Hematopoietic Stem Cell Gene Therapy for Storage Disease: Current and New Indications

Abstract

Lysosomal storage disorders (LSDs) are a broad class of monogenic diseases with an overall incidence of 1:7,000 newborns, due to the defective activity of one or more lysosomal hydrolases or related proteins resulting in storage of un-degraded substrates in the lysosomes. The over 40 different known LSDs share a life-threatening nature, but they are present with extremely variable clinical manifestations, determined by the characteristics and tissue distribution of the material accumulating due to the lysosomal dysfunction. The majority of LSDs lack a curative treatment. This is particularly true for LSDs severely affecting the CNS. Based on current preclinical and clinical evidences, among other treatment modalities, hematopoietic stem cell gene therapy could potentially result in robust therapeutic benefit for LSD patients, with particular indication for those characterized by severe brain damage. Optimization of current approaches and technology, as well as implementation of clinical trials for novel indications, and prolonged and more extensive follow-up of the already treated patients will allow translating this promise into new medicinal products.

Keywords: central nervous system; gene therapy; hematopoietic stem cells; lentiviral vectors; lysosomal enzymes; storage diseases.

Figure 1

Lysosomal Enzyme Deficiency and Its Consequences The defective activity of a lysosomal enzyme (E) determines the accumulation of undegraded substrates in LSD cells, leading to the activation of a pathologic cascade of events.

Figure 2

The Mechanisms of Cross-Correction Functional enzyme secreted by wild-type cells is taken up and sorted to the lysosomal compartment of the LSD cells through the mannose-6-phosphate receptor (M6P-R) pathway. This leads to restoration of substrate metabolism.