Current and Future Treatments for Lysosomal Storage Disorders

Abstract

Purpose of review Lysosomal storage disorders (LSDs) are a class of genetic disorders that are a testing ground for the invention of novel therapeutics including enzyme replacement therapy (ERT), substrate reduction therapy (SRT), gene therapy, and hematopoietic stem cell transplant (HSCT). This review summarizes recently approved drugs, then examines the successful clinical trials in gene therapy and HSCT. Recent findings The FDA has recently approved a second SRT by reversing an earlier FDA decision, suggesting a favorable regulatory landscape going forward. Adeno-associated virus therapies, adenovirus therapies, and HSCT have overcome limitations of earlier clinical and preclinical trials, suggesting that gene therapy may be a reality for LSDs in the near future. At the same time, the first EU-approved gene therapy drug, Glybera, has been discontinued, and other ex vivo-based therapies although approved for clinical use have failed to be widely adapted and are no longer economically viable. Summary There are now 11 ERTs and two SRTs approved for LSDs in the USA. Gene therapy approaches and HSCT have also demonstrated promising clinical trial results suggesting that these therapies are on the frontier. Challenges that remain include navigating immune responses, developing drugs capable of crossing the blood-brain barrier (BBB), developing therapies that can reverse end-organ damage, and achieving these goals in a safe, ethical, and financially sustainable manner. The amount of active development and a track record of iterative progress suggest that treatments for LSDs will continue to be a field of innovation, problem solving, and success.

In vitro Validation of Chimeric β-Galactosylceramidase Enzymes With Improved Enzymatic Activity and Increased Secretion

“…The therapeutic efficacy of lysosomal enzymes relies on their capability to be secreted by donor cells and recaptured by deficient cells in the mechanism known as cross-correction ( Rastall and Amalfitano, 2017 ). We evaluated the capacity and efficacy of chimeric GALC enzymes secreted by neural and hematopoietic cells to cross-correct TWI neural progeny, thus modeling the mechanisms acting in the context of CNS-directed GT approaches.…”

Lysosomal diseases: Overview on current diagnosis and treatment

“…A functional version of the missing or hypoactive enzyme is produced by genetically engineered cell lines in a cGMP-compliant fashion. The purified enzyme may sometimes be modified to better target the lysosomal targeting pathways (Rastall and Amalfitano, 2017).…”

“…Development of ERT for FD followed (Biegstraaten et al , 2015). ERT has also been developed for PD, MPS types I, II, IVA, VI, and VII, and lysosomal acid lipase deficiency, becoming the mainstay of treatment for individuals affected by these disorders (Rastall and Amalfitano, 2017). ERT has been the most successful treatment for LDs to-date and is currently being explored for other conditions such as acid sphingomyelinase deficiency (Wasserstein et al , 2018) and alpha-mannosidosis (Borgwardt et al.…”

“…ERT represents a major advancement in the treatment of genetic disorders. However, the development and implementation of large-scale ERTs has unmasked several challenges in the treatment of LDs (Rastall and Amalfitano, 2017). Recombinant enzymes are very expensive and not all patients may benefit from them.…”

Chitosan in Non-Viral Gene Delivery: Role of Structure, Characterization Methods, and Insights in Cancer and Rare Diseases Therapies

“…LSDs are promising targets for gene therapy because the delivery of a single gene, into a small percentage of the appropriate target cells may be sufficient to impact the clinical course of the disease. In addition to these characteristics, another important one is the possibility for the “cross-correction phenomenon” of affected tissues in patients via the extra-cellular provision of recombinant forms of the deficient lysosomal enzyme [281]. Adeno-associated virus therapies, adenovirus therapies, and hematopoietic stem cell (HSC) transplant have overcome limitations associated with earlier clinical and preclinical trials, suggesting that gene therapy may be a reality for LSDs soon.…”