AAV-mediated gene therapy for sialidosis

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• Sialidosis (mucolipidosis I) is a rare genetic disorder caused by NEU1 enzyme deficiency, leading to toxic accumulation of sialylated molecules.
• Clinical manifestations include systemic and neurological symptoms, with no current treatment options available.
• Neu1 knockout mice model severe sialidosis, exhibiting widespread cellular pathology and organ dysfunction.

Purpose of the Study:

• To evaluate the therapeutic efficacy of adeno-associated virus (AAV)-mediated gene therapy for sialidosis.
• To investigate the potential of delivering NEU1 and its chaperone PPCA via AAV vectors in a mouse model.

Main Methods:

• Neu1 knockout mice received co-injections of scAAV2/8 vectors encoding human NEU1 and PPCA.
• Phenotypic, biochemical, and cellular analyses were performed on treated mice and compared to wild-type controls.

Main Results:

• AAV gene therapy restored NEU1 activity in multiple organs, including the brain, heart, and muscles.
• Treated mice showed normalization of lysosomal storage, reduced sialyl-oligosacchariduria, and diminished neuroinflammation.
• Restored NEU1 function led to a reversal of disease phenotypes, with treated mice being phenotypically indistinguishable from wild-type controls.

Conclusions:

• AAV-mediated gene therapy is a viable and effective treatment strategy for sialidosis.
• This approach holds potential for treating other lysosomal storage diseases associated with NEU1 deficiency.