Gene therapy for lysosomal storage diseases: Current clinical trial prospects

Abstract

Lysosomal storage diseases (LSDs) are a group of metabolic inborn errors caused by defective enzymes in the lysosome, resulting in the accumulation of undegraded substrates. LSDs are progressive diseases that exhibit variable rates of progression depending on the disease and the patient. The availability of effective treatment options, including substrate reduction therapy, pharmacological chaperone therapy, enzyme replacement therapy, and bone marrow transplantation, has increased survival time and improved the quality of life in many patients with LSDs. However, these therapies are not sufficiently effective, especially against central nerve system abnormalities and corresponding neurological and psychiatric symptoms because of the blood-brain barrier that prevents the entry of drugs into the brain or limiting features of specific treatments. Gene therapy is a promising tool for the treatment of neurological pathologies associated with LSDs. Here, we review the current state of gene therapy for several LSDs for which clinical trials have been conducted or are planned. Several clinical trials using gene therapy for LSDs are underway as phase 1/2 studies; no adverse events have not been reported in most of these studies. The administration of viral vectors has achieved good therapeutic outcomes in animal models of LSDs, and subsequent human clinical trials are expected to promote the practical application of gene therapy for LSDs.

Exploring Pro-Inflammatory Immunological Mediators: Unraveling the Mechanisms of Neuroinflammation in Lysosomal Storage Diseases

“…The end result is tissue destruction in lysosomal storage disease. Studies have demonstrated a comprehensive understanding of current approaches (e.g., gene therapy, enzyme replacement therapy, substrate reduction therapy, hematopoietic stem cell transplantation, pharmacological chaperone therapy, and the proteostasis regulators) for the management of complications of lysosomal storage diseases [ 205 , 206 , 207 , 208 , 209 ]. However, the current treatment experiences difficulty targeting the pathologic organs, including the CNS, PNS, retina, and skeletal system.…”

Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step Towards Understanding and Treating Mucopolysaccharidoses

“…Despite their limitations, ERTs for Gaucher Disease [16], Fabry Disease [17], Acid Lipase Deficiency [18], Ceroid lipofuscinosis type 2 [19], Niemann-Pick diseases type A/B [20] , α-Mannosidosis [21], and MPS I, II, IV, VI, and VII [22] are, nowadays, a reality and numerous patients have benefited from them over the last decades. Additional clinical trials with novel enzymes and alternative delivery routes are also ongoing [23]. Overall, ERT is not a cure, but it does significantly increase enzyme activity in many disorders, thus improving their associated clinical symptoms [24].…”

N‐Methyl‐N‐Alkylaminocyclopentanes: Powerful and Selective β‐d‐Glucocerebrosidase Inhibitors

“…While LSDs are typically challenging to treat, several strategies for disease management have emerged. These include enzyme replacement therapy (ERT), [6] gene therapy (GT), [7,8] substrate reduction therapy (SRT) [9] and the chaperone-mediated therapy (CMT). [10 -16] Within the group of LSDs, Morbus Gaucher stands out as the most frequently observed one, with an estimated global prevalence of 1 : 50,000 to 1 : 100,000.…”

“…While LSDs are typically challenging to treat, several strategies for disease management have emerged. These include enzyme replacement therapy (ERT), [6] gene therapy (GT), [7,8] substrate reduction therapy (SRT) [9] and the chaperone‐mediated therapy (CMT) [10–16] …”