Gene therapy for neurodegenerative disorders: advances, insights and prospects

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.

Keywords: AADC, aromatic-l-amino-acid; AAVs, adeno-associated viruses; AD, Alzheimer's disease; ARSA, arylsulfatase A; ASOs, antisense oligonucleotides; ASPA, aspartoacylase; Adeno-associated viruses; Adv, adenovirus; BBB, blood–brain barrier; BCSFB, blood–cerebrospinal fluid barrier; BRB, blood–retina barrier; Bip, glucose regulated protein 78; CHOP, CCAAT/enhancer binding homologous protein; CLN6, ceroidlipofuscinosis neuronal protein 6; CNS, central nervous system; CSF, cerebrospinal fluid; Central nervous system; Delivery routes; ER, endoplasmic reticulum; FDA, U.S. Food and Drug Administration; GAA, lysosomal acid α-glucosidase; GAD, glutamic acid decarboxylase; GDNF, glial derived neurotrophic factor; Gene therapy; HD, Huntington's disease; HSPGs, heparin sulfate proteoglycans; HTT, mutant huntingtin; IDS, iduronate 2-sulfatase; LVs, retrovirus/lentivirus; Lamp2a, lysosomal-associated membrane protein 2a; NGF, nerve growth factor; Neurodegenerative disorders; PD, Parkinson's disease; PGRN, Progranulin; PINK1, putative kinase 1; PTEN, phosphatase and tensin homolog; RGCs, retinal ganglion cells; RNAi, RNA interference; RPE, retinal pigmented epithelial; SGSH, lysosomal heparan-N-sulfamidase gene; SMN, survival motor neuron; SOD, superoxide dismutase; SUMF, sulfatase-modifying factor; TFEB, transcription factor EB; TPP1, tripeptidyl peptidase 1; TREM2, triggering receptor expressed on myeloid cells 2; UPR, unfolded protein response; ZFPs, zinc finger proteins; mTOR, mammalian target of rapamycin; siRNA, small interfering RNA.

Graphical abstract

Figure 1

Delivery routes of gene therapy for neurodegenerative disorders. Although intravenous or cerebrospinal fluid (intrathecal, intracerebroventricular, and subpial routes) administration can effectively treat multifocal disorders, intraparenchymal injection is the most frequently applied delivery route for brain diseases. Local gene delivery is preferable for diseases of the eye, because of its relatively straightforward surgical and instrumental accessibility. Intramuscular injection provides a strategy for vaccine and antibody delivery and production, and intrauterine injection may provide an approach to treat inherited neurodegenerative diseases.