Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by ZFN-Mediated In Vivo Genome Editing

Area of Science:

• Genetics
• Biochemistry
• Molecular Biology

Background:

• Mucopolysaccharidosis type II (MPS II) is a severe X-linked genetic disorder caused by iduronate 2-sulfatase (IDS) deficiency.
• Accumulation of glycosaminoglycans (GAGs) leads to progressive multi-systemic damage and reduced lifespan.
• Current enzyme replacement therapy (ERT) has limitations, including the need for lifelong infusions and lack of neurological benefit.

Purpose of the Study:

• To evaluate the efficacy of zinc finger nuclease (ZFN)-mediated genome editing for MPS II treatment.
• To assess the therapeutic potential of inserting the human IDS (hIDS) gene into a safe harbor locus in hepatocytes.
• To investigate the impact of this gene therapy on GAG accumulation and neurocognitive function in an MPS II mouse model.

Main Methods:

• Systemic administration of recombinant AAV2/8 vectors encoding ZFNs and a hIDS cDNA donor into MPS II mice.
• Targeted insertion of the hIDS coding sequence into intron 1 of the albumin locus in hepatocytes.
• Measurement of IDS enzyme levels, GAG content in tissues, and neurocognitive function in treated mice.

Main Results:

• Supraphysiological and dose-dependent IDS enzyme levels were detected in circulation and peripheral organs.
• Significant reduction in GAG content was observed across all treated groups.
• ZFN-mediated genome editing prevented the development of neurocognitive deficits in young MPS II mice treated at high vector doses.

Conclusions:

• ZFN-based genome editing targeting the albumin locus is a viable strategy for treating MPS II.
• This platform demonstrates potential for sustained therapeutic protein expression and correction of disease phenotypes, including neurological aspects.
• The approach holds promise for treating MPS II and other lysosomal storage disorders.