Substrate reduction therapy in juvenile GM2 gangliosidosis

Highly phosphomannosylated enzyme replacement therapy for GM2 gangliosidosis

“…In these experiments, the restoration of enzyme activities and reduction of substrates accumulated in the brains of disease model animals were demonstrated, although the effectiveness varied among diseases. On the other hand, experimental and clinical approaches, including bone marrow transplantation, 34 substrate deprivation therapy, 35,36 normal gene transfer, 37 and stem cell therapy, 38 have been developed to treat…”

Protease-resistant modified human β-hexosaminidase B ameliorates symptoms in GM2 gangliosidosis model

“…The underlying mechanism of the neuropathogenesis is still unclear, although it has been reported that lysosomal accumulation of their substrates, including glycosphingolipids, oligosaccharides, and glycosaminoglycans, leading to inflammatory responses (microglial activation and astrogliosis) and neuronal injury are the hallmarks during the course of these disorders (1,2). There are currently no effective treatments for GM2 gangliosidoses, although several therapeutic approaches have been developed, including gene therapy (GT) (2,3), enzyme replacement therapy (ERT) (4,5), substrate reduction therapy (SRT) (6,7), and pharmacological chaperone therapy (PCT) (8). An SD model mouse was generated by targeted disruption of the Hexb gene allele (9,10) and was utilized for investigating the neuropathogenic mechanism and evaluating the therapeutic approaches as an authentic infantile GM2 gangliosidosis model, which develops the pathological features -including spasticity, muscle weakness, rigidity, tremor, and ataxia -that closely resemble those observed in the acute form of human disorders.…”

Small Molecules

“…Moreover, treatment with the same drug prevented accumulation of GM-2 in the brain of the TSD model. 29,30 Unfortunately, these results were not confirmed in a trial performed in 5 teenagers with GM-2 gangliosidosis observed over 2 years, failing to prevent neurological deterioration, 31 nor it did with patients with TSD, 32 in spite of previously reported positive data of an isolated study performed with patients with SD. 33 Treatment with miglustat also failed to show any improvement or stabilization in patients with Sanfilippo syndrome, either in terms of clinical condition or of ganglioside concentration in the brain.…”