Diseases of the nervous system have devastating effects and are widely distributed among the population, being especially prevalent in the elderly. These diseases are often caused by inherited genetic mutations that result in abnormal nervous system development, neurodegeneration, or impaired neuronal function. Other causes of neurological diseases include genetic and epigenetic changes induced by environmental insults, injury, disease-related events or inflammatory processes. Standard medical and surgical practice has not proved effective in curing or treating these diseases, and appropriate pharmaceuticals do not exist or are insufficient to slow disease progression. Gene therapy is emerging as a powerful approach with potential to treat and even cure some of the most common diseases of the nervous system. Gene therapy for neurological diseases has been made possible through progress in understanding the underlying disease mechanisms, particularly those involving sensory neurons, and also by improvement of gene vector design, therapeutic gene selection, and methods of delivery. Progress in the field has renewed our optimism for gene therapy as a treatment modality that can be used by neurologists, ophthalmologists and neurosurgeons. In this Review, we describe the promising gene therapy strategies that have the potential to treat patients with neurological diseases and discuss prospects for future development of gene therapy.
Standard pharmacological and surgical interventions are either inadequate or unavailable for most diseases of the PNS and CNS
Gene therapy is a viable approach to the prevention of neurological disease progression, and might offer a cure or slow down the disease process
The efficacy of gene therapy depends on the development of gene delivery vehicles (mostly viral vectors) to target disease-modifying products to where they are needed
Gene therapy strategies to treat some diseases that affect vision and hearing or that cause debilitating pain are at an advanced stage of development
Gene therapy for degenerative diseases requires a more in-depth understanding of the underlying pathophysiology and, for some diseases, global brain delivery of the transgene
With ongoing development of gene therapy applications for nervous system disease, such treatments are expected to be available to patients within 10 years
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The authors' research is supported by grants from the European Community (PIAPP-GA-2011-285827 [EPIXCHANGE Project] to M. Simonato) and from the NIH (CA119298, NS40923 and DK044935 to J. C. Glorioso; EY023177 and EY019861 to J. Bennett; NS038850 and NS069378 to D. J. Fink; NS038690, DK063973, NS056243, NS029390, DK047757, OD010939 and TR000003 to J. H. Wolfe; NS052465, NS052465-04S1, NS057711 and NS074387 to M. G. Castro and 1NS054193, NS061107 and TR000433 to P. R. Lowenstein). The authors thank A. Pizzirani and J. Coulter for preparation of the figures before submission.
L. H. Vandenberghe has been an ad hoc paid consultant for Novartis Institutes of Biomedical Research. L. H. Vandenberghe and J. Bennett are co-founders of GenSight Biologics, an ocular gene therapy company. N. M. Boulis was a consultant for the company Ceregene up to 2012. L. H. Vandenberghe is an inventor on the following patent applications: WO/2005/033321 (adeno-associated virus [AAV] clades, sequences, vectors containing same, and uses thereof); WO/2006/110689 (method of increasing the function of an AAV vector); WO/2007/127264 (scalable production method for AAV); and WO/2009/136977 (adeno-associated viral vectors for targeted transduction of retinal pigment epithelial cells). P. R. Lowenstein and M. G. Castro are inventors on the following European patent applications: 1181376B1 (gene construct for prodrug activation encoding a heterologous, glycosylphosphatidylinositol-modified carboxypeptidase G2 and a cell surface targeting signal peptide); and 1786474B1 (combined gene therapy for the treatment of macroscopic gliomas); and on granted US patent 7,858,590B2 (treatment of Parkinson disease and related disorders). J. H. Wolfe is an inventor on granted US patents 7,402,308 (method of delivering genes to the central nervous system of a mammal), 5,958,767, 6,528,306, 6,541,255, and 6,680,198 (engraftable human neural stem cells). J. C. Glorioso is an inventor on granted US patents 5,658,724, 5,879,934, 5,804,413, 6,261,552 and 7,078,029; European patent application 904395, and Australian patent applications 733945 (herpes simplex virus strains for gene transfer); granted US patents 5,849,571 and 5,849,572 (vectors comprising lap2 promoter and promoter active fragments); US patent 7,531,167 and Australian patent application 2005302408 (peripherally delivered glutamic acid decarboxylase gene therapy for injured spinal cord injury pain); granted US patent 8,309,349 (cell line) and patent application WO/07/922,839 (novel herpes simplex virus strains deficient for the essential immediate early genes ICP4 and ICP27 and methods for their production, growth and use). The other authors declare no competing interests.
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Simonato, M., Bennett, J., Boulis, N. et al. Progress in gene therapy for neurological disorders. Nat Rev Neurol 9, 277–291 (2013). https://doi.org/10.1038/nrneurol.2013.56
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