Gene Therapy for Neurodegenerative Disorders: Advances, Insights and Prospects

Overview

Journal Acta Pharm Sin B

Publisher Elsevier

Specialty Pharmacology

Date 2020 Sep 23

PMID 32963936

Citations 63

Authors

Wei Chen

Yang Hu

Dianwen Ju

Affiliations

Soon will be listed here.

Abstract

Gene therapy is rapidly emerging as a powerful therapeutic strategy for a wide range of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Some early clinical trials have failed to achieve satisfactory therapeutic effects. Efforts to enhance effectiveness are now concentrating on three major fields: identification of new vectors, novel therapeutic targets, and reliable of delivery routes for transgenes. These approaches are being assessed closely in preclinical and clinical trials, which may ultimately provide powerful treatments for patients. Here, we discuss advances and challenges of gene therapy for neurodegenerative disorders, highlighting promising technologies, targets, and future prospects.

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References

Filezac de LEtang A, Maharjan N, Cordeiro Brana M, Ruegsegger C, Rehmann R, Goswami A . Marinesco-Sjögren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS. Nat Neurosci. 2015; 18(2):227-38. DOI: 10.1038/nn.3903. View

Samaranch L, Salegio E, San Sebastian W, Kells A, Bringas J, Forsayeth J . Strong cortical and spinal cord transduction after AAV7 and AAV9 delivery into the cerebrospinal fluid of nonhuman primates. Hum Gene Ther. 2013; 24(5):526-32. PMC: 3655626. DOI: 10.1089/hum.2013.005. View

Hockly E, Richon V, Woodman B, Smith D, Zhou X, Rosa E . Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci U S A. 2003; 100(4):2041-6. PMC: 149955. DOI: 10.1073/pnas.0437870100. View

Samaranch L, Blits B, San Sebastian W, Hadaczek P, Bringas J, Sudhakar V . MR-guided parenchymal delivery of adeno-associated viral vector serotype 5 in non-human primate brain. Gene Ther. 2017; 24(4):253-261. PMC: 5404203. DOI: 10.1038/gt.2017.14. View

Samaranch L, Salegio E, San Sebastian W, Kells A, Foust K, Bringas J . Adeno-associated virus serotype 9 transduction in the central nervous system of nonhuman primates. Hum Gene Ther. 2011; 23(4):382-9. PMC: 3327605. DOI: 10.1089/hum.2011.200. View

Dong Z, Wolfer D, Lipp H, Bueler H . Hsp70 gene transfer by adeno-associated virus inhibits MPTP-induced nigrostriatal degeneration in the mouse model of Parkinson disease. Mol Ther. 2004; 11(1):80-8. DOI: 10.1016/j.ymthe.2004.09.007. View

Liu S, Gao Y, Zhou D, Zeng M, Alshehri F, Newland B . Highly branched poly(β-amino ester) delivery of minicircle DNA for transfection of neurodegenerative disease related cells. Nat Commun. 2019; 10(1):3307. PMC: 6656726. DOI: 10.1038/s41467-019-11190-0. View

Oddo S . The role of mTOR signaling in Alzheimer disease. Front Biosci (Schol Ed). 2011; 4(3):941-52. PMC: 4111148. DOI: 10.2741/s310. View

Nault J, Datta S, Imbeaud S, Franconi A, Mallet M, Couchy G . Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet. 2015; 47(10):1187-93. DOI: 10.1038/ng.3389. View

10.

Soto C . Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci. 2003; 4(1):49-60. DOI: 10.1038/nrn1007. View

11.

Dirren E, Aebischer J, Rochat C, Towne C, Schneider B, Aebischer P . SOD1 silencing in motoneurons or glia rescues neuromuscular function in ALS mice. Ann Clin Transl Neurol. 2015; 2(2):167-84. PMC: 4338957. DOI: 10.1002/acn3.162. View

12.

Deverman B, Ravina B, Bankiewicz K, Paul S, Sah D . Gene therapy for neurological disorders: progress and prospects. Nat Rev Drug Discov. 2018; 17(9):641-659. DOI: 10.1038/nrd.2018.110. View

13.

Minami S, Min S, Krabbe G, Wang C, Zhou Y, Asgarov R . Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models. Nat Med. 2014; 20(10):1157-64. PMC: 4196723. DOI: 10.1038/nm.3672. View

14.

Aguzzi A, OConnor T . Protein aggregation diseases: pathogenicity and therapeutic perspectives. Nat Rev Drug Discov. 2010; 9(3):237-48. DOI: 10.1038/nrd3050. View

15.

Takahashi K, Igarashi T, Miyake K, Kobayashi M, Yaguchi C, Iijima O . Improved Intravitreal AAV-Mediated Inner Retinal Gene Transduction after Surgical Internal Limiting Membrane Peeling in Cynomolgus Monkeys. Mol Ther. 2017; 25(1):296-302. PMC: 5363307. DOI: 10.1016/j.ymthe.2016.10.008. View

16.

Du F, Yu Q, Yan S, Hu G, Lue L, Walker D . PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer's disease. Brain. 2017; 140(12):3233-3251. PMC: 5841141. DOI: 10.1093/brain/awx258. View

17.

Her L, Mao S, Chang C, Cheng P, Chang Y, Yang H . miR-196a Enhances Neuronal Morphology through Suppressing RANBP10 to Provide Neuroprotection in Huntington's Disease. Theranostics. 2017; 7(9):2452-2462. PMC: 5525749. DOI: 10.7150/thno.18813. View

18.

Balazs A, Bloom J, Hong C, Rao D, Baltimore D . Broad protection against influenza infection by vectored immunoprophylaxis in mice. Nat Biotechnol. 2013; 31(7):647-52. PMC: 4030719. DOI: 10.1038/nbt.2618. View

19.

Steffan J, Bodai L, PALLOS J, Poelman M, McCampbell A, Apostol B . Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature. 2001; 413(6857):739-43. DOI: 10.1038/35099568. View

20.

Biferi M, Cohen-Tannoudji M, Cappelletto A, Giroux B, Roda M, Astord S . A New AAV10-U7-Mediated Gene Therapy Prolongs Survival and Restores Function in an ALS Mouse Model. Mol Ther. 2017; 25(9):2038-2052. PMC: 5589057. DOI: 10.1016/j.ymthe.2017.05.017. View