Hematopoietic stem cell gene therapy of neurometabolic lysosomal storage diseases

Abstract

Neurometabolic disorders are rare, inherited monogenic diseases arising from mutations in genes whose products are essential for brain functions and cause local accumulation of toxic substrates. Central nervous system involvement can be severe, is progressive and frequently appears early in life. Current treatment options for neurometabolic disorders are represented mainly by enzyme replacement therapy (ERT) and allogeneic hematopoietic stem cell transplantation (HSCT) which do not sufficiently address clinical manifestations and leave patients with a substantial residual disease burden. Given this unmet medical need, alternative strategies based on genetic manipulation of patient's cells have been developed. Hematopoietic stem progenitor cells-gene therapy (HSPC-GT) entails the harvest autologous HSPCs which are ex-vivo manipulated by means of viral vectors to express the therapeutic gene and infused back into the patient after chemotherapy-based preparation. Modified HSPCs engraft and differentiate into the various hematopoietic cell lineages, producing the functional enzyme at either normal or supranormal levels. The number of clinical trials with HSPC-GT in neurometabolic disorders is rapidly increasing and some HSPC-GT products have recently received market approval. This review focuses on HSPC-GT strategies summarizing the most recent developments in the field of neurometabolic disorders.