradermal, or subcutaneous administration.
75. The method of any one of claims 1 to 74, wherein the anti-cholestasis agent is selected from the group consisting of: bile acids, farnesol X Receptor (FXR) ligands, fibroblast growth factor 19 (FGF-19) mimics, takeda-G protein receptor 5 (TGR 5) agonists, peroxisome proliferator-activated receptor (PPAR) agonists, PPAR-alpha agonists, PPAR-delta agonists, dual PPAR-alpha and PPAR-delta agonists, apical sodium-dependent bile acid transporter (ASBT) inhibitors, immunomodulatory drugs, anti-fibrotic therapies, and nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitors.
76. The method of claim 75, wherein:
(i) The FXR ligand is obeticholic acid, cilofaxomic, tetroxide Luo Fasuo, tretinoin or EDP-305;
(ii) The FGF-19 mimetic is Aldarifenacin;
(iii) The TGR5 agonist is INT-777 or INT-767;
(iv) The PPAR agonist is bezafibrate, seladerpa or elabeno;
(v) The PPAR-alpha agonist is fenofibrate;
(vi) The PPAR-delta agonist is seladelpha;
(vii) The dual PPAR-alpha and PPAR-delta agonists are alafilno;
(viii) The ASBT inhibitor is ondevixibat, maraxibat, or linexibat;
(ix) The immunomodulator is rituximab, abamectin, utiliamab, infliximab or Barituximab or FFP-104;
(x) The anti-fibrosis therapy is vitamin D receptor agonist or Xin Tuozhu monoclonal antibody; and/or
(xi) The NOX inhibitor is celecoxib.
77. The method of claim 75, wherein the bile acid is ursodeoxycholic acid, norursodeoxycholic acid, or a pharmaceutically acceptable salt thereof.
78. The method of claim 77, wherein said bile acid is bear diol.
79. The method of any one of claims 75, 77 and 78, wherein the bile acid is administered to the patient in a single dose.
80. The method of any one of claims 75, 77 and 78, wherein said bile acid is administered to said patient in a plurality of doses.
81. The method of claim 79 or 80, wherein the bile acid is administered to the patient in an amount of about 5 mg/kg/dose to about 20 mg/kg/dose, optionally wherein the bile acid is administered to the patient in an amount of about 6 mg/kg/dose to about 19 mg/kg/dose, about 7 mg/kg/dose to about 18 mg/kg/dose, about 8 mg/kg/dose to about 17 mg/kg/dose, about 10 mg/kg/dose to about 15 mg/kg/dose, or about 12 mg/kg/dose to about 13 mg/kg/dose.
82. The method of claim 81, wherein the bile acid is administered to the patient in an amount of about 5 mg/kg/dose to about 11 mg/kg/dose, optionally wherein the bile acid is administered to the patient in an amount of about 6 mg/kg/dose to about 10 mg/kg/dose or about 7 mg/kg/dose to about 9 mg/kg/dose.
83. The method of claim 82, wherein the bile acid is administered to the patient at one or more doses daily, weekly, or monthly.
84. The method of claim 83, wherein the bile acid is administered to the patient in one or more doses per day, optionally wherein the bile acid is administered to the patient in one dose per day, two doses per day, three doses per day, four doses per day, or five doses per day.
85. The method of claim 84, wherein the bile acid is administered to the patient at a dose of one per day.
86. The method of any one of claims 75 to 85, wherein the bile acid is administered to the patient in an amount of about 5 mg/kg/day to about 40 mg/kg/day, optionally wherein (i) the bile acid is administered to the patient in an amount of about 6 mg/kg/day to about 39 mg/kg/day, about 8 mg/kg/day to about 37 mg/kg/day, about 13 mg/kg/day to about 32 mg/kg/day, or about 20 mg/kg/day to about 25 mg/kg/day, or (ii) the bile acid is administered to the patient in an amount of about 17 mg/kg/day to about 23 mg/kg/day, about 18 mg/kg/day to about 22 mg/kg/day, or about 19 mg/kg/day to about 21 mg/kg/day.
87. The method of any one of claims 75-86, wherein the bile acid is administered to the patient in an amount of 20 mg/kg/day.
88. The method of any one of claims 75-87, wherein the bile acid is administered to the patient by a unit dosage form comprising 250mg of the bile acid.
89. The method of any one of claims 75-87, wherein the bile acid is administered to the patient by a unit dosage form comprising 500mg of the bile acid.
90. The method of any one of claims 75-89, wherein the bile is administered to the patient by enteral administration.
91. The method of any one of claims 1-90, wherein the patient has no history of cholestasis or hyperbilirubinemia.
92. The method of claim 91, wherein the patient does not have a history of any potential liver disease.
93. The method of any one of claims 1-92, wherein the patient is greater than or equal to 35 weeks gestational age at birth and is or was from term to about 5 years of age at the time of administration of the viral vector.
94. The method of any one of claims 1-93, wherein the patient is male.
95. The method of any one of claims 1-94, wherein the patient requires mechanical ventilation support, optionally wherein mechanical ventilation support comprises invasive mechanical ventilation support and non-invasive mechanical ventilation support.
96. The method of any one of claims 1-95, wherein the patient exhibits a change in the number of hours of mechanical ventilatory support over time relative to baseline after administration of the viral vector to the patient, optionally wherein the patient exhibits a change in the number of hours of mechanical ventilatory support over time relative to baseline about 24 weeks after administration of the viral vector to the patient, optionally wherein the patient exhibits a change in the number of hours of mechanical ventilatory support over time relative to baseline about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
97. The method of any one of claims 1-96, wherein the patient achieves functional independence for at least 30 seconds after administration of the viral vector to the patient, optionally wherein the patient achieves functional independence for about 24 weeks after administration of the viral vector to the patient, optionally wherein the patient exhibits functional independence for at least 30 seconds about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
98. The method of any one of claims 1-97, wherein the patient exhibits a reduction in required mechanical ventilator support to about 16 hours or less per day after administration of the viral vector to the patient, optionally wherein the patient exhibits a reduction in required mechanical ventilator support about 24 weeks after administration of the viral vector to the patient, optionally wherein the patient exhibits a reduction in required mechanical ventilator support about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
99. The method of any one of claims 1-98, wherein the patient exhibits a change from baseline in a philadelphia hospital neuromuscular disorder infant test (CHOP end) after administration of the viral vector to the patient, optionally wherein the patient exhibits a change from baseline in CHOP end about 24 weeks after administration of the viral vector to the patient, optionally wherein the patient exhibits a change from baseline in CHOP end about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
100. The method of any one of claims 1-99, wherein the patient exhibits a change in Maximum Inspiratory Pressure (MIP) from baseline after administration of the viral vector to the patient, optionally wherein the patient exhibits a change in MIP from baseline about 24 weeks after administration of the viral vector to the patient, optionally wherein the patient exhibits a change in MIP from baseline about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
101. The method of any one of claims 1-100, wherein the patient exhibits a change from baseline in a quantitative analysis of myo-tubulin expression in a muscle biopsy after administration of the viral vector to the patient, optionally wherein the patient exhibits a change from baseline in a quantitative analysis of myo-tubulin expression in a muscle biopsy about 24 weeks after administration of the viral vector to the patient, optionally wherein the patient exhibits a change from baseline in a quantitative analysis of myo-tubulin expression in a muscle biopsy about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
102. The method of claim 101, wherein the quantitative analysis of myotubulin expression in the muscle biopsy continues for at least 48 weeks from baseline after administration of the viral vector to the patient.
103. The method of any one of claims 1-102, wherein the patient exhibits a reduction in stiffness and/or joint contracture after administration of the viral vector to the patient, optionally wherein the patient exhibits a reduction in stiffness and/or joint contracture about 24 weeks after administration of the viral vector to the patient, optionally wherein the patient exhibits a reduction in stiffness and/or joint contracture about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
104. The method of any one of claims 1-103, wherein the patient exhibits diaphragmatic and/or respiratory muscle progression after administration of the viral vector to the patient, optionally wherein the patient exhibits diaphragmatic and/or respiratory muscle progression about 24 weeks after administration of the viral vector to the patient, optionally wherein the patient exhibits diaphragmatic and/or respiratory muscle progression about 20 weeks, 16 weeks, 12 weeks, 8 weeks, or 4 weeks after administration of the viral vector to the patient.
105. The method of any one of claims 16-104, wherein the patient is determined to exhibit cholestasis or one or more symptoms thereof by finding that the patient exhibits a serum total bile acid level of greater than 14 μmol/L.
106. The method of any one of claims 16-105, wherein the patient is determined to exhibit cholestasis or one or more symptoms thereof by finding that the patient exhibits an increase or decrease in one or more parameters in a blood test relative to a reference level.
107. The method of claim 106, wherein the blood test is a liver function test.
108. The method of claim 106 or 107, wherein the one or more parameters comprise levels of γ -glutamyl transferase, alkaline phosphatase, aspartate aminotransferase, and/or alanine aminotransferase.
109. The method of any one of claims 16-108, wherein the patient is determined to exhibit hyperbilirubinemia or one or more symptoms thereof by finding that the patient exhibits a bilirubin level of greater than 1mg/dL in a bilirubin test.
110. The method of claim 109, wherein the patient exhibits a bilirubin level of greater than 1mg/dL in a bilirubin test about 3 weeks after administration of the viral vector to the patient.
111. The method of claim 109 or 110, wherein the bilirubin level comprises a direct bilirubin level or a total bilirubin level.
112. The method of any one of claims 16-111, wherein the patient is determined to exhibit cholestasis, hyperbilirubinemia, or one or more symptoms thereof by finding that the patient exhibits an increase in a parameter in a blood test relative to a reference level.
113. The method of claim 112, wherein the parameter comprises the level of serum bile acid.
114. The method of claim 113, wherein the serum bile acid is cholic acid, chenodeoxycholic acid, deoxycholic acid, or ursodeoxycholic acid.
115. The method of claim 112, wherein the blood test is a liver function test.
116. The method of claim 115, wherein the parameter comprises the level of aspartate aminotransferase or alanine aminotransferase.
117. A kit comprising a viral vector comprising a transgene encoding MTM1 and a package insert, wherein the package insert directs a user of the kit to administer the viral vector to a patient having xltm according to the method of any one of claims 1 to 52 and 60 to 116.
118. A kit comprising an anti-cholestasis agent and a package insert, wherein the package insert directs a user of the kit to administer the anti-cholestasis agent to a patient according to the method of any one of claims 53 to 116 to treat or prevent cholestasis or hyperbilirubinemia.
CN202280051606.0A 2021-05-24 2022-05-24 Compositions and methods for improved treatment of X-linked myotubulomyopathy Pending CN117769441A (en)

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