Compositions and methods for treatment of neurological disorders
View Patent ↗The present disclosure provides methods and compositions for the treatment of diseases and/or disorders in a subject, including, but not limited to neurological disorders such as giant axonal neuropathy. The methods described herein include direct administration of a gene therapy (e.g. an rAAV viral vector) to a subject via injection into a vagus nerve (e.g. the left vagus nerve) of the subject.
1 . A method of treating a disease and/or disorder in a subject comprising administering to the subject at least one therapeutically effective amount of a transgene nucleic acid molecule, by injecting the at least one therapeutically effective amount of the transgene nucleic acid molecule into a left vagus nerve of the subject
wherein the transgene nucleic acid molecule comprises a codon optimized nucleic acid sequence encoding for a gigaxonin (GAN) polypeptide, the codon optimized nucleic acid sequence comprising a nucleic acid sequence set forth in SEQ ID NO: 3.
2 . The method of claim 1 , wherein the disease and/or disorder is a neurological disease and/or disorder.
3 . The method of claim 2 , wherein the neurological disease and/or disorder is characterized by at least one autonomic dysfunction, and wherein administration of the at least one therapeutically effective amount of the transgene nucleic acid molecule via injection into the vagus nerve alleviates at least one symptom of the at least one autonomic dysfunction.
4 . The method of claim 3 , wherein the at least one symptom is selected from dysarthria, dysphagia, inadequate control of gastrointestinal tract motility, inadequate control of blood pressure, respiratory difficulties, orthostatic hypotension, sweating abnormalities, inadequate control of urinary tract, sexual dysfunction, and any combination thereof.
5 . The method of claim 1 , wherein the disease and/or disorder is selected from Spinal muscular atrophy, Friedrich's ataxia, CLN3 Batten, CLN6 Batten, CLN7 Batten, Epileptic encephalopathy, Leigh Syndrome, Charcot Marie Tooth disease, Giant Axonal Neuropathy, Lafora disease, SLC13A5 Epileptic Encephalopathy, Congenital Disorder of Glycosylation, Type Iq, Kahrizi Syndrome, Angelman Syndrome, Rett Syndrome, Spastic paraplegia, Alternating hemiplegia of childhood, and Zellweger spectrum disorder.
6 . The method of claim 5 , wherein the disease and/or disorder is Giant Axonal Neuropathy.
7 . The method of claim 1 , wherein the transgene nucleic acid molecule further comprises
a promoter sequence.
8 . The method of claim 7 , wherein
the promoter sequence comprises a nucleic acid sequence set forth in SEQ ID NO: 8.
9 . The method of claim 1 , wherein the subject has been previously administered at least one therapeutically effective amount of a transgene nucleic acid molecule that is the same transgene nucleic acid molecule that is administered via injection into the left vagus nerve of the subject.
10 . The method of claim 9 , wherein the initial transgene nucleic acid molecule was administered to the subject intravenously, intrathecally, intracerebrally, intraventricularly, intranasally, intratracheally, intra-aurally, intra-ocularly, peri-ocularly, orally, rectally, transmucosally, inhalationally, transdermally, parenterally, subcutaneously, intradermally, intramuscularly, intranervally, intrapleurally, topically, intralymphatically, or intracisternally.
11 . The method of claim 10 , wherein the initial transgene nucleic acid molecule was administered to the subject intrathecally.
12 . A method of treating a Giant Axonal Neuropathy in a subject comprising administering to the subject at least one therapeutically effective amount of a transgene nucleic acid molecule by injecting the at least one therapeutically effective amount of the transgene nucleic acid molecule into a vagus nerve of the subject, wherein the transgene nucleic acid molecule comprises a codon optimized nucleic acid sequence encoding for a gigaxonin (GAN) polypeptide, the codon optimized nucleic acid sequence comprising a nucleic acid sequence set forth in SEQ ID NO: 3.
13 . The method of claim 12 , wherein the vagus nerve is a left vagus nerve of the subject.
14 . The method of claim 12 , wherein the the transgene nucleic acid molecule further comprises
a promoter sequence.
15 . The method of claim 14 , wherein
the promoter sequence comprises a nucleic acid sequence set forth in SEQ ID NO: 8.
16 . A method of treating a disease and/or disorder in a subject comprising administering to the subject at least one therapeutically effective amount of a transgene nucleic acid molecule by injecting the at least one therapeutically effective amount of the transgene nucleic acid molecule into a vagus nerve of the subject, wherein the subject has been previously administered at least one therapeutically effective amount of a transgene nucleic acid molecule that is the same transgene nucleic acid molecule that is administered via injection into the left vagus nerve of the subject, wherein the transgene nucleic acid molecule comprises a codon optimized nucleic acid sequence encoding for a gigaxonin (GAN) polypeptide, the codon optimized nucleic acid sequence comprising a nucleic acid sequence set forth in SEQ ID NO: 3.
17 . The method of claim 16 , wherein the vagus nerve is a left vagus nerve of the subject.
18 . The method of claim 16 , wherein the transgene nucleic acid molecule further comprises
a promoter sequence.