Pathobiological Insights into the Newly Targeted Therapies of Lysosomal Storage Disorders

Abstract

Lysosomal storage disorders (LSDs) are a heterogeneous group of inborn errors of metabolism caused by inherited deficiencies of any of the lysosomal functions, leading to the accumulation of undegraded substrates in multiple tissues and organs. Two-third of LSDs involves the central nervous system, thus representing the most common cause of pediatric neurodegenerative diseases. Substantial progress has been made in our understanding of the pathophysiology of LSDs, leading to newly targeted therapeutic options. Enzyme replacement therapy (ERT) is currently available for seven LSDs including Gaucher disease, Fabry disease, Pompe disease, and mucopolysaccharidosis (MPS) I (Hurler disease), II (Hunter disease), IV A (Morquio A), and VI (Maroteaux?Lamy disease). ERT reduces lysosomal storage, thus slowing or sometimes avoiding progressive visceral damage altogether. However, ERT is unable to cross the blood?brain barrier (BBB), thus lacking efficacy on neurological manifestations. In patients with MPS I (Hurler disease) under 2 years of age and in selected patients with other LSD, hematopoietic stem cell transplantation is indicated. To bypass the BBB, other approaches, using small molecules are currently being tested and include substrate reduction therapy, which decreases the amount of substrate (currently available for type 1 Gaucher disease and for Niemann?Pick type C disease) and pharmacological chaperones, which enhance the residual activity of the mutant enzyme.

Anderson–Fabry Disease: From Endothelial Dysfunction to Emerging Therapies

“…e resulting endosomes containing the enzyme fuse with the lysosomes, providing the functioning enzyme in the LD cell and correcting the storage defect. is phenomenon is called cross correction and constitutes the point on which the lysosomal ERT is based [49] ere are currently two available ERT options: agalsidase-α (0.2 mg/kg/14 days) and agalsidase-β (1 mg/kg/14 days), which are administered intravenously [41,42,47,48].…”

“…According to systematic reviews and meta-analyses, ERT stabilizes and may slow disease progression, especially when started at an early age, with evidence of a dose effect and benefits on major outcomes, such as cerebrovascular, cardiac, and renal complications [42][43][44][48][49][50]. Specifically, a recent systematic literature review on 166 publications including 36 clinical trials examined the efficacy of ERT in adult men [42,48].…”

“…An updated Cochrane review of 9 randomized controlled trials (RCTs) of agalsidase-α or -β compared to other or no interventions, for a total of 351 participants, showed significant improvement with ERT in terms of microvascular endothelial deposits of GL-3 and pain-related quality of life, as well as positive effects on cardiac morphology and renal function, with a good safety profile and tolerability [43,49]. However, no specific information was provided in the included trials on correlations of GL-3 with clinical events or survival, but these data would be better provided by patient registries, since long-term, large studies are required for this purpose [43,49].…”

Gastrointestinal Involvement in Anderson-Fabry Disease: A Narrative Review

“…These small molecules stabilize misfolded proteins, improving enzymatic activity and reducing substrate accumulation. Although they can be given by oral administration, pharmacological chaperons can be used only for FD cases related to missense mutations [ 19 ].…”

Long-term safety and efficacy of agalsidase beta in Japanese patients with Fabry disease: aggregate data from two post-authorization safety studies

“…The number of therapies available for patients with lysosomal storage diseases has expanded considerably in the past several years [15,16]. Enzyme replacement therapy (ERT) represents the mainstay of treatment for Fabry Disease, with two different human recombinant α-GAL ERTs developed for Fabry disease.…”