Gene Therapy for Pediatric Neurologic Disease

Lysosomal and peroxisomal storage disorders, leukodystrophies, and motor neuron dis-eases include diverse groups of monogenic disorders that have a spectrum of devas-tating neurologic manifestations that affect the pediatric population. Currently, many of these disorders and diseases lack any definitive treatment despite efforts over the past several decades to exploit cross-correction through ERT and allo-HCT. Gene therapy is a cell-based method to administer corrected gene to patients, which allows for the secretion of functional enzymes. Appropriate conditioning regimens enable cerebral myeloid remodeling for the potential arrest or reversal of cerebral disease. In many cases, there is also the potential to treat nearby unmodified impaired cells via cross-correction. Ex vivo gene therapies systemically distribute functional enzyme, which allows for the targeting of multi-organ systems, including the central and peripheral nervous sys-tems. This is being trialed for many disorders, including X-ALD, Fabry disease, and MLD with promising preliminary results. By transducing autologous HSPCs with cor-rected gene using LV vectors, the patient & rsquo;s body recognizes the foreign gene product as self, alleviating concerns of immunogenicity.39 In vivo delivery of functional gene is ideal for targeting select organ systems with relatively lower cell turnover, including the brain. In vivo efforts are currently being trialed for many disorders as well, including Canavan disease, Fabry disease, GD2, GLD, GM1 and GM2 gangliosidoses, neuronal ceroid lipofuscinoses, and SMA. Potential complications and concerns related to these therapeutic methods include the risks associated with conditioning regimens as well as the potential for insertional oncogenesis. Future directions are focused on enhancing gene therapy methods, including minimizing the likelihood of insertional oncogenesis, improving the penetration of the BBB, and optimizing tissue uptake.