Central Nervous System-Targeted Gene Therapy for the Treatment of Neurocognitive Deficits in Mucopolysaccharidosis...

Area of Science:

• Genetics
• Neurology
• Biochemistry

Background:

• Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder caused by pathogenic variants in the *IDS* gene.
• Current treatments like enzyme replacement therapy and hematopoietic stem cell transplantation (HSCT) have limited blood-brain barrier penetration, impacting neurological treatment efficacy.

Purpose of the Study:

• To evaluate the effectiveness of central nervous system (CNS)-directed adeno-associated virus (AAV)2/9-mediated human *IDS* gene transfer in an MPS II mouse model.
• To assess sustained IDS expression and behavioral improvements following gene therapy.

Main Methods:

• Generation of an MPS II mouse model using CRISPR/Cas9.
• Intracerebroventricular (ICV) and intravenous (IV) administration of AAV2/9 carrying the human *IDS* gene.
• Measurement of IDS activity in the CNS and assessment of auditory function.

Main Results:

• Intracerebroventricular administration of AAV2/9-hIDS resulted in higher IDS activity in the CNS compared to intravenous administration.
• Improved auditory function was observed in the ICV-treated group.
• The study demonstrated sustained IDS expression and improved behavioral performance in the MPS II mouse model.

Conclusions:

• CNS-directed AAV2/9-mediated *IDS* gene transfer is a promising therapeutic strategy for MPS II.
• This approach offers a potential treatment for neurological deficits and cognitive impairment associated with MPS II.
• The findings provide a strong proof of concept for clinical translation in MPS II patients.