WO2011028800A2

WO2011028800A2 - Treatment of cognitive dysfunction with gangliosides

Info

Publication number: WO2011028800A2
Application number: PCT/US2010/047528
Authority: WO
Inventors: Jay S. Schneider; Gerri Henwood; Robert Florentine
Original assignee: Lazarus Therapeutics, Inc.
Priority date: 2009-09-01
Filing date: 2010-09-01
Publication date: 2011-03-10
Also published as: WO2011028800A3

Abstract

A method of treating or preventing cognitive dysfunction in a human patient in need thereof comprising administering one or more gangliosides to said patient, wherein said patient is undergoing chemotherapy or irradiation treatment for cancer.

Description

TREATMENT OF COGNITIVE DYSFUNCTION WITH G ANGLIO SIDE S

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application seeks priority to U.S. provisional application 61/238,735 filed September 1, 2009, herein incorporated by reference in its entirety. The application is related to

PCT Patent Application Nos. , filed September 1, 2010, based on US Provisional applications 61/238,775; 61/238,748 and 61/238,726, each of which is incorporated by reference in its entirety.

FIELD

[0002] Described herein are methods of using gangliosides and analogs thereof in the treatment or prevention of cognitive dysfunction, and more particularly cognitive dysfunction associated with cancer chemotherapy or irradiation.

BACKGROUND

[0003] Neurotoxic side effects of chemotherapy occur frequently and are often a reason to limit the dose, and therefore the effectiveness, of chemotherapy. Because bone marrow toxicity, as the major limiting factor in most chemotherapeutic regimens, can be overcome with growth factors or bone marrow transplantation, the use of higher doses of chemotherapy is possible, which increases the risk of neurotoxicity. Chemotherapy may cause both peripheral neurotoxicity, mainly including peripheral neuropathy, and central neurotoxicity, ranging from minor cognitive deficits to encephalopathy with dementia.

[0004] The vinca-alkaloids, cisplatin and the taxanes are amongst the most important drugs inducing peripheral neurotoxicity. These drugs are widely used for various malignancies such as ovarian and breast cancer, and haemato logical cancers. Methotrexate, cytarabine (cytosine arabinoside) and ifosfamide are primarily associated with central neurotoxic side effects. Central neurotoxicity can be acute or delayed consisting of cognitive deficits, hemiparesis, aphasia and progressive dementia. [0005] In addition to chemotherapy-induced cognitive dysfunction, cognitive effects after cranial radiotherapy are also widely recognized. Over 50 reports from January 1980 to July 2003 assessed cognitive effects of irradiation or chemotherapy in over 3,000 patients by neuropsychological evaluation. Both chemotherapy and irradiation were found to result in cognitive deficits, with no clinically relevant differences in cognitive deficits, cognitive impairment rate, and cognitive domains affected, when chemotherapy, cranial irradiation and combined radio- and chemotherapy were compared. In 28 trials reporting on 1,000 patients with cognitive deficits after therapy, 44.1% (range 18-75%) of chemotherapy patients, 44.0% (range 29-83%) of radiotherapy patients, and 64.5% (range 30-100%) of combined irradiation and chemotherapy patients had cognitive deficits.

[0006] Risk factors include high doses of such drugs, frequent administration, and radiotherapy preceding methotrexate chemotherapy, which appears to be more neurotoxic than methotrexate as single modality. Management of Central Nervous System (CNS) toxicity mainly includes dose-reduction, especially in patients who are at higher risk to develop neurotoxic side effects.

[0007] There are currently no neuroprotective agents in use to protect against development of chemotherapy-induced cognitive dysfunction and CNS toxicity, and a continuing and unmet need exists for new and improved methods of mitigating the neurotoxic side effects of cancer therapies.

SUMMARY

[0008] GM1 (monosialotetrahexosylganglioside) has important physiological properties and impacts neuronal plasticity and repair mechanisms, and the release of neurotrophins in the brain. Provided herein is a therapy and/or preventative of cognitive dysfunction induced in patients due to chemotherapy or radiotherapy.

[0009] An embodiment of the invention provides a method of treating or preventing cognitive dysfunction in a human patient in need thereof by administering one or more gangliosides to the patient, where the patient is undergoing chemotherapy or irradiation treatment for cancer. [0010] The gangliosides can be selected from the group consisting of GMl, GD3, GM2, GDla, GDlb, GTl or any combination thereof. The ganglosides can be GMl . In another aspect, the gangliosides comprise GMl and at least one other ganglioside selected from the group consisting of GMl, GD3, GM2, GDla, GDlb, GTl or any combination thereof.

[0011] The gangliosides can be administered as a co-therapy to a patient concurrently with administration of chemotherapy or irradiation. The gangliosides can also be administered to a patient subsequent or prior to administration of chemotherapy or irradiation.

[0012] Another embodiment discloses a method for alleviating a disorder due to nerve cell degeneration in the brain by administering, to a patient suffering from the disorder, a therapeutically effective amount of a ganglioside sufficient to alleviate the symptoms of the disease.

[0013] Additional features may be understood by referring to the following detailed description and examples.

DETAILED DESCRIPTION

[0014] Described herein is a new method for treating or preventing cognitive dysfunction in a human cancer patient in need thereof. The method provided herein includes administering a therapeutically effective amount of one or more gangliosides.

[0015] Provided herein is a composition for treating or preventing cognitive dysfunction in a human patient in need thereof by administering a therapeutically effective amount of one or more gangliosides to the patient. The gangliosides used in the present composition can be selected from the group consisting of GMl, GD3, GM2, GDla, GDlb, GTl or any combination thereof.

[0016] In a specific embodiment, the ganglosides can be GMl . In another aspect, the gangliosides comprise GMl and at least one other ganglioside selected from the group consisting of GMl, GD3, GM2, GDla, GDlb, GTl or any combination thereof. The gangliosides can be administered as a co-therapy with a chemotherapeutic agent or irradiation.

[0017] In another embodiment, the method of treating or preventing cognitive dysfunction in a human patient in need thereof can be by administering a therapeutically effective amount of one or more gangliosides to a patient, where the patient is undergoing chemotherapy or irradiation treatment for cancer. The gangliosides can be selected from the group consisting of GM1, GD3, GM2, GDla, GDlb, GT1 or any combination thereof. In another aspect, the gangliosides comprise GM1 and at least one other ganglioside selected from the group consisting of GM1, GD3, GM2, GDla, GDlb, GT1 or any combination thereof. The gangliosides can be administered as a co-therapy with a chemotherapeutic agent or irradiation.

[0018] In an embodiment, the gangliosides can be administered as a co-therapy to a patient concurrently with administration of chemotherapy or irradiation. In another embodiment, the gangliosides can be administered to a patient subsequent to administration of chemotherapy or irradiation. In yet another embodiment, the gangliosides can be administered to a patient prior to administration of chemotherapy or irradiation.

[0019] Another embodiment discloses a method for alleviating a disorder due to nerve cell degeneration in the brain by administering to a patient suffering from a disorder, a therapeutically effective amount of a ganglioside sufficient to alleviate the symptoms of the disease.

[0020] The gangliosides can be selected from the group consisting of GM1, GD3, GM2, GDla, GDlb, GT1 or any combination thereof. In another aspect, the gangliosides comprise GM1 and at least one other ganglioside selected from the group consisting of GM1, GD3, GM2, GDla, GDlb, GT1 or any combination thereof. The gangliosides can be administered as a co- therapy with a chemotherapeutic agent or irradiation.

[0021] Further aspects provide the administering of gangliosides as a co-therapy to a patient with a disorder due to nerve cell degeneration, concurrently with administration of chemotherapy or irradiation, subsequent to administration of chemotherapy or irradiation, or prior to administration of chemotherapy or irradiation.

[0022] Although the available evidence suggests a fairly diffuse pattern of changes occurs in patients with cognitive dysfunction that is associated with cancer treatment, memory (including working memory), attention, psychomotor functioning, and executive functions may be preferentially affected. Several pathophysiological candidates have been suggested to underlie cancer therapy-induced CNS toxicity including direct neurotoxic effects leading to atrophy of cerebral gray matter or damage to white matter fibers, inflammatory reactions, microvascular injury, excitotoxicty, and free radical toxicity. Altered neurotransmitter levels and metabolites may also contribute to additional mechanisms related to neurotoxic effects.

[0023] Based on this information, GMl ganglioside, other gangliosides (eg. GD3 and others), and GMl derivatives and analogs may function as neuroprotective drugs for use in the treatment or prevention of chemotherapy-induced or irradiation-induced cognitive dysfunction.

[0024] Although GMl has been identified as having therapeutic potential in Alzheimer's Disease and Parkinson's Disease, other gangliosides as described herein may be used in certain embodiments alone or in combination with GMl to ameliorate the symptoms or cognitive dysfunction associated with chemotherapy or radiotherapy in cancer patients.

[0025] In general, gangliosides are the group of glycosphingo lipids that show the greatest structural variation and also the more complex structure and are characteristic of nervous tissues. The main gangliosides of the brain are GMl, GDI a, GDlb and GT1. GM3 is present mainly in nervous tissues outside brain tissues. GMl activates trkB signaling and potentiates neurotrophins, and exogenous administration of GMl has been shown to reduce nerve cell degeneration. Gangliosides are glycosphingolipids that localize in the outer leaflet of the plasma membrane of vertebrate cells. Gangliosides are highly concentrated in the nervous system and play a critical role in the normal development, growth and function of neurons.

[0026] Numerous studies have shown that gangliosides, and in particular, GMl ganglioside, have strong neurotrophic, neuroprotective and immunosuppressive properties. Due to their role in modulating cell signaling pathways, gangliosides can affect multiple cellular processes that are critical to normal cell functioning, cell survival and response to injury. Among its many actions, GMl ganglioside binds calmodulin, inhibits nitric oxide synthase catalytic activity, blocks nitric oxide -mediated cell death, is anti-apoptotic under a variety of circumstances, activates transmembrane tyrosine kinase receptors, mimics or potentiates the action of neurotrophic factors, enhances the synthesis of certain neurotrophic factors, modulates cytoplasmic and nuclear calcium fluxes, stimulates neurite outgrowth, inhibits glutamate -related excitotoxic processes without interfering with glutamate receptor function, and enhances neurotransmitter synthesis in damaged systems.

[0027] Accordingly, this invention involves the use of GM1 ganglioside, other gangliosides including GD3, GM2, GDla, GDlb and GT1, and GM1 derivatives and analogs as a neuroprotective drug for cognitive dysfunction associated with cancer therapies (chemotherapy, irradiation, or combination therapies). Gangliosides may be administered prior to the initiation of the cancer therapy, coincident with the cancer therapy, following the cancer therapy, or at any combination of the foregoing time periods.

[0028] Core pathophysiological mechanisms contributing to cognitive dysfunction following radiation therapy are the interruption of frontal-subcortical circuits, possibly caused by progressive microvascular alterations, loss of oligodendrocyte progenitors, or oxidative stress. Candidate mechanisms for chemotherapy-induced cognitive dysfunction include direct neurotoxic effects, e.g., injury to neurons or surrounding cells, altered neurotransmitter levels, oxidative stress, induced hormonal changes, inflammation, and blood clotting in small CNS vessels resulting in ischemic damage similar to that observed after a stroke. This latter process in particular may lead to excitotoxicity and neuronal death.

[0029] GM1, and other gangliosides and derivatives and analogs, may prevent or lessen chemotherapy or irradiation-induced cognitive dysfunction and promote recovery of cognitive functioning following cancer therapy. GM1 and derivatives and analogs thereof exert the above- mention effects due to ability to counter effects of excitotoxicity, oxidative stress and other potential neurotoxic factors contributing to cancer therapy-induced cognitive dysfunction, as well as neurotrophic effects promoted or stimulated by GM 1.

[0030] GM1 alone or in combination with other gangliosides would be effective. Gangliosides may be administered parenterally by intravenous or subcutaneous administration or via nasal or mucosal administration, e.g., alone or with appropriate absorption enhancers. This may include prolonged action dosage forms. Gangliosides may be administered using controlled release formulations (e.g., liposomes, nanoparticles, microspheres, implants) to prolong drug activity, or they may be coupled to appropriate transporter molecules in order to cross the blood brain barrier following systemic administration. Because radiotherapy itself disrupts the blood brain barrier, GM1 should have good penetration into the brain in patients receiving radiation therapy or combined radiation/chemotherapy so that the compound may exert its beneficial effects on the CNS.

[0031] Gangliosides could be administered parenterally or via nasal administration (alone or with appropriate absorption enhancers). Suitable formulations for intranasal administration may also include a therapeutic dose of GMl in a gel formulation with in situ gelling and mucoadhesive properties such that there is an increased permeation rate and prolonged nasal residence time and thereby increased nasal absorption. Such formulations would increase retention time of the GMl solution in nasal cavity resulting in greater bioavailability and greater transfer of GMl to the brain via the olfactory pathway. Chitosan-based mucoadhesive formulations could be used to enhance the retention time and bioavailability of GMl . Nasal bioadhesive gels could also provide enhanced bioavailability compared with other delivery routes and be combined in a formulation with other absorption enhancers.

[0032] Such a formulation may include a therapeutically active amount of GMl together with gelling solutions of tri-block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., Pluronic F127 ("PF127")) that exhibit thermoreversible properties. By modulating the gelation temperature of different PF 127 solutions, liquid bases for nasal use can be formulated that form a gel in the nasal cavity at body temperature with suitable gel strength resulting in enhancement of the residence time in the nasal cavity. The high solubilizing capacity and nontoxic properties of PF127 make it suitable for nasal drug delivery. GMl formulations for intranasal delivery may therefore include thermoreversible polymer PF 127 and a mucoadhesive polymer (such as C934P), which enhances nasal residence time and absorption of drug across nasal-mucosal membrane.

[0033] For oral or buccal mucosal administration, a transmucosal product can be formulated with GMl to be administered via the oral/buccal route using mucoadhesive, quick dissolve tablets or an oral spray formulation. Potential mucoadhesive polymers include hydrophilic polymers containing carboxylic group (which exhibit the favorable mucoadhesive properties) such as poly vinyl-pyrrolidone ("PVP"), methyl cellulose ("MC"), sodium carboxy methylcellulose ("SCMC"), hydroxy propyl cellulose ("HPC"), and other cellulose derivatives. Hydrogels that may also be used include carbopol, polyacrylates and their crosslinked modifications, chitosan and its derivatives, Eudragit-NE30D etc. PEGylating various polymers could also enhance mucoadhesion. Carbopol-934, hydroxypropylmethylcellulose, hydroxyethylcellulose, and sodium carboxymethylcellulose may also be used in various combination ratios, together with a therapeutic amount of GM1 for buccal drug delivery. Transmucosal routes of administration are described in US Patent Application Number

, herein incorporated by reference in its entirety.

[0034] In summary, there currently is no cure or effective treatment for cognitive dysfunction associated with chemotherapy or radiation therapy for various cancers. This innovative new approach, using ganglioside therapy, promotes protection of cognitive functioning and helps restore function resulting in a more favorable long-term outcome for patients. Patients will not need to compromise their cancer therapy because of severe adverse effects on cognitive functioning.

[0035] While this description is made with reference to exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope. In addition, many modifications may be made to adapt a particular situation or material to the teachings hereof without departing from the essential scope. Also, in the drawings and the description, there have been disclosed exemplary embodiments and, although specific terms may have been employed, they are unless otherwise stated used in a generic and descriptive sense only and not for purposes of limitation, the scope of the claims therefore not being so limited. Moreover, one skilled in the art will appreciate that certain steps of the methods discussed herein may be sequenced in alternative order or steps may be combined. Therefore, it is intended that the appended claims not be limited to the particular embodiment disclosed herein.

[0036] Each of the applications and patents cited in this text, as well as each document or reference cited in each of the applications and patents (including during the prosecution of each issued patent; "application cited documents"), and each of the PCT and foreign applications or patents corresponding to and/or claiming priority from any of these applications and patents, and each of the documents cited or referenced in each of the application cited documents, are hereby expressly incorporated herein by reference in their entirety. More generally, documents or references are cited in this text, either in a Reference List before the claims; or in the text itself; and, each of these documents or references ("herein-cited references"), as well as each document or reference cited in each of the herein-cited references (including any manufacturer's specifications, instructions, etc.), is hereby expressly incorporated herein by reference.

REFERENCES

Leake PA et al. Neurotrophic effects of GMl ganglioside and electrical stimulation on cochlear spiral ganglion neurons in cats deafened as neonates. J Comp Neurol. 2007 Apr 20;501(6):837- 53.

Claims

1. A composition for treating or preventing cognitive dysfunction in a human patient in need thereof comprising a therapeutically effective amount of one or more gangliosides.

2. The composition according to claim 1, wherein said gangliosides are selected from the group consisting of GMl, GD3, GM2, GDla, GDlb, GTl or any combination thereof.

3. The composition according to claim 1, wherein said ganglosides comprises GMl .

4. The composition according to claim 1, wherein said gangliosides comprise GMl and at least one other ganglioside.

5. The composition according to claim 1, wherein said other ganglioside is selected from the group consisting of GMl, GD3, GM2, GDla, GDlb, GTl or any combination thereof.

6. The composition according to claim 1, wherein said gangliosides are administered as a co- therapy with a chemotherapeutic agent or irradiation.

7. A method of treating or preventing cognitive dysfunction in a human patient in need thereof comprising administering a therapeutically effective amount of one or more gangliosides to said patient, wherein said patient is undergoing chemotherapy or irradiation treatment for cancer.

8. The method according to claim 7, wherein said gangliosides are selected from the group consisting of GMl, GD3, GM2, GDla, GDlb, GTl or any combination thereof.

9. The method according to claim 7, wherein said ganglosides comprises GMl .

10. The method according to claim 7, wherein said gangliosides comprise GMl and at least one other ganglioside.

11. The method according to claim 10, wherein said other ganglioside is selected from the group consisting of GMl, GD3, GM2, GDla, GDlb, GTl or any combination thereof.

12. The method according to claim 7, wherein said gangliosides are administered as a co-therapy to said patient concurrently with administration of chemotherapy or irradiation.

13. The method according to claim 7, wherein said gangliosides are administered to said patient subsequent to administration of chemotherapy or irradiation.

14. The method according to claim 7, wherein said gangliosides are administered to said patient prior to administration of chemotherapy or irradiation.

15. A method for alleviating a disorder due to nerve cell degeneration in the brain comprising administering to a patient suffering from said disorder a therapeutically effective amount of a ganglioside sufficient to alleviate the symptoms of said disease.

16. The method according to claim 15, wherein said gangliosides are selected from the group consisting of GM1, GD3, GM2, GDI a, GDlb, GT1 or any combination thereof.

17. The method according to claim 15, wherein said ganglosides comprises GM1.

18. The method according to claim 15, wherein said gangliosides comprise GM1 and at least one other ganglioside.

19. The method according to claim 18, wherein said other ganglioside is selected from the group consisting of GM1, GD3, GM2, GDI a, GDlb, GT1 or any combination thereof.

20. The method according to claim 15, wherein said gangliosides are administered as a co- therapy to said patient concurrently with administration of chemotherapy or irradiation.

21. The method according to claim 15, wherein said disorder due to nerve cell degeneration is in a patient undergoing chemotherapy or irradiation treatment for cancer.

22. The method according to claim 15, wherein said gangliosides are administered to said patient subsequent to administration of chemotherapy or irradiation.

23. The method according to claim 15, wherein said gangliosides are administered to said patient prior to administration of chemotherapy or irradiation.