Clinical Trials for Gene Therapy in Lysosomal Diseases With CNS Involvement

Abstract

There are over 70 known lysosomal storage disorders (LSDs), most caused by mutations in genes encoding lysosomal hydrolases. Central nervous system involvement is a hallmark of the majority of LSDs and, if present, generally determines the prognosis of the disease. Nonetheless, brain disease is currently poorly targeted by available therapies, including systemic enzyme replacement therapy, mostly (but not only) due to the presence of the blood–brain barrier that restricts the access of orally or parenterally administered large molecules into the brain. Thus, one of the greatest and most exciting challenges over coming years will be to succeed in developing effective therapies for the treatment of central nervous system manifestations in LSDs. Over recent years, gene therapy (GT) has emerged as a promising therapeutic strategy for a variety of inherited neurodegenerative diseases. In LSDs, the ability of genetically corrected cells to cross-correct adjacent lysosomal enzyme-deficient cells in the brain after gene transfer might enhance the diffusion of the recombinant enzyme, making this group of diseases a strong candidate for such an approach. Both in vivo (using the administration of recombinant adeno-associated viral vectors) and ex vivo (auto-transplantation of lentiviral vector-modified hematopoietic stem cells-HSCs) strategies are feasible. Promising results have been obtained in an ever-increasing number of preclinical studies in rodents and large animal models of LSDs, and these give great hope of GT successfully correcting neurological defects, once translated to clinical practice. We are now at the stage of treating patients, and various clinical trials are underway, to assess the safety and efficacy of in vivo and ex vivo GT in several neuropathic LSDs. In this review, we summarize different approaches being developed and review the current clinical trials related to neuropathic LSDs, their results (if any), and their limitations. We will also discuss the pitfalls and the remaining challenges.

Engineered AAVs for non-invasive gene delivery to rodent and non-human primate nervous systems

“…2021; Duan et al, 2022;Monteys et al, 2021). With several therapeutic candidates now in the pipeline for various neurological disorders (Deverman et al, 2018;Hudry and Vandenberghe, 2019;Sevin and Deiva, 2021;Privolizzi et al, 2021), the new systemic AAV vectors described in this study, AAV-MaCPNS1 and AAV-MaCPNS2, offer hope to accelerate translational research as well.…”

A Compendium of Information on the Lysosome

“…In a screen, NCGC607 was able to reduce lysosome substrate accumulation in stem cells derived from patients diagnosed with Gaucher disease; however, further testing is needed to test its effectiveness in LSD patient directly ( Aflaki et al, 2016 ; Platt, 2018 ). Gene therapy for the treatment of LSD has also started to garner attention, with preclinical and clinical trial underway ( Sevin and Deiva, 2021 ). Altogether, more clinical trials are needed to determine the robustness of these approaches.…”

Navigating the ventricles: Novel insights into the pathogenesis of hydrocephalus

“…For example, AAV vectors have been shown to produce strong long-term expression within the choroid plexus and ependyma in mouse models, 62 and human trials for intrathecal recombinant protein delivery as well as AAV based enzyme replacement therapy using AAV viruses are well underway. 63 …”