GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies

Abstract

GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay–Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood–brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g., intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.

Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord

“…GM2 gangliosidoses include the Tay-Sachs disease, the Sandhoff disease, and the GM2 AB, which result from LoF mutations in the genes HEXA, HEXB, and GM2A, respectively (Dastsooz et al, 2018). These variants of GM2 gangliosidoses are clinically indistinguishable, but are all associated with betahexosaminidase deficiency (Leal et al, 2020). All three variants are usually fatal by early childhood.…”

Update on Neuropathies in Inborn Errors of Metabolism

“…Patients with Sandhoff disease may also exhibit prominent dysautonomic features, including urine incontinence or constipation, especially those with adult-onset disease [52][53][54][55].…”

Human recombinant lysosomal β‐Hexosaminidases produced in Pichia pastoris efficiently reduced lipid accumulation in Tay‐Sachs fibroblasts

“…Since GM2 ganglioside buildup promotes the accumulation of others lipids such as phospholipids, cerebrosides, sphingomyelin, and cholesterol (Leal, Benincore-Florez, et al, 2020), the staining of these lipids could be used as an assay for drug development. In this sense, it was reported that Nile Red staining offers a valid method for evaluating drug efficacy and compound screening in TSD patient neural stem cells (Vu et al, 2018).…”

“…Currently, the treatment of GM2 gangliosidoses is mainly focused on palliative interventions, and in the delay of disease progression in the late-onset form. However, several therapy approaches for TSD or SD are under development including enzyme replacement therapy (ERT), bone marrow or neural progenitor cell transplantation, gene therapy, and substrate reduction therapy (Leal, Benincore-Florez, et al, 2020;Solovyeva et al, 2018). Nowadays, ERT is available for 11 LSDs treatment including Gaucher, Fabry, Pompe, neuronal ceroid lipofuscinoses type II, α-mannosidosis, acid lipase deficiency, and mucopolysaccharidoses type I, II, IVA, VI, and VII .…”

“…In the case of GM2 gangliosidoses ERT, some of the recombinant enzymes have been modified to improve the cellular uptake and lysosome delivery (Leal, Benincore-Florez, et al, 2020). For instance, the use of a highly mannosylated recombinant Hex-A produced in the yeast Ogataea minuta, and treated with α-mannosidase to expose the mannose-6-phosphate (M6P) residues on the N-glycans, resulted in a GM2 storage reduction and an improvement in the motor function and lifespan in a SD mouse model (Akeboshi et al, 2007;Tsuji et al, 2011).…”