CN115135347A - Methods of treating Parkinson's disease - Google Patents
Methods of treating Parkinson's disease Download PDFInfo
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- CN115135347A CN115135347A CN202080096586.XA CN202080096586A CN115135347A CN 115135347 A CN115135347 A CN 115135347A CN 202080096586 A CN202080096586 A CN 202080096586A CN 115135347 A CN115135347 A CN 115135347A
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Abstract
Methods of using glutamate decarboxylase (GAD) to treat neurological disorders such as Parkinson's Disease (PD) and to identify PD patients who will most readily receive treatment for PD are disclosed. In one aspect, the present disclosure provides a method of treating PD in a subject in need thereof, the method comprising: (a) identifying a subject having an on-time of less than about 10 hours, preferably less than about 8 hours per day; and (b) administering to the subject a composition comprising a therapeutically effective amount of one or more vectors to the subthalamic nucleus of the patient, wherein each vector comprises a nucleic acid sequence encoding a glutamate decarboxylase (GAD), and wherein the on-time of the subject is extended.
Description
Cross Reference to Related Applications
This application claims priority to U.S. provisional application No. 62/947,418, filed on 12/2019, which is incorporated herein by reference in its entirety.
Technical Field
The present disclosure relates to methods and compositions for treating Parkinson's Disease (PD) and other neurodegenerative disorders. More specifically, described herein are methods comprising administering to a subject one or more vectors comprising a nucleic acid sequence encoding an isoform of glutamate decarboxylase (GAD) and identifying a target patient population most susceptible to a method of treating PD.
Technical Field
Central nervous system disorders, particularly those involving dopamine neurotransmitters, affect millions of people worldwide each year. Over 1000 million patients worldwide and nearly 100 million patients in the united states have Parkinson's Disease (PD), one of the most common central nervous system disorders.
PD is a multifactorial disease involving both genetic and non-genetic factors. Some of the mechanisms that may lead to the development of PD include accumulation of misfolded protein aggregates, failure of protein clearance pathways, mitochondrial damage, oxidative stress, excitotoxicity, neuroinflammation, and genetic mutations. PD affects a portion of the brain nerve cells known as the basal ganglia and substantia nigra. The substantia nigra is a basal ganglia structure located in the midbrain, which plays an important role in reward and exercise. This region is composed primarily of dopaminergic neurons (DA) that produce the neurotransmitter dopamine. In the brain, dopamine, as an inhibitory neurotransmitter, regulates the excitability of neurons that are involved in controlling balance and body movement. In the normal brain, DA neurons release dopamine, which crosses synapses and fits into receptors on recipient cells. The cells transmit information upon stimulation. Following information transmission, the receptor releases dopamine molecules back into the synapse, where excess dopamine is "taken up" or recirculated within the releasing neuron.
Gamma-aminobutyric acid or gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the developing adult mammalian central nervous system. Most nigral DA neurons express gamma-aminobutyric acid (a) ((GABA (a)) and gamma-aminobutyric acid (B) (GABA (B)) receptors, DA neurons regulate monosynaptic GABA output in the substantia nigra, recirculation of dopamine is regulated by the gamma-aminobutyric acid (GABA) pathway it is well known in the art that activation of the GABA pathway results in an increase in dopamine, which in turn reduces the firing rate of nerve cells.
For reasons that are not fully understood, dopamine-producing nerve cells of the substantia nigra in PD patients begin to die off, which leads to dopamine deficiency and loss of signaling through dopamine receptors in multi-synaptic neurons. In addition, the absence of DA neurons leads to a decrease in the gamma aminobutyric acid (GABA) inhibitory input to the subthalamic nucleus, resulting in increased activity of the subthalamic nucleus. The subthalamic nucleus, in turn, signals an increase in activity to other cells within the basal ganglia. When GABA levels are below a certain threshold, they lead to dopamine depletion in the brain. Loss of dopamine alters the activity of neurons within the basal ganglia, resulting in uncontrolled firing of nerve cells. When dopamine levels fall below a certain point (about 80% drop), symptoms of PD such as motor loss control, tremor begin to appear.
PD is characterized by progressive deterioration of body muscle movement; poor balance and coordination; and uncontrolled judder. Standard treatments for PD include oral administration of the dopamine precursor L-3, 4-dihydroxyphenylalanine (levodopa or L-dopa), which eliminates symptoms associated with PD but does not ultimately prevent the degeneration of dopaminergic cells. Thus, currently used PD treatments only alleviate PD symptoms, but do not slow or stop disease progression.
Administration of L-dopa gives PD patients an "on-time", a period of time during which PD patients adequately control PD symptoms. When the effects of L-dopa disappear, the symptoms of PD reappear. This period is called "off-time". The measurement of the on-time and off-time is typically calculated by asking the patient to keep a medication diary. In this diary, patients recorded how long it took for L-dopa to become effective and to be depleted. In the early stages of PD, the patient has an on-time of about 16 hours for L-dopa administration. However, as the disease progresses, the amount of open time gradually decreases, even with larger doses of drug. In addition, side effects associated with chronic administration of L-dopa can be very severe, including mental changes such as depression, hallucinations, mania, delusions, agitation, and hypersomnia. Administration of L-dopa may also have adverse effects on patients with cardiovascular or pulmonary, renal, hepatic or endocrine diseases. Some of the side effects associated with chronic administration of L-dopa can be alleviated by co-administration of N-amino- α -methyl-3-hydroxy-L-tyrosine monohydrate, an aromatic Amino Acid Decarboxylase (AADC), an enzyme that decarboxylates L-dopa to dopamine. However, this combination of drugs may still cause nausea, dyskinesias, psychosis and hypotension.
One of the major obstacles to the treatment of PD with small molecule drugs is the inability of most systemically administered drugs to cross the blood-brain barrier. One approach has focused on increasing the lipid content of polypeptides to facilitate their transport across the blood-brain barrier. Another approach has focused on enhancing the permeability of capillaries in the brain. However, none of these approaches address the problem of crossing the blood-brain barrier. Other methods of treating PD, such as transplantation of dopamine-producing engineered cells to the brain and deep brain stimulation, are characterized by serious side effects such as high mortality, increased chance of serious infection, and potential brain damage. More importantly, there is no available drug that addresses the root cause of PD or provides PD patients with more on-time without serious side effects.
In view of the limitations of current PD treatments, there remains an unmet need for (1) non-transitory treatment of PD, particularly in PD patients who do not respond to current standard of care, (2) non-transitory treatment that effectively extends the turn-on time of PD patients without causing significant side effects, and (3) reliable methods for identifying patient populations most susceptible to non-transitory treatment of PD.
Disclosure of Invention
In one aspect, the present disclosure provides a method of treating PD in a subject in need thereof, the method comprising: (a) identifying a subject having an on-time of less than about 10 hours, preferably less than about 8 hours per day; and (b) administering to the subject a composition comprising a therapeutically effective amount of one or more vectors to the subthalamic nucleus of the patient, wherein each vector comprises a nucleic acid sequence encoding a glutamate decarboxylase (GAD), and wherein the on-time of the subject is extended. In one embodiment, the one or more vectors are introduced bilaterally into the subthalamic nucleus of the patient.
In one embodiment, the present disclosure provides a method of treating PD in a subject in need thereof, wherein the subject has an on-time of less than 10 hours, less than 9 hours, less than 8 hours, less than 7 hours, less than 6 hours, less than 5 hours, or less than 4 hours per day prior to treatment.
In one embodiment, the present disclosure provides a method of treating PD in a subject in need thereof, wherein the one or more vectors comprise a nucleic acid sequence encoding GAD-65 and/or a nucleic acid sequence encoding GAD-67. In embodiments, two vectors are administered, wherein one vector comprises a GAD-65 encoding nucleic acid and the other vector comprises a GAD-67 encoding nucleic acid. In further embodiments, the vector comprising the GAD-65 encoding nucleic acid and the vector comprising the GAD-67 encoding nucleic acid are administered in a ratio of about 1: 2 to about 2: 1, preferably about 1: 1.
In one embodiment, the present disclosure provides a method of treating PD in a subject in need thereof, wherein the one or more vectors used in the method comprise a nucleic acid sequence encoding GAD-65 and encoding GAD-67. In one embodiment, the amino acid sequence of human GAD-65 is provided as SEQ ID NO: 1(Genbank accession No. NM 000818; M81882). In another embodiment, the amino acid sequence of human GAD-65 is provided as SEQ ID NO: 3. in some embodiments, the nucleic acid sequence encodes a polypeptide that is identical to SEQ ID NO: 1 or SEQ ID NO: 3, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical. In embodiments, the nucleic acid sequence encoding GAD-65 comprises SEQ ID NO: 2 or SEQ ID NO: 4. in some embodiments, the nucleic acid sequence encoding GAD-65 comprises a nucleotide sequence identical to SEQ ID NO: 2 or SEQ ID NO: 4, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical. In one embodiment, the amino acid sequence of human GAD-67 is provided as SEQ ID NO: 5 (accession number M81883). In another embodiment, the amino acid sequence of human GAD-67 is provided as SEQ ID NO: 7. in some embodiments, the nucleic acid sequence encodes a polypeptide that differs from SEQ ID NO: 5 or SEQ ID NO: 7, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical. In embodiments, the nucleic acid sequence encoding GAD-67 comprises SEQ ID NO: 6. in embodiments, the nucleic acid sequence encoding GAD-67 comprises SEQ ID NO: 8. in embodiments, the nucleic acid sequence encoding GAD-67 comprises a nucleotide sequence identical to SEQ ID NO: 6 or SEQ ID NO: 8, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical.
In one embodiment, the present disclosure provides a method of treating PD in a subject in need thereof, wherein the one or more vectors used in the method are viral vectors. In one embodiment, the present disclosure provides a method of treating PD in a subject in need thereof, wherein the disclosed viral vector is an adeno-associated virus (AAV) vector.
In one embodiment, the present disclosure provides a method of treating PD in a subject in need thereof, wherein the composition comprises at least 1x10 11 Vector genome/ml. In one embodiment, the present disclosure provides a method of treating PD in a subject in need thereof, wherein the composition comprises at least 3x10 11 Vector genome/ml. In one embodiment, the present disclosure provides a method of treating PD in a subject in need thereof, wherein the composition comprises at least 1x10 12 Vector genome/ml.
In one embodiment, the present disclosure provides a method of treating PD in a subject in need thereof, wherein the subject exhibits a mean prolongation of on-time of at least 20%, at least 30%, at least 40% compared to before treatment 12 months after treatment. In embodiments, the subject has an extended open time of about 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, or 5 hours at 12 months post-treatment.
Drawings
FIG. 1 extension of the "on" time following AAV-GAD gene therapy. Subjects receiving AAV-gad (gad) into STN or sham (sham) recorded the on-and off-times in hours for 2 weeks in a diary daily at each of the listed time points (1 month, 3 months, 6 months, and 12 months post-surgery). The average daily on-time and off-time over two weeks as measured from the diary was compared to the baseline diary 30 days prior to surgery to determine the change in hours of on-time post-surgery. There were gross differences between groups throughout the 12 month study period by analysis of variance (ANOVA; p ═ 0.44). The two-tailed t-test showed significant increases in the opening time at 3 and 12 months post-surgery (p < 0.05), with a significant trend at 1 month. The average increase in the opening time of the AAV-GAD group was 1 to 2.5 hours throughout the study, with little or no change in the mean of the sham group at any time point.
FIG. 2 correlation between baseline on-time and change in on-time after AAV-GAD gene therapy. At 12 months post-surgery, changes in the mean daily open time from baseline for each subject in the AAV-GAD treated group correlated with changes in the clinical score for the same subject over the same time period. The clinical score used was part 3 of the Unified Parkinson's Disease Rating Scale (UPDRS), which is a gold standard assessment of motor function in parkinson's disease patients. This indicates a strong correlation between baseline opening time and prolongation of opening time at 12 months post-thalamic AAV-GAD gene therapy (r ═ 0.59), indicating that fewer hours of opening time at baseline (more severe patients) are predictive of a greater increase in hours of opening time after treatment (greater response). Subjects with lower baseline opening times showed increased gains in opening time after treatment. Patients with an open time of less than 8 hours had the greatest response to AAV-GAD therapy, with an average increase in open time of 3.5 hours per day.
Detailed Description
The present disclosure provides methods for treating PD in a subject in need thereof, and methods of identifying PD patients who are most receptive to methods of treating PD. In one aspect, methods of treating PD are provided by identifying a subject with an on-time per day of less than 10 hours, less than 9 hours, less than 8 hours, less than 7 hours, less than 6 hours, less than 5 hours, less than 4 hours, and administering a therapeutically effective amount of GAD (e.g., by expressing GAD-65 and GAD-67) in the subthalamic nucleus of the patient to increase the on-time to treat PD.
Patient selection
In one aspect, the present disclosure provides methods of treating patients most benefited from the treatments provided by the present disclosure. In some embodiments, the patient has an on-time of about 10 hours or less per day. In some embodiments, the patient has an on-time of about 9 hours or less, about 8 hours or less, about 7 hours or less, about 6 hours or less, or about 5 hours or less per day. At the onset of the disease, usually within the first 3-5 years after diagnosis, a single dose of L-dopa can give the patient an on-time of about 16 hours. The period of on-time becomes progressively shorter as the disease progresses, even with increasing doses of L-dopa medication. In the metaphase stage of PD, usually about 5-10 years after diagnosis, 50-70% of patients suffer from L-dopa-induced motor complications. At this stage, the benefits of L-dopa are depleted after about 4 hours or less, and patients begin to fluctuate between the on-period and off-time motor responses. As the disease progresses, the duration of remission after a single dose of L-dopa gradually shortens, eventually possibly reflecting the L-dopa serum half-life (approximately 60 to 90 minutes) of patients with advanced PD (usually > 10 years post-diagnosis). In some cases, patients may not respond to a given dose of L-dopa. The most difficult clinical situation is described as the true "on-off" or yo-yo phenomenon, in which patients fluctuate rapidly between on-and off-times, seemingly losing the relationship with L-dopa dosing. At this stage, the dyskinesia and off-time are severe and it may be difficult or impossible to satisfactorily control the patient with the available therapies. In addition, patients in the middle and late stages suffer from adverse side effects due to increased L-dopa medication.
Standard treatment for stage 3 or higher PD patients is L-dopa in combination with an AADC inhibitor. This therapy causes a temporary resolution of PD symptoms, thereby allowing the patient to regain control of his or her abilities. As used herein, the period of time during which a PD patient experiences remission from PD is referred to as the "on time". Symptoms of PD that are alleviated during the opening time include, but are not limited to, loss of motor control, pain, slurred mouth, tremor, and impaired balance. Tremor and other PD symptoms reappear as the drug effect subsides. As used herein, the period of time during which a patient experiences a reoccurrence of PD symptoms due to drug depletion is referred to as the "off-time".
The measurement between the on time and the off time can be determined by the patient's stored dose daily gain. Patients note the time they feel the medication is effective, enabling them to control their exercise facility and the time they feel the medication is depleting, resulting in the reoccurrence of PD symptoms. The clinician uses the schedule recorded in the diary to determine the on and off times of PD patients at specific time points. The on-time and off-time may also be measured using wearable devices including, but not limited to, motion sensors, accelerometers, and posture detection devices, by, for example, measuring and tracking the characteristics of hypokinesia and hyperkinesia associated with PD.
In embodiments, the patient has had PD for at least three years prior to receiving the therapy described herein. In some embodiments, the patient has PD for at least four years, or at least five years. In embodiments, the patient receiving the therapy described herein is in stage 2, stage 3, stage 4, or stage 5 of the disease. Progression of PD can be divided into five stages. Stage 1 of PD is characterized by disorders of facial expression, speech, and/or movement. Symptoms are initially seen on only one side of the body (unilateral involvement) and are usually slightly or non-dysfunctional. During phase 2 of PD, both hemispheres of the brain are affected by disease. As a result, tremor becomes bilateral and can affect the midline of the patient. Other symptoms of PD at stage 2 may include loss of facial expression on both sides of the face, decreased blinking, speech abnormalities, soft voice, monotonous voice, unclear mouth and teeth, stiffness or rigidity of trunk muscles (which may lead to neck or back pain, hunched posture, and generally slow activities of daily living). Stage 3 is characterized by loss of balance and slow movement. The balance is impaired by the inability to make the rapid, automatic and involuntary adjustments necessary to prevent falls, and falls are common during this period. Stage 4 patients exhibited severe restrictive symptoms. The patient may be able to stand without assistance, but the exercise may require a walker. Stage 5 is the most advanced and debilitating stage of PD. Stiffness in the legs may result in inability to stand or walk. The patient needs a wheelchair or is bedridden. All activities of the patient during this phase of PD require all-weather care.
In embodiments, one or more of the UPDRS selected for the therapies disclosed herein that have a score of about 20 or more, about 30 or more, or about 40 or more at part III of the UPDRS in the dosed state and/or have motor complications resulting from the administration of L-dopa can measure the stage of PD using a Unified Parkinson's Disease Rating Scale (UPDRS) (see, e.g., Metman et al, mov. disorder.19: 1079 + 1084 (2004)). The UPDRS scale includes a series of ratings for typical PD symptoms. The scale consists of four parts: assessment of behavioral problems such as mental decline, hallucinations, and depression; part II assess the patient's perception of their ability to perform activities of daily living, including dressing, walking, and eating; part III covers assessment of dyskinesias including ranking of tremor, slowness (bradykinesia), stiffness (rigidity) and balance; part IV covers a number of treatment complications, including the ranking of involuntary movements (dyskinesias), painful spasms (dystonia) and irregular drug responses (motor fluctuations). Part III or motor examination is scored by the clinician through a structured neurological examination. It consists of 14 terms, which can have a score from zero (normal) to four (severe). The scores are added to give the total score of involuntary movements. The clinician uses the scores obtained from the evaluations listed in section III to determine the severity of PD and the appropriate treatment.
Methods of treating PD
In embodiments, the present disclosure provides methods of treating, preventing, and/or reducing the severity or extent of PD by administering to a subject in need thereof a therapeutically effective amount of one or more compositions comprising one or more vectors comprising a nucleic acid encoding GAD-65 and/or vectors comprising a nucleic acid encoding GAD-67. In an embodiment, a method for treating a PD patient comprises administering one or more compositions to a patient in need thereof, wherein the one or more compositions comprise one or more vectors for expressing GAD-65 and/or vectors for expressing GAD-67.
As used herein, "treating", "treatment" and "treatment" refer to alleviating, ameliorating or alleviating at least one symptom of a disease or disorder, or reversing one or more symptoms of the disease or disorder after its onset. The purpose of treatment is to prevent or alleviate or stop an undesired physical condition, disorder or disease or to achieve a beneficial clinical outcome.
The terms "prevent", "prevention" and the like refer to acting before the onset of an apparent disease or condition to prevent or minimize the development of the disease or condition, or to slow the progression of the disease or condition.
The term "cure" or the like means to heal, moderate, or restore health, or to allow a period of time without recurrence of the disease so that the risk of recurrence is small.
The phrase "therapeutically effective amount" is used herein to refer to an amount sufficient to cause clinically significant amelioration of a disorder in a subject, or to delay or minimize or alleviate one or more symptoms associated with a disease or condition, or to cause a desired beneficial physiological change in a subject.
In embodiments, a subject receiving a therapy described herein (e.g., receiving a therapeutically effective amount of a composition comprising one or more vectors comprising a nucleic acid encoding GAD-65 and/or vectors comprising a nucleic acid encoding GAD-67) has an average extension of the on-time of about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, or about 4 hours at 12 months after receiving the therapy. In embodiments, the subject has an extension of about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% open time at 12 months after receiving therapy.
Standard PD therapy involves administration of dopamine precursors, L-dopa, to supplement dopamine. However, increasing GABA levels also leads to these uncontrolled motor stops, as higher concentrations of GABA allow dopamine levels to recover or increase. In embodiments, the disclosure provides methods of increasing GABA levels in the subthalamic nucleus by administering one or more vectors comprising a glutamate decarboxylase (GAD) isoform. GABA is produced in the brain by GAD, which catalyzes the decarboxylation of glutamate to GABA and CO 2 . The mammalian brain expresses two different GAD isoforms GAD-65 and GAD-67, named for their respective molecular weights of 65kDa and 67kDa, respectively. The combination of these isoforms provides a dual system for controlling neuronal GABA concentration. In humans, the GAD-67 and GAD-65 genes are located on different chromosomes (the GAD1 and GAD2 genes are located on chromosome 4 and chromosome 10, respectively). GAD-65 and GAD-67 differ significantly in the expression levels of different brain regions. GAD-67 is uniformly expressed throughout the brain, while GAD-65 expression is mainly concentrated at the axon terminals. These two enzymes together maintain most of the physiological supply of GABA in mammals. The human GAD-65 cDNA encodes a 585 amino acid residue polypeptide (Genbank accession No. NM 000818; M81882). In embodiments, the amino acid sequence of human GAD-65 is provided as SEQ ID NO: 1. in another embodiment, the amino acid sequence of human GAD-65 is provided as SEQ ID NO: 3. human GAD-67 encodes a polypeptide of 594 amino acid residues (Genbank accession number M81883). In embodiments, the amino acid of human GAD-67The sequence is provided as SEQ ID NO: 5(Genbank accession number M81883). In another embodiment, the amino acid sequence of human GAD-67 is provided as SEQ ID NO: 7.
in embodiments, the vector comprises a nucleic acid sequence encoding a GAD isoform. In one embodiment, the nucleic acid sequence encodes GAD-65. In one embodiment, the nucleic acid sequence encodes GAD-67. In embodiments, the vector comprises a nucleic acid sequence encoding GAD-65 and a nucleic acid sequence encoding GAD-67. In embodiments, the nucleic acid sequence encoding GAD-65 comprises a nucleic acid sequence encoding SEQ ID NO: 1. In other embodiments, the nucleic acid sequence encoding GAD-65 comprises a nucleic acid sequence encoding SEQ ID NO: 3 in a sequence of the protein of seq id no. In some embodiments, the nucleic acid sequence encodes a polypeptide that differs from SEQ ID NO: 1 or SEQ ID NO: 3, is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical. In another embodiment, the nucleic acid sequence encoding GAD-65 comprises SEQ ID NO: 2 or SEQ ID NO: 4. in some embodiments, the nucleic acid sequence encoding GAD-65 comprises a nucleotide sequence identical to SEQ ID NO: 2 or SEQ ID NO: 4, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical.
In embodiments, the nucleic acid sequence encoding GAD-67 comprises a nucleic acid sequence encoding SEQ ID NO: 5 or SEQ ID NO: 7 in a sequence of the protein of seq id no. In some embodiments, the nucleic acid sequence encodes a polypeptide that differs from SEQ ID NO: 5 or SEQ ID NO: 7, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical. In embodiments, the nucleic acid sequence encoding GAD-67 comprises the nucleic acid sequence of SEQ ID NO: 6. in embodiments, the nucleic acid sequence encoding GAD-67 comprises SEQ ID NO: 8. in embodiments, the nucleic acid sequence encoding GAD-67 comprises a nucleotide sequence identical to SEQ ID NO: 6 or SEQ ID NO: 8, or a sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity.
The term "identity", as used herein, refers to sequence identity between two nucleic acid molecules or polypeptides. Identity can be determined by comparing the position in each sequence aligned for comparison purposes. For example, when a position in the nucleotide sequences being compared is occupied by the same base, then the molecules are identical at that position. The degree of identity between nucleic acid or amino acid sequences is a function of the number of identical or matching nucleotides or amino acids at the shared position. For example, polypeptides that are at least 85%, 90%, 95%, 98%, or 99% identical to, and preferably exhibit substantially the same function as, a particular polypeptide described herein are contemplated, as are polynucleotides encoding such polypeptides. Methods and computer programs for determining sequence identity and similarity are publicly available, including but not limited to the GCG package BLASTP, BLASTN, FASTA, and ALIGN programs (version 2.0). The well-known Smith Waterman algorithm may also be used to determine similarity. BLAST programs are publicly available from NCBI and other sources. These methods take into account various substitutions, deletions and other modifications when comparing sequences.
In some embodiments, the GAD-65 encoding sequence and/or the GAD-67 encoding sequence is codon optimized.
The present disclosure provides methods of treating, preventing, and/or reducing the severity or extent of PD symptoms by administering to a subject in need thereof a therapeutically effective amount of a composition comprising a first vector comprising a nucleic acid encoding GAD-65 and/or a second vector comprising a nucleic acid encoding GAD-67. In embodiments, the ratio of the two vectors (one encoding GAD-65 and the other encoding GAD-67) in the composition is from about 2: 1 to about 1: 2. For example, when the vector is an AAV vector, the ratio of viral particles comprising a nucleic acid encoding GAD-65 to viral particles comprising a nucleic acid encoding GAD-67 is from about 2: 1 to about 1: 2, specifically about 1: 1.
In some embodiments, the method comprises administering a therapeutically effective amount of a first composition comprising a vector comprising a nucleic acid encoding GAD-65 and a therapeutically effective amount of a second composition comprising a vector comprising a nucleic acid encoding GAD-67. In some embodiments, the first AAV vector and the second AAV vector are administered simultaneously. In some embodiments, the first AAV vector is administered before the second AAV vector. In some embodiments, the second AAV vector is administered before the third AAV vector.
In embodiments, provided herein are methods of treating, preventing and/or curing a neurodegenerative disease or disorder in a subject in need thereof, wherein the neurodegenerative disease or disorder is mediated by GABA deficiency. In one aspect, the disclosure provides methods for treating a disease or disorder of a central nervous system disorder associated with dopaminergic inactivity, a disease, injury, or chemical injury. In one embodiment, the neurodegenerative disease or disorder is a cognitive disorder. In one embodiment, the neurodegenerative disease or disorder is PD.
Carrier
In one aspect, a method for treating PD in a subject in need thereof is provided, the method comprising administering to the subject one or more vectors comprising a nucleic acid sequence encoding GAD. As used herein, a vector is a vehicle for delivering genetic material into a cell. In embodiments, the vector is a nucleic acid, including but not limited to a plasmid, an episome, an RNA molecule, or a DNA molecule. In embodiments, the nucleic acid is circular. In embodiments, the nucleic acid is linear. In embodiments, the vector is a viral vector.
Vectors useful in the methods and compositions disclosed herein include vectors capable of autonomous replication (episomal vectors) and/or vectors designed for gene expression in a cell (expression vectors). In certain embodiments, the vector described herein is an expression vector. The expression vector allows expression of the nucleic acid in the target cell. Expression vectors can contain prokaryotic sequences that allow the vector to be propagated in bacteria and eukaryotic sequences that facilitate expression of the encoded polypeptide in eukaryotic cells. Various methods for the preparation of plasmids and transformation of host organisms are known in the art.
In some embodiments, the GAD expression vector can be delivered by ex vivo gene therapy, replacing lost cells with GAD-expressing transplanted cells. An advantageous aspect of using such cells is to reduce the likelihood of immune resistance, as the patient's own cells can be used in the autograft procedure.
In some embodiments, non-viral delivery systems may be used, for example, delivery vehicles using colloidally dispersed systems such as macromolecular complexes, nanocapsules, microspheres, beads, and lipid-based systems (including oil-in-water emulsions, micelles, mixed micelles, and liposomes).
In certain embodiments, the vector described herein is a viral vector. Examples of viral vectors include, but are not limited to, retroviruses, adenoviruses, parvoviruses (e.g., adeno-associated viruses, AAV), coronaviruses, negative strand RNA viruses such as orthomyxoviruses (e.g., influenza viruses), rhabdoviruses (e.g., rabies and vesicular stomatitis virus), paramyxoviruses (e.g., measles and sendai virus), positive strand RNA viruses such as picornaviruses and alphaviruses, and double stranded DNA viruses including adenoviruses, herpesviruses (e.g., herpes simplex virus types 1 and 2, epstein-barr virus, cytomegalovirus), and poxviruses (e.g., vaccinia, fowlpox, and canarypox). Other viruses include, for example, norwalk virus, togavirus, flavivirus, reovirus, papovavirus, hepadnavirus, and hepatitis virus. Examples of retroviruses may include: avian leukemia-sarcoma, mammalian type C, type B viruses, type D viruses, HTLV-BLV group, lentiviruses, and foamy viruses.
In embodiments, the vector comprising the GAD encoding nucleic acid is a viral vector for use in gene therapy. The GAD transgene can be incorporated into any type of viral vector used in gene therapy, such as recombinant retroviruses, adenoviruses, adeno-associated viruses (AAV), and herpes simplex virus-1.
In embodiments, the recombinant aav (raav) is one or more vectors for GAD transgene delivery. The AAV particles comprise a linear single-stranded AAV nucleic acid genome associated with an AAV capsid protein coat. AAV cannot replicate without a helper virus (which may be an adenovirus, vaccinia or herpes virus). In the absence of helper virus, AAV inserts its genome into the host cell chromosome, assuming a latent state. Subsequent infection by the helper virus rescues the latent integrated copy, which then replicates to produce infectious viral progeny.
Recombinant aav (raav) vectors comprise a recombinant viral genome and capsid proteins. A rAAV genome comprising one or more GAD transgenes can be assembled from polynucleotides encoding one or more transgenes, suitable regulatory elements, and viral elements necessary for packaging of the rAAV genome. General methods for constructing rAAV genomes are known in the art. AAV-based expression vectors can consist of AAV Inverted Terminal Repeats (ITRs) flanking restriction sites that can be used to directly access available restriction sites, or can be used to subclone transgenes by removing the transgene with a restriction endonuclease and then polishing the ends and optionally ligating into an AAV expression vector using a linker. The GAD transgene may be integrated into an AAV-based expression vector along with one or more expression control elements, including, for example, enhancers, promoters, and/or post-transcriptional Regulatory Sequences (PREs), flanked by AAV ITRs.
Methods for preparing rAAV vectors with specific capsid proteins are known in the art. Viral particles can be prepared by providing the components required to trans-package the rAAV genome in a capsid, or the components required can be provided by an engineered host cell. Both methods use standard molecular biology techniques known to those skilled in the art. Some or all of the necessary elements may be under the control of an inducible or constitutive promoter. The recombinant AAV genome, rep sequences, cap sequences and helper functions for producing rAAV can be delivered to the packaging host cell using any suitable genetic element (vector). Typically, recombinant AAV is produced by transfecting a host cell with a recombinant AAV genome (comprising a transgene), an AAV helper function vector, and a helper function vector to be packaged into an AAV particle. AAV helper function vectors encode AAV helper function sequences (i.e., rep and cap) that act in trans to perform productive AAV replication and encapsidation. Helper-function vectors typically encode nucleotide sequences for non-AAV-derived viral and/or cellular functions required for AAV replication, including, but not limited to, those elements involved in AAV gene transcriptional activation, stage-specific AAV mRNA splicing, AAV DNA replication, synthesis of cap expression products, and AAV capsid assembly.
As used herein, the terms "AAV 1," "AAV 2," "AAV 3," "AAV 4," and the like refer to an AAV vector comprising Inverted Terminal Repeats (ITRs) from AAV1, AAV2, AAV3, or AAV4, respectively, and a capsid protein from AAV1, AAV2, AAV3, or AAV4, respectively. The terms "AAV 2/1", "AAV 2/8", "AAV 2/9", and the like, refer to pseudotyped AAV vectors comprising ITRs from AAV2 and capsid proteins from AAV1, AAV8, or AAV9, respectively.
The AAV vectors described herein typically comprise a rAAV genome encoding one or more GAD transgenes operably linked to one or more regulatory elements in a manner that allows for transcription, translation, and/or expression of the transgene in a target cell or tissue, and flanked by 5 'and 3' ITRs. ITR sequences are typically about 145bp in length. As long as the modification of the ITR sequences does not interfere with the function of the AAV vector (such as efficient encapsidation of rAAV genomes), the AAV ITR sequences can be modified using standard molecular biology techniques, for example by insertion, deletion or substitution of one or more nucleotides. AAV ITRs can be derived from any of several AAV serotypes. The AAV ITR sequences at 3 'and 5' can be the same or derived from different AAV serotypes.
Expression control or regulatory elements operably linked to a transgene may include promoters or enhancers, such as the chicken β actin promoter or cytomegalovirus enhancer, as well as other elements described herein. The recombinant AAV genome is typically encapsidated by a capsid protein (e.g., from the same AAV serotype as the one from which the ITRs are derived or from a different AAV serotype than the one from which the ITRs are derived). In some embodiments, the transgene is a nucleic acid sequence heterologous to the vector sequence, which encodes GAD-65 or GAD-67. Described herein are components of exemplary AAV vectors that can be used in conjunction with the compositions and methods of the present disclosure.
Any suitable AAV serotype or combination of AAV serotypes can be used in the methods and compositions of the present disclosure. Because the methods and compositions of the present disclosure are useful for treating and curing neurodegenerative diseases or disorders, AAV serotypes that target at least the central nervous system, including but not limited to AAV1, AAV2, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, and AAV10, may be used in some embodiments.
In addition, the rAAV genome comprises an expression control element operably linked to one or more GAD transgenes in a manner that allows for its transcription, translation, and/or expression in a cell infected with the virus. As used herein, "operably linked" refers to a relationship between two or more nucleic acid sequences in which certain nucleic acid sequences (e.g., control elements) affect a characteristic of another nucleotide sequence (e.g., affect expression of a transgene). Operably linked sequences include expression control elements that are included in or adjacent to the GAD transgene, as well as expression control elements that act in trans or remotely to control transgene expression. Expression control elements as used herein include appropriate transcription initiation, termination, promoter, and enhancer sequences; highly efficient RNA processing signals, such as splicing and polyadenylation (poly a) signals; sequences that stabilize cytoplasmic mRNA; sequences that increase translation efficiency (i.e., Kozak consensus sequence); sequences that enhance protein stability; and, when desired, enhancing the sequence encoding the secretion of the product. For example, as used herein, a nucleic acid sequence (e.g., a GAD coding sequence) is considered to be operably linked when it is covalently linked to a regulatory sequence in a manner that places expression or transcription of the nucleic acid sequence under the influence or control of the regulatory sequence. In embodiments, human GAD-65 and/or GAD-67 is under the control of the cytomegalovirus enhancer, chicken β -actin promoter, and woodchuck post-transcriptional regulatory elements.
The promoter operably linked to the GAD transgene may be inducible or constitutive. Inducible promoters allow for the regulation of gene expression and can be regulated by exogenous environments or compounds. Examples of inducible promoters regulated by exogenously provided promoters include the zinc-inducible sheep Metallothionein (MT) promoter, the dexamethasone (Dex) inducible Mouse Mammary Tumor Virus (MMTV) promoter, the T7 polymerase promoter system; ecdysone insect, a tetracycline repressible system. Constitutive promoters are unregulated promoters that allow continuous transcription of their associated genes. Examples of constitutive promoters include, but are not limited to, the chicken beta actin promoter, the retroviral Rous Sarcoma Virus (RSV) LTR promoter (optionally with the RSV enhancer), the Cytomegalovirus (CMV) promoter (optionally with the CMV enhancer), the SV40 promoter, the dihydrofolate reductase promoter, and the beta actin promoter.
In embodiments, if expression of a transgene that mimics natural expression is preferred, a natural promoter of the GAD transgene, or a fragment thereof, may be used. In another embodiment, tissue-specific promoters are used to allow expression in specific tissues for targeted gene therapy. Tissue-specific promoters such as neuron-specific and glial-specific promoters allow for expression of proteins in specific tissues of interest. In embodiments, the promoter is tissue specific and has activity substantially only or greater activity within the central nervous system. In embodiments, the promoter may be specific for a particular cell type or neuron. In another embodiment, the promoter is specific for cells located in a specific region of the brain (e.g., cortex, subthalamic nucleus, stranium, substantia nigra, and/or hippocampus).
Some suitable neuron-specific promoters include, but are not limited to, neuron-specific enolase (NSE) (GenBank accession number: X51956) and human neurofilament light chain promoter (NEFL) (GenBank accession number: L04147). Glial-specific promoters include, but are not limited to, Glial Fibrillary Acidic Protein (GFAP) promoter (GenBank accession number: M65210), S100 promoter (GenBank accession number: M65210), and glutamine synthase promoter (GenBank accession number: X59834).
In some embodiments, the viral vector is a rAAV vector, such as rAAV2-retro, AAV10, AAV2/10, AAV9, or AAV 2/9. In some embodiments, a composition comprising a nucleic acid encoding GAD-65 and/or GAD-67 is administered to a patient with advanced PD. In some embodiments, the administered composition comprises a nucleic acid encoding GAD-65 and GAD-67. In some embodiments, the methods comprise administering, either simultaneously or sequentially, one or more compositions comprising a vector comprising a nucleic acid encoding GAD-65 and a nucleic acid encoding GAD-67. In some embodiments, the methods comprise administering, simultaneously or sequentially, one or more compositions comprising a nucleic acid encoding GAD-65, a nucleic acid encoding GAD-67, and other agents useful for treating PD.
An effective amount of rAAV is an amount sufficient to infect a sufficient number of cells of the target tissue in the subject to which it is administered. An effective amount of a rAAV may be defined as an amount sufficient to produce a therapeutic benefit to a subject (e.g., to ameliorate one or more symptoms of a disease in a subject). The effective amount may vary depending on the species, age, weight, health of the subject, and CNS tissue to be targeted. The effective amount may also vary depending on the mode of administration. In some cases, multiple doses of rAAV are administered to achieve an effective amount to achieve the desired therapeutic benefit. The effective amount may vary depending on the serotype of the rAAV. In certain instances, an effective amount of rAAV is 10 per subject 10 1, 10 11 1, 10 12 1, 10 13 1, 10 14 Or 10 15 And (4) genome copy. In some embodiments, the AAV vector comprising one or more GAD transgenes is administered at a concentration of about 1x10 11 2, about 2x10 11 About 3x10 11 About 4x10 11 About 5x10 11 2, about 6x10 11 2, about 7x10 11 About 8x10 11 About 9x10 11 1, about 10 12 Or about 1x10 13 Vector genome/ml.
Pharmaceutical composition
In one embodiment, the present disclosure provides a pharmaceutical composition comprising one or more vectors comprising a nucleic acid encoding GAD-65 and one or more vectors comprising a nucleic acid encoding GAD-67. These compositions can be administered alone or in combination with other agents to treat subjects with PD. A pharmaceutical composition may refer to a composition comprising one or more carriers and a pharmaceutically acceptable carrier, and optionally other materials, such as one or more inert components (e.g., a detectable agent or label) or one or more active ingredients. Pharmaceutically acceptable carriers can include one or more physiologically compatible solvents, dispersions, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The composition may include components such as adjuvants, diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, or mixtures thereof. Examples of pharmaceutically acceptable carriers include, but are not limited to, water, saline, phosphate buffered saline, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides, derivatized sugars such as sugar alcohols, aldonic acids, esterified sugars, and the like, and polysaccharides or sugar polymers). Carbohydrates such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides such as raffinose, melezitose, maltodextrin, dextran, starch, and the like; and sugar alcohols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (sorbitol) and inositol may also be used as excipients.
The carrier may also include buffers or pH adjusting agents, such as salts prepared from organic acids or bases. Examples of buffers include, but are not limited to, organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride, and phosphate buffers. Other carriers may include polymeric excipients or additives such as polyvinylpyrrolidone, ficoll (polysaccharose), dextran (e.g., cyclodextrins, such as 2-hydroxypropyl-. quadrature. -cyclodextrin), polyethylene glycol, flavoring agents, antimicrobial agents, sweetening agents, antioxidants, antistatic agents, surfactants (e.g., polysorbates, such as TWEEN)And TWEEN) Lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelators (e.g., EDTA).
Application method
Methods of delivering one or more GAD transgenes to a subject can include administering a rAAV by a single or multiple routes of administration. For example, rAAV may be administered to a subject by intravenous injection of an effective amount of rAAV that crosses the blood-brain barrier. Intrathecal or intracerebral administration (e.g., by intracerebroventricular injection) may also be used to deliver an effective amount of rAAV to the CNS. In a non-limiting example, an effective amount of rAAV may be co-administered by two different routes of administration, e.g., by intrathecal administration and by intracerebral administration. The co-administration may be performed at about the same time or at different times.
The term "intrathecal administration" refers to the administration of an agent into the spinal canal or subarachnoid space so that it reaches the cerebrospinal fluid (CSF). The term "intracerebral administration" refers to the administration of an agent in and/or around the brain. Intracerebral administration includes, but is not limited to, administration of agents in the brain, pons, cerebellum, intracranial space, and meninges around the brain. Intracerebral administration may include administration in the dura mater, arachnoid material, and pia mater of the brain. In some cases, intracerebral administration may include administration of the agent in the cerebrospinal fluid (CSF) of the subarachnoid space around the brain. In some cases, intracerebral administration may include administering the agent in a ventricle (e.g., the right ventricle, the left ventricle, the third ventricle, the fourth ventricle).
Intracerebral injection may involve direct injection into and/or around the brain. In some cases, intracerebral administration involves injection using stereotactic procedures for precise delivery. Stereotactic microinjection techniques are well known in the art and have been used in the art to deliver vectors precisely to specific parts of the brain. The program involves the use of a computer and a three-dimensional scanning device. In this method, the subject being treated may be placed within the stereotactic frame base and then imaged using high resolution MRI to determine the three-dimensional location of the specific region to be treated. The MRI images can then be used to determine the precise target location for microinjection of the composition. Stereotactic computer software provides three-dimensional coordinates that are precisely registered for the stereotactic frame. For intracranial administration, a bore is drilled above the access site, and a stereotactic device is used to position the needle and ensure implantation to a predetermined depth. For bilateral delivery, a cool down period may be implemented in which the document administrator and surgeon manually confirm the target site to avoid any errors. Stereotactic microinjection can be used to deliver the vector to any specific part of the brain, including but not limited to the hippocampus, cortex, subthalamic nucleus, and/or substantia nigra. In some cases, a microinjection pump may be used to deliver a composition of rAAV as described herein. The infusion rate may vary between 1 μ l/min and 100 μ l/min depending on various factors such as the age of the subject, the weight/size of the subject, the serotype of the AAV, the selected intracerebral region, and the like. In another embodiment, the carrier is delivered using other delivery methods suitable for local delivery, such as local penetration of the blood-brain barrier.
The dosage regimen required for therapy can be adjusted to provide the optimum desired response (e.g., therapeutic or prophylactic response). For example, a single dose may be administered, several divided doses may be administered over a period of time or the dose may be reduced or increased proportionally to the responsiveness of the subject to therapy.
The vectors described herein may be used in combination with one or more therapeutic agents other than GAD. For example, the therapy may be used in combination with dopamine replacement therapy (such as levodopa or carbidopa), dopamine agonists (such as pramipexole, ropinirole, and bromocriptine), MAO-inhibitors (such as selegiline and rasagiline), catechol O-methyltransferase (COMT) inhibitors (such as entacapone and tolcapone), and various other compounds (including, but not limited to, any agent known in the art for treating one or more symptoms associated with PD as described herein). One or more carriers and other agents for treating a disease can be administered to a subject with PD either simultaneously or separately.
Kits as described herein can include any combination of agents, compositions, components, agents, administration devices or mechanisms, or other entities provided herein. For example, a kit described herein can include one or more AAV-GAD vectors and one or more vector compositions, administration devices, and combination therapeutics. The kit may also include a device to facilitate delivery, such as a syringe for injection or a tool to facilitate delivery of the therapeutic composition to the brain (e.g., substantia nigra). Any of the kits provided herein can be included in a container, package, or dispenser with instructions for administration.
Examples
Example 1: design of research
The population of PD patients most receptive to the disclosed treatment is identified.
Patient selection
66 patients with advanced PD were screened for eligibility for randomized, double-blind, sham-operated control multicenter phase 2 trial with STN AAV2-GAD gene therapy and 45 patients were randomized. All patients had progressive levodopa-reactive PD as defined according to british parkinson's disease association standards. In addition to levodopa, other drugs to treat the condition are allowed if the dose or type of drug is not changed 4 weeks or more prior to enrollment. A need for 25 or more nighttime stops-Unified Parkinson's Disease Rating Scale (UPDRS) part 3 total subscore (motor score). Other inclusion criteria were age 30-75 years, duration of PD symptoms for at least 5 years and levodopa response for at least 12 months. Patients who have failed brain surgery, have used dopamine receptor blocking drugs, have focal neurological deficit or cranial MRI abnormalities; according to the brain metabolic pattern criteria specific to PD excluding patients with atypical parkinson's disease or uncertain patterns, 18 the F-fluorodeoxyglucose PET scan needs to be compatible with PD. Patients were also excluded from cognitive impairment as defined by a martian dementia rating scale score below 130.
Randomization
A statistician and a programmer (each not further contributing to the study) of PharmaNet Inc generated randomized code. Prior to randomization, all subjects were subjected to metabolic brain imaging using FDG PET at rest. After screening to eliminate atypical parkinson's disease, 45 PD subjects were randomized to STN AAV2-GAD gene therapy (n-22) or sham surgery (n-23) at a 1: 1 ratio. When the patient arrives at the operating room, the neurosurgeon opens an envelope containing a computer-generated random treatment assignment (ratio 1: 1) for AAV2-GAD or sham surgery. Patients, caregivers and researchers were blinded to treatment assignment. For the sham-assigned patients, the operating room team created a previously spared plan to simulate the same bilateral stereotactic procedure as was performed for the AAV2-GAD group. Those treated with the sham surgery receive a partial thickness of the borehole after placement of the stereotactic frame. Simulating sound comprising microelectro-electrophysiological recording; infusion pumps and external catheters for saline infusion into the drilling site were identical to those receiving AAV2-GAD infusion. Careful planning of all information about treatment allocation was performed and no deviation occurred at any site. All evaluators were blinded to treatment assignment and no isolated post-operative images and operative records were available. On the third day after surgery and in all subsequent visits, the patient was asked for treatment assignment. Of the first 45 subjects, 8 were excluded from data analysis before blinding due to drug delivery failure (pump failure, STN targeting inaccuracy) according to pre-determined criteria.
Post-treatment selection of patient populations for analysis
Subjects and investigators were blinded to treatment status for at least 6 months post-surgery; due to missing surgical targets or catheter/pump failures, 6 subjects in the treatment group and 2 subjects in the sham group were excluded from the analysis. At baseline, there were no differences between groups in age, gender, UPDRS motor rating, or cognitive testing (P > 0.07). Subjects were rescanned without knowledge at 6 months post-surgery (except one subject in each group) and rescanned without knowledge at the end of the 12-month study. Subjects were blinded at the same time after the last participant completed a 6-month blind follow-up. Surgery was staggered within 1 year, so most participants [ 16 of the 22 people in the sham group (73%); 11 of the 20 GAD subjects (55%) ] were imaged at 12 months after blindness, while the remaining 6 sham subjects and 9 GAD subjects were still blinded at this 12-month time point.
Example 2: construction of viral vectors
AAV-GAD plasmids were generated containing DNA encoding the open reading frame of human GAD-65 or GAD-67, which is regulated by the cytomegalovirus enhancer-chicken β -actin promoter and woodchuck post-transcriptional regulatory elements. Recombinant AAV genomes were packaged in Human Embryonic Kidney (HEK)293 cells and purified by heparin affinity chromatography according to standard procedures and as described previously. The final formulation buffer was 1x phosphate buffered saline solution. Genomic vector titers were measured by absolute quantification using the ABI7000 sequence detection system (Applied Biosystems, Foster City, CA, USA).
Example 3: vector delivery
Viruses encoding GAD-65 or GAD-67 were mixed in a 1 to 1 ratio and diluted to 1X10 with 2X phosphate buffered saline solution 11 Individual viral genome (vg)/mL (low dose), 3X10 11 vg/mL (Medium dose) and 1X10 12 vg/mL (high dose). The batch harvest and final formulated product were rigorously checked by batch release testing (lot-release testing) according to FDA guidelines. Biological safety tests for mycoplasma, endotoxin, sterility and foreign viruses as well as general safety tests (AppTec Laboratory Services, Philadelphia, USA) were performed. Sham treatment was performed with saline solution.
The subthalamic nucleus was located using a Leksell stereotactic frame and MRI image guidance. Standard intra-operative microelectrode recordings were performed with the subject awake to verify the precise location of the subthalamic nucleus. The tip of the microelectrode is then withdrawn to a position considered to be the centre of the subthalamic nucleus. After removal of the microelectrode, the catheter was inserted 10mm above the center of the nucleus. A catheter with a 10mm tip with a diameter of 200 μ M I was flushed with an AAV2-GAD infusion and inserted into the presumed nuclear center. The catheter is locked in place with a cover with a rip cord that ties the catheter for release after a bedside procedure. The scalp is closed after placement of the first catheter to avoid catheter blockage. Bilateral administration of one dose of AAV2-GAD per hemisphere (35. mu.l of 1X 10) to the subthalamic nucleus of PD subjects 12 Individual genome/ml). The method is performed on both sides of the scalp. When the research coordinator or other members of the operating team confirm the coordinates recorded by the surgeon and write before penetrating the brainWith formula recording, pauses occur before surgery is initiated on each side of the brain. Another group of PD subjects received a single subthalamic nucleus at one dose per hemisphere of AAV2-GAD (35. mu.l of 1X 10) 11 Individual genome/ml). Another group of PD subjects received a single dose of AAV2-GAD per hemisphere in the subthalamic nucleus of the unilateral thalamus (35. mu.l of 3X 10) 11 Individual genome/ml). Another group of PD subjects received a single subthalamic nucleus at one dose per hemisphere of AAV2-GAD (35. mu.l of 1X 10) 12 Individual genome/ml). After the infusion is completed, a fine cut head CT scan is performed to determine the location of the catheter tip location. Post-catheter CT and MRI scans were performed on all subjects at 24 and 48 hour intervals post-treatment.
Example 3: determination of post-treatment "on-time
Subjects receiving AAV-gad (gad) into the subthalamic nucleus or sham surgery (sham) recorded hourly on-and off-times in a diary for 2 weeks per day for each listed period (1 month, 3 months, 6 months and 12 months post-surgery). Using the two-tailed T-test, the average daily open and closed times over two weeks as determined from the diary were compared to a baseline diary obtained 30 days prior to surgery to determine the change in hours of post-operative open time. At 12 months post-surgery, changes in the mean daily open time from baseline for each subject in the AAV-GAD treated group correlated with changes in the clinical score for the same subject over the same time period. The clinical score used was part 3 of UPDRS.
Sequence of
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gcaaagggga ctaccgggtt tgaagcgcat gttgataaat gtttggagtt ggcagagtat 1440
ttatacaaca tcataaaaaa ccgagaagga tatgagatgg tgtttgatgg gaagcctcag 1500
cacacaaatg tctgcttctg gtacattcct ccaagcttgc gtactctgga agacaatgaa 1560
gagagaatga gtcgcctctc gaaggtggct ccagtgatta aagccagaat gatggagtat 1620
ggaaccacaa tggtcagcta ccaacccttg ggagacaagg tcaatttctt ccgcatggtc 1680
atctcaaacc cagcggcaac tcaccaagac attgacttcc tgattgaaga aatagaacgc 1740
cttggacaag atttataa 1758
<210> 3
<211> 600
<212> PRT
<213> Intelligent (HOMO SAPIENS)
<400> 3
Met Ser Pro Ile His His His His His His Leu Val Pro Arg Gly Ser
1 5 10 15
Glu Ala Ser Asn Ser Gly Phe Trp Ser Phe Gly Ser Glu Asp Gly Ser
20 25 30
Gly Asp Ser Glu Asn Pro Gly Thr Ala Arg Ala Trp Cys Gln Val Ala
35 40 45
Gln Lys Phe Thr Gly Gly Ile Gly Asn Lys Leu Cys Ala Leu Leu Tyr
50 55 60
Gly Asp Ala Glu Lys Pro Ala Glu Ser Gly Gly Ser Gln Pro Pro Arg
65 70 75 80
Ala Ala Ala Arg Lys Ala Ala Cys Ala Cys Asp Gln Lys Pro Cys Ser
85 90 95
Cys Ser Lys Val Asp Val Asn Tyr Ala Phe Leu His Ala Thr Asp Leu
100 105 110
Leu Pro Ala Cys Asp Gly Glu Arg Pro Thr Leu Ala Phe Leu Gln Asp
115 120 125
Val Met Asn Ile Leu Leu Gln Tyr Val Val Lys Ser Phe Asp Arg Ser
130 135 140
Thr Lys Val Ile Asp Phe His Tyr Pro Asn Glu Leu Leu Gln Glu Tyr
145 150 155 160
Asn Trp Glu Leu Ala Asp Gln Pro Gln Asn Leu Glu Glu Ile Leu Met
165 170 175
His Cys Gln Thr Thr Leu Lys Tyr Ala Ile Lys Thr Gly His Pro Arg
180 185 190
Tyr Phe Asn Gln Leu Ser Thr Gly Leu Asp Met Val Gly Leu Ala Ala
195 200 205
Asp Trp Leu Thr Ser Thr Ala Asn Thr Asn Met Phe Thr Tyr Glu Ile
210 215 220
Ala Pro Val Phe Val Leu Leu Glu Tyr Val Thr Leu Lys Lys Met Arg
225 230 235 240
Glu Ile Ile Gly Trp Pro Gly Gly Ser Gly Asp Gly Ile Phe Ser Pro
245 250 255
Gly Gly Ala Ile Ser Asn Met Tyr Ala Met Met Ile Ala Arg Phe Lys
260 265 270
Met Phe Pro Glu Val Lys Glu Lys Gly Met Ala Ala Leu Pro Arg Leu
275 280 285
Ile Ala Phe Thr Ser Glu His Ser His Phe Ser Leu Lys Lys Gly Ala
290 295 300
Ala Ala Leu Gly Ile Gly Thr Asp Ser Val Ile Leu Ile Lys Cys Asp
305 310 315 320
Glu Arg Gly Lys Met Ile Pro Ser Asp Leu Glu Arg Arg Ile Leu Glu
325 330 335
Ala Lys Gln Lys Gly Phe Val Pro Phe Leu Val Ser Ala Thr Ala Gly
340 345 350
Thr Thr Val Tyr Gly Ala Phe Asp Pro Leu Leu Ala Val Ala Asp Ile
355 360 365
Cys Lys Lys Tyr Lys Ile Trp Met His Val Asp Ala Ala Trp Gly Gly
370 375 380
Gly Leu Leu Met Ser Arg Lys His Lys Trp Lys Leu Ser Gly Val Glu
385 390 395 400
Arg Ala Asn Ser Val Thr Trp Asn Pro His Lys Met Met Gly Val Pro
405 410 415
Leu Gln Cys Ser Ala Leu Leu Val Arg Glu Glu Gly Leu Met Gln Asn
420 425 430
Cys Asn Gln Met His Ala Ser Tyr Leu Phe Gln Gln Asp Lys His Tyr
435 440 445
Asp Leu Ser Tyr Asp Thr Gly Asp Lys Ala Leu Gln Cys Gly Arg His
450 455 460
Val Asp Val Phe Lys Leu Trp Leu Met Trp Arg Ala Lys Gly Thr Thr
465 470 475 480
Gly Phe Glu Ala His Val Asp Lys Cys Leu Glu Leu Ala Glu Tyr Leu
485 490 495
Tyr Asn Ile Ile Lys Asn Arg Glu Gly Tyr Glu Met Val Phe Asp Gly
500 505 510
Lys Pro Gln His Thr Asn Val Cys Phe Trp Tyr Ile Pro Pro Ser Leu
515 520 525
Arg Thr Leu Glu Asp Asn Glu Glu Arg Met Ser Arg Leu Ser Lys Val
530 535 540
Ala Pro Val Ile Lys Ala Arg Met Met Glu Tyr Gly Thr Thr Met Val
545 550 555 560
Ser Tyr Gln Pro Leu Gly Asp Lys Val Asn Phe Phe Arg Met Val Ile
565 570 575
Ser Asn Pro Ala Ala Thr His Gln Asp Ile Asp Phe Leu Ile Glu Glu
580 585 590
Ile Glu Arg Leu Gly Gln Asp Leu
595 600
<210> 4
<211> 1803
<212> DNA
<213> Intelligent (HOMO SAPIENS)
<400> 4
atgtccccta tacatcacca tcaccatcac ctggttccgc gtggatccga agcttcgaat 60
tctggctttt ggtctttcgg gtcggaagat ggctctgggg attccgagaa tcccggcaca 120
gcgcgagcct ggtgccaagt ggctcagaag ttcacgggcg gcatcggaaa caaactgtgc 180
gccctgctct acggagacgc cgagaagccg gcggagagcg gcgggagcca acccccgcgg 240
gccgccgccc ggaaggccgc ctgcgcctgc gaccagaagc cctgcagctg ctccaaagtg 300
gatgtcaact acgcgtttct ccatgcaaca gacctgctgc cggcgtgtga tggagaaagg 360
cccactttgg cgtttctgca agatgttatg aacattttac ttcagtatgt ggtgaaaagt 420
ttcgatagat caaccaaagt gattgatttc cattatccta atgagcttct ccaagaatat 480
aattgggaat tggcagacca accacaaaat ttggaggaaa ttttgatgca ttgccaaaca 540
actctaaaat atgcaattaa aacagggcat cctagatact tcaatcaact ttctactggt 600
ttggatatgg ttggattagc agcagactgg ctgacatcaa cagcaaatac taacatgttc 660
acctatgaaa ttgctccagt atttgtgctt ttggaatatg tcacactaaa gaaaatgaga 720
gaaatcattg gctggccagg gggctctggc gatgggatat tttctcccgg tggcgccata 780
tctaacatgt atgccatgat gatcgcacgc tttaagatgt tcccagaagt caaggagaaa 840
ggaatggctg ctcttcccag gctcattgcc ttcacgtctg aacatagtca tttttctctc 900
aagaagggag ctgcagcctt agggattgga acagacagcg tgattctgat taaatgtgat 960
gagagaggga aaatgattcc atctgatctt gaaagaagga ttcttgaagc caaacagaaa 1020
gggtttgttc ctttcctcgt gagtgccaca gctggaacca ccgtgtacgg agcatttgac 1080
cccctcttag ctgtcgctga catttgcaaa aagtataaga tctggatgca tgtggatgca 1140
gcttggggtg ggggattact gatgtcccga aaacacaagt ggaaactgag tggcgtggag 1200
agggccaact ctgtgacgtg gaatccacac aagatgatgg gagtcccttt gcagtgctct 1260
gctctcctgg ttagagaaga gggattgatg cagaattgca accaaatgca tgcctcctac 1320
ctctttcagc aagataaaca ttatgacctg tcctatgaca ctggagacaa ggccttacag 1380
tgcggacgcc acgttgatgt ttttaaacta tggctgatgt ggagggcaaa ggggactacc 1440
gggtttgaag cgcatgttga taaatgtttg gagttggcag agtatttata caacatcata 1500
aaaaaccgag aaggatatga gatggtgttt gatgggaagc ctcagcacac aaatgtctgc 1560
ttctggtaca ttcctccaag cttgcgtact ctggaagaca atgaagagag aatgagtcgc 1620
ctctcgaagg tggctccagt gattaaagcc agaatgatgg agtatggaac cacaatggtc 1680
agctaccaac ccttgggaga caaggtcaat ttcttccgca tggtcatctc aaacccagcg 1740
gcaactcacc aagacattga cttcctgatt gaagaaatag aacgccttgg acaagattta 1800
taa 1803
<210> 5
<211> 594
<212> PRT
<213> Intelligent (HOMO SAPIENS)
<400> 5
Met Ala Ser Ser Thr Pro Ser Ser Ser Ala Thr Ser Ser Asn Ala Gly
1 5 10 15
Ala Asp Pro Asn Thr Thr Asn Leu Arg Pro Thr Thr Tyr Asp Thr Trp
20 25 30
Cys Gly Val Ala His Gly Cys Thr Arg Lys Leu Gly Leu Lys Ile Cys
35 40 45
Gly Phe Leu Gln Arg Thr Asn Ser Leu Glu Glu Lys Ser Arg Leu Val
50 55 60
Ser Ala Phe Arg Glu Arg Gln Ser Ser Lys Asn Leu Leu Ser Cys Glu
65 70 75 80
Asn Ser Asp Arg Asp Ala Arg Phe Arg Arg Thr Glu Thr Asp Phe Ser
85 90 95
Asn Leu Phe Ala Arg Asp Leu Leu Pro Ala Lys Asn Gly Glu Glu Gln
100 105 110
Thr Val Gln Phe Leu Leu Glu Val Val Asp Ile Leu Leu Asn Tyr Val
115 120 125
Arg Lys Thr Phe Asp Arg Ser Thr Lys Val Leu Asp Phe His His Pro
130 135 140
His Gln Leu Leu Glu Gly Met Glu Gly Phe Asn Leu Glu Leu Ser Asp
145 150 155 160
His Pro Glu Ser Leu Glu Gln Ile Leu Val Asp Cys Arg Asp Thr Leu
165 170 175
Lys Tyr Gly Val Arg Thr Gly His Pro Arg Phe Phe Asn Gln Leu Ser
180 185 190
Thr Gly Leu Asp Ile Ile Gly Leu Ala Gly Glu Trp Leu Thr Ser Thr
195 200 205
Ala Asn Thr Asn Met Phe Thr Tyr Glu Ile Ala Pro Val Phe Val Leu
210 215 220
Met Glu Gln Ile Thr Leu Lys Lys Met Arg Glu Ile Val Gly Trp Ser
225 230 235 240
Ser Lys Asp Gly Asp Gly Ile Phe Ser Pro Gly Gly Ala Ile Ser Asn
245 250 255
Met Tyr Ser Ile Met Ala Ala Arg Tyr Lys Tyr Phe Pro Glu Val Lys
260 265 270
Thr Lys Gly Met Ala Ala Val Pro Lys Leu Val Leu Phe Thr Ser Glu
275 280 285
Gln Ser His Tyr Ser Ile Lys Lys Ala Gly Ala Ala Leu Gly Phe Gly
290 295 300
Thr Asp Asn Val Ile Leu Ile Lys Cys Asn Glu Arg Gly Lys Ile Ile
305 310 315 320
Pro Ala Asp Phe Glu Ala Lys Ile Leu Glu Ala Lys Gln Lys Gly Tyr
325 330 335
Val Pro Phe Tyr Val Asn Ala Thr Ala Gly Thr Thr Val Tyr Gly Ala
340 345 350
Phe Asp Pro Ile Gln Glu Ile Ala Asp Ile Cys Glu Lys Tyr Asn Leu
355 360 365
Trp Leu His Val Asp Ala Ala Trp Gly Gly Gly Leu Leu Met Ser Arg
370 375 380
Lys His Arg His Lys Leu Asn Gly Ile Glu Arg Ala Asn Ser Val Thr
385 390 395 400
Trp Asn Pro His Lys Met Met Gly Val Leu Leu Gln Cys Ser Ala Ile
405 410 415
Leu Val Lys Glu Lys Gly Ile Leu Gln Gly Cys Asn Gln Met Cys Ala
420 425 430
Gly Tyr Leu Phe Gln Pro Asp Lys Gln Tyr Asp Val Ser Tyr Asp Thr
435 440 445
Gly Asp Lys Ala Ile Gln Cys Gly Arg His Val Asp Ile Phe Lys Phe
450 455 460
Trp Leu Met Trp Lys Ala Lys Gly Thr Val Gly Phe Glu Asn Gln Ile
465 470 475 480
Asn Lys Cys Leu Glu Leu Ala Glu Tyr Leu Tyr Ala Lys Ile Lys Asn
485 490 495
Arg Glu Glu Phe Glu Met Val Phe Asn Gly Glu Pro Glu His Thr Asn
500 505 510
Val Cys Phe Trp Tyr Ile Pro Gln Ser Leu Arg Gly Val Pro Asp Ser
515 520 525
Pro Gln Arg Arg Glu Lys Leu His Lys Val Ala Pro Lys Ile Lys Ala
530 535 540
Leu Met Met Glu Ser Gly Thr Thr Met Val Gly Tyr Gln Pro Gln Gly
545 550 555 560
Asp Lys Ala Asn Phe Phe Arg Met Val Ile Ser Asn Pro Ala Ala Thr
565 570 575
Gln Ser Asp Ile Asp Phe Leu Ile Glu Glu Ile Glu Arg Leu Gly Gln
580 585 590
Asp Leu
<210> 6
<211> 1785
<212> DNA
<213> Intelligent (HOMO SAPIENS)
<400> 6
atggcgtctt cgaccccatc ttcgtccgca acctcctcga acgcgggagc ggaccccaat 60
accactaacc tgcgccccac aacgtacgat acctggtgcg gcgtggccca tggatgcacc 120
agaaaactgg ggctcaagat ctgcggcttc ttgcaaagga ccaacagcct ggaagagaag 180
agtcgccttg tgagtgcctt cagggagagg caatcctcca agaacctgct ttcctgtgaa 240
aacagcgacc gggatgcccg cttccggcgc acagagactg acttctctaa tctgtttgct 300
agagatctgc ttccggctaa gaacggtgag gagcaaaccg tgcaattcct cctggaagtg 360
gtggacatac tcctcaacta tgtccgcaag acatttgatc gctccaccaa ggtgctggac 420
tttcatcacc cacaccagtt gctggaaggc atggagggct tcaacttgga gctctctgac 480
caccccgagt ccctggagca gatcctggtt gactgcagag acaccttgaa gtatggggtt 540
cgcacaggtc atcctcgatt tttcaaccag ctctccactg gattggatat tattggccta 600
gctggagaat ggctgacatc aacggccaat accaacatgt ttacatatga aattgcacca 660
gtgtttgtcc tcatggaaca aataacactt aagaagatga gagagatagt tggatggtca 720
agtaaagatg gtgatgggat attttctcct gggggcgcca tatccaacat gtacagcatc 780
atggctgctc gctacaagta cttcccggaa gttaagacaa agggcatggc ggctgtgcct 840
aaactggtcc tcttcacctc agaacagagt cactattcca taaagaaagc tggggctgca 900
cttggctttg gaactgacaa tgtgattttg ataaagtgca atgaaagggg gaaaataatt 960
ccagctgatt ttgaggcaaa aattcttgaa gccaaacaga agggatatgt tcccttttat 1020
gtcaatgcaa ctgctggcac gactgtttat ggagcttttg atccgataca agagattgca 1080
gatatatgtg agaaatataa cctttggttg catgtcgatg ctgcctgggg aggtgggctg 1140
ctcatgtcca ggaagcaccg ccataaactc aacggcatag aaagggccaa ctcagtcacc 1200
tggaaccctc acaagatgat gggcgtgctg ttgcagtgct ctgccattct cgtcaaggaa 1260
aagggtatac tccaaggatg caaccagatg tgtgcaggat atctcttcca gccagacaag 1320
cagtatgatg tctcctacga caccggggac aaggcaattc agtgtggccg ccacgtggat 1380
atcttcaagt tctggctgat gtggaaagca aagggcacag tgggatttga aaaccagatc 1440
aacaaatgcc tggaactggc tgaatacctc tatgccaaga ttaaaaacag agaagaattt 1500
gagatggttt tcaatggcga gcctgagcac acaaacgtct gtttttggta tattccacaa 1560
agcctcaggg gtgtgccaga cagccctcaa cgacgggaaa agctacacaa ggtggctcca 1620
aaaatcaaag ccctgatgat ggagtcaggt acgaccatgg ttggctacca gccccaaggg 1680
gacaaggcca acttcttccg gatggtcatc tccaacccag ccgctaccca gtctgacatt 1740
gacttcctca ttgaggagat agaaagactg ggccaggatc tgtaa 1785
<210> 7
<211> 594
<212> PRT
<213> Intelligent (HOMO SAPIENS)
<400> 7
Met Ala Ser Ser Thr Pro Ser Ser Ser Ala Thr Ser Ser Asn Ala Gly
1 5 10 15
Ala Asp Pro Asn Thr Thr Asn Leu Arg Pro Thr Thr Tyr Asp Thr Trp
20 25 30
Cys Gly Val Ala His Gly Cys Thr Arg Lys Leu Gly Leu Lys Ile Cys
35 40 45
Gly Phe Leu Gln Arg Thr Asn Ser Leu Glu Glu Lys Ser Arg Leu Val
50 55 60
Ser Ala Phe Lys Glu Arg Gln Ser Ser Lys Asn Leu Leu Ser Cys Glu
65 70 75 80
Asn Ser Asp Arg Asp Ala Arg Phe Arg Arg Thr Glu Thr Asp Phe Ser
85 90 95
Asn Leu Phe Ala Arg Asp Leu Leu Pro Ala Lys Asn Gly Glu Glu Gln
100 105 110
Thr Val Gln Phe Leu Leu Glu Val Val Asp Ile Leu Leu Asn Tyr Val
115 120 125
Arg Lys Thr Phe Asp Arg Ser Thr Lys Val Leu Asp Phe His His Pro
130 135 140
His Gln Leu Leu Glu Gly Met Glu Gly Phe Asn Leu Glu Leu Ser Asp
145 150 155 160
His Pro Glu Ser Leu Glu Gln Ile Leu Val Asp Cys Arg Asp Thr Leu
165 170 175
Lys Tyr Gly Val Arg Thr Gly His Pro Arg Phe Phe Asn Gln Leu Ser
180 185 190
Thr Gly Leu Asp Ile Ile Gly Leu Ala Gly Glu Trp Leu Thr Ser Thr
195 200 205
Ala Asn Thr Asn Met Phe Thr Tyr Glu Ile Ala Pro Val Phe Val Leu
210 215 220
Met Glu Gln Ile Thr Leu Lys Lys Met Arg Glu Ile Val Gly Trp Ser
225 230 235 240
Ser Lys Asp Gly Asp Gly Ile Phe Ser Pro Gly Gly Ala Ile Ser Asn
245 250 255
Met Tyr Ser Ile Met Ala Ala Arg Tyr Lys Tyr Phe Pro Glu Val Lys
260 265 270
Thr Lys Gly Met Ala Ala Val Pro Lys Leu Val Leu Phe Thr Ser Glu
275 280 285
Gln Ser His Tyr Ser Ile Lys Lys Ala Gly Ala Ala Leu Gly Phe Gly
290 295 300
Thr Asp Asn Val Ile Leu Ile Lys Cys Asn Glu Arg Gly Lys Ile Ile
305 310 315 320
Pro Ala Asp Phe Glu Ala Lys Ile Leu Glu Ala Lys Gln Lys Gly Tyr
325 330 335
Val Pro Phe Tyr Val Asn Ala Thr Ala Gly Thr Thr Val Tyr Gly Ala
340 345 350
Phe Asp Pro Ile Gln Glu Ile Ala Asp Ile Cys Glu Lys Tyr Asn Leu
355 360 365
Trp Leu His Val Asp Ala Ala Trp Gly Gly Gly Leu Leu Met Ser Arg
370 375 380
Lys His Arg His Lys Leu Asn Gly Ile Glu Arg Ala Asn Ser Val Thr
385 390 395 400
Trp Asn Pro His Lys Met Met Gly Val Leu Leu Gln Cys Ser Ala Ile
405 410 415
Leu Val Lys Glu Lys Gly Ile Leu Gln Gly Cys Asn Gln Met Cys Ala
420 425 430
Gly Tyr Leu Phe Gln Pro Asp Lys Gln Tyr Asp Val Ser Tyr Asp Thr
435 440 445
Gly Asp Lys Ala Ile Gln Cys Gly Arg His Val Asp Ile Phe Lys Phe
450 455 460
Trp Leu Met Trp Lys Ala Lys Gly Thr Val Gly Phe Glu Asn Gln Ile
465 470 475 480
Asn Lys Cys Leu Glu Leu Ala Glu Tyr Leu Tyr Ala Lys Ile Lys Asn
485 490 495
Arg Glu Glu Phe Glu Met Val Phe Asn Gly Glu Pro Glu His Thr Asn
500 505 510
Val Cys Phe Trp Tyr Ile Pro Gln Ser Leu Arg Gly Val Pro Asp Ser
515 520 525
Pro Gln Arg Arg Glu Lys Leu His Lys Val Ala Pro Lys Ile Lys Ala
530 535 540
Leu Met Met Glu Ser Gly Thr Thr Met Val Gly Tyr Gln Pro Gln Gly
545 550 555 560
Asp Lys Ala Asn Phe Phe Arg Met Val Ile Ser Asn Pro Ala Ala Thr
565 570 575
Gln Ser Asp Ile Asp Phe Leu Ile Glu Glu Ile Glu Arg Leu Gly Gln
580 585 590
Asp Leu
<210> 8
<211> 1785
<212> DNA
<213> Intelligent (HOMO SAPIENS)
<400> 8
atggcgtctt cgaccccatc ttcgtccgca acctcctcga acgcgggagc ggaccccaat 60
accactaacc tgcgccccac aacgtacgat acctggtgcg gcgtggccca tggatgcacc 120
agaaaactgg ggctcaagat ctgcggcttc ttgcaaagga ccaacagcct ggaagagaag 180
agtcgccttg tgagtgcctt caaggagagg caatcctcca agaacctgct ttcctgtgaa 240
aacagcgacc gggatgcccg cttccggcgc acagagactg acttctctaa tctgtttgct 300
agagatctgc ttccggctaa gaacggtgag gagcaaaccg tgcaattcct cctggaagtg 360
gtggacatac tcctcaacta tgtccgcaag acatttgatc gctccaccaa ggtgctggac 420
tttcatcacc cacaccagtt gctggaaggc atggagggct tcaacttgga gctctctgac 480
caccccgagt ccctggagca gatcctggtt gactgcagag acaccttgaa gtatggggtt 540
cgcacaggtc atcctcgatt tttcaaccag ctctccactg gattggatat tattggccta 600
gctggagaat ggctgacatc aacggccaat accaacatgt ttacatatga aattgcacca 660
gtgtttgtcc tcatggaaca aataacactt aagaagatga gagagatagt tggatggtca 720
agtaaagatg gtgatgggat attttctcct gggggcgcca tatccaacat gtacagcatc 780
atggctgctc gctacaagta cttcccggaa gttaagacaa agggcatggc ggctgtgcct 840
aaactggtcc tcttcacctc agaacagagt cactattcca taaagaaagc tggggctgca 900
cttggctttg gaactgacaa tgtgattttg ataaagtgca atgaaagggg gaaaataatt 960
ccagctgatt ttgaggcaaa aattcttgaa gccaaacaga agggatatgt tcccttttat 1020
gtcaatgcaa ctgctggcac gactgtttat ggagcttttg atccgataca agagattgca 1080
gatatatgtg agaaatataa cctttggttg catgtcgatg ctgcctgggg aggtgggctg 1140
ctcatgtcca ggaagcaccg ccataaactc aacggcatag aaagggccaa ctcagtcacc 1200
tggaaccctc acaagatgat gggcgtgctg ttgcagtgct ctgccattct cgtcaaggaa 1260
aagggtatac tccaaggatg caaccagatg tgtgcaggat acctcttcca gccagacaag 1320
cagtatgatg tctcctacga caccggggac aaggcaattc agtgtggccg ccacgtggat 1380
atcttcaagt tctggctgat gtggaaagca aagggcacag tgggatttga aaaccagatc 1440
aacaaatgcc tggaactggc tgaatacctc tatgccaaga ttaaaaacag agaagaattt 1500
gagatggttt tcaatggcga gcctgagcac acaaacgtct gtttttggta tattccacaa 1560
agcctcaggg gtgtgccaga cagccctcaa cgacgggaaa agctacacaa ggtggctcca 1620
aaaatcaaag ccctgatgat ggagtcaggt acgaccatgg ttggctacca gccccaaggg 1680
gacaaggcca acttcttccg gatggtcatc tccaacccag ccgctaccca gtctgacatt 1740
gacttcctca ttgaggagat agaaagactg ggccaggatc tgtaa 1785
<210> 9
<211> 224
<212> PRT
<213> Intelligent (HOMO SAPIENS)
<400> 9
Met Ala Ser Ser Thr Pro Ser Ser Ser Ala Thr Ser Ser Asn Ala Gly
1 5 10 15
Ala Asp Pro Asn Thr Thr Asn Leu Arg Pro Thr Thr Tyr Asp Thr Trp
20 25 30
Cys Gly Val Ala His Gly Cys Thr Arg Lys Leu Gly Leu Lys Ile Cys
35 40 45
Gly Phe Leu Gln Arg Thr Asn Ser Leu Glu Glu Lys Ser Arg Leu Val
50 55 60
Ser Ala Phe Lys Glu Arg Gln Ser Ser Lys Asn Leu Leu Ser Cys Glu
65 70 75 80
Asn Ser Asp Arg Asp Ala Arg Phe Arg Arg Thr Glu Thr Asp Phe Ser
85 90 95
Asn Leu Phe Ala Arg Asp Leu Leu Pro Ala Lys Asn Gly Glu Glu Gln
100 105 110
Thr Val Gln Phe Leu Leu Glu Val Val Asp Ile Leu Leu Asn Tyr Val
115 120 125
Arg Lys Thr Phe Asp Arg Ser Thr Lys Val Leu Asp Phe His His Pro
130 135 140
His Gln Leu Leu Glu Gly Met Glu Gly Phe Asn Leu Glu Leu Ser Asp
145 150 155 160
His Pro Glu Ser Leu Glu Gln Ile Leu Val Asp Cys Arg Asp Thr Leu
165 170 175
Lys Tyr Gly Val Arg Thr Gly His Pro Arg Phe Phe Asn Gln Leu Ser
180 185 190
Thr Gly Leu Asp Ile Ile Gly Leu Ala Gly Glu Trp Leu Thr Ser Thr
195 200 205
Ala Asn Thr Asn Met Pro Ser Asp Met Arg Glu Cys Trp Leu Leu Arg
210 215 220
Claims (14)
1.A method of treating Parkinson's Disease (PD) in a subject in need thereof, the method comprising:
(a) identifying subjects with less than 10 hours of opening per day; and
(b) administering to the subject a composition comprising a therapeutically effective amount of one or more vectors to the subthalamic nucleus of the patient, wherein each vector comprises a nucleic acid sequence encoding a glutamate decarboxylase (GAD), and wherein the subject's on-time is extended.
2. The method of claim 1, wherein the subject has an on-time of less than 8 hours per day prior to treatment.
3. The method of any one of claims 1-2, wherein the subject scores 30 or greater on part III of UPDRS in a withdrawal state.
4. The method of any one of claims 1-3, wherein the one or more vectors are introduced bilaterally into the subthalamic nucleus of the patient.
5. The method of any one of claims 1-4, wherein the one or more vectors comprise a nucleic acid sequence encoding GAD-65 and/or a nucleic acid sequence encoding GAD-67.
6. The method of claim 5 wherein the composition comprises a GAD-65 encoding vector and a GAD-67 encoding vector in a ratio of about 1: 1.
7. The method of any one of claims 1-6, wherein the one or more vectors are viral vectors.
8. The method of claim 7, wherein the viral vector is an adeno-associated virus (AAV) vector.
9. The method of claim 7 or 8, wherein the composition comprises at least 1x10 11 Vector genome/ml.
10. The method of claim 7 or 8, wherein the composition comprises at least 3x10 11 Vector genome/ml.
11. The method of claim 7 or 8, wherein the composition comprises at least 1x10 12 Vector genome/ml.
12. The method of any one of claims 1-11, wherein the subject exhibits an extension in on-time of at least 40% at 12 months post-treatment.
13. The method of any one of claims 1-15, wherein the subject exhibits an extension in turn-on time of at least 30% after 12 months post-treatment.
14. The method of any one of claims 1-15, wherein the subject exhibits an extension in turn-on time of at least 20% after 12 months post-treatment.
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PCT/US2020/064928 WO2021119615A1 (en) | 2019-12-12 | 2020-12-14 | Methods for treating parkinson's disease |
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001089583A2 (en) * | 2000-05-23 | 2001-11-29 | Neurologix, Inc. | Glutamic acid decarboxylase (gad)_delivery system for treating neurodegenerative diseases |
US20050025746A1 (en) * | 2000-05-23 | 2005-02-03 | Neurologix, Inc. | Glutamic acid decarboxylase (GAD) based delivery systems |
WO2006130639A2 (en) * | 2005-05-31 | 2006-12-07 | Neurologix, Inc. | Novel glutamic acid decarboxylase (gad) chimera and methods of use |
WO2008016629A2 (en) * | 2006-08-01 | 2008-02-07 | Neurologix, Inc. | Novel glutamic acid decarboxylase (gad) proteins and methods of use |
CN107106689A (en) * | 2014-11-05 | 2017-08-29 | 沃雅戈治疗公司 | AADC polynucleotides for treating Parkinson's |
US20190060425A1 (en) * | 2017-06-15 | 2019-02-28 | Voyager Therapeutics, Inc. | Aadc polynucleotides for the treatment of parkinson's disease |
-
2020
- 2020-12-14 CN CN202080096586.XA patent/CN115135347A/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001089583A2 (en) * | 2000-05-23 | 2001-11-29 | Neurologix, Inc. | Glutamic acid decarboxylase (gad)_delivery system for treating neurodegenerative diseases |
US20050025746A1 (en) * | 2000-05-23 | 2005-02-03 | Neurologix, Inc. | Glutamic acid decarboxylase (GAD) based delivery systems |
WO2006130639A2 (en) * | 2005-05-31 | 2006-12-07 | Neurologix, Inc. | Novel glutamic acid decarboxylase (gad) chimera and methods of use |
WO2008016629A2 (en) * | 2006-08-01 | 2008-02-07 | Neurologix, Inc. | Novel glutamic acid decarboxylase (gad) proteins and methods of use |
CN107106689A (en) * | 2014-11-05 | 2017-08-29 | 沃雅戈治疗公司 | AADC polynucleotides for treating Parkinson's |
US20190060425A1 (en) * | 2017-06-15 | 2019-02-28 | Voyager Therapeutics, Inc. | Aadc polynucleotides for the treatment of parkinson's disease |
Non-Patent Citations (1)
Title |
---|
MARTIN NIETHAMMER等: "Long-term follow-up of a randomized AAV2-GAD gene therapy trial for Parkinson’s disease", JCI INSIGHT, 6 April 2017 (2017-04-06), pages 90133 * |
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