Intrathecal or intravenous AAV9-IDUA/RGX-111 at minimal effective dose prevents cardiac, skeletal and neurologic manifestations of murine MPS I

Mucopolysaccharidosis type I (MPS I) is a rare metabolic disorder caused by deficiency of α-L-iduronidase (IDUA), resulting in glycosaminoglycan (GAG) accumulation and multisystemic disease. Current treatments include hematopoietic stem cell transplantation and enzyme replacement therapy, but these do not address all manifestations of the disease. We infused MPS I mice with an adeno-associated virus 9 (AAV9)-IDUA vector (RGX-111) at doses from 10⁷ to 10¹⁰ vector genomes (vg) via intrathecal (IT), intravenous (IV), and intrathecal+intravenous (IT+IV) routes of administration. In mice administered doses ≤10⁹ vg IT or ≤10⁸ vg IV, there was no therapeutic benefit, while in mice administered 10⁹ vg IV, there was a variable increase in IDUA activity with inconclusive neurocognitive and cardiac assessments. However, at the 10¹⁰ vg dose, we observed substantial metabolic correction, with restored IDUA levels and normalized tissue GAGs for all treatment groups. Aortic insufficiency was mostly normalized, neurologic deficit was prevented, and microcomputed tomography (micro-CT) analysis showed normalization of skeletal parameters. Histologic analysis showed minimal GAG storage and lysosomal pathology. We thus report a minimal effective dose of 10¹⁰ vg (5 × 10¹¹ per kg) RGX-111 for IV and IT routes of administration in MPS I mice, which prevented neurocognitive deficit, cardiac insufficiency, and skeletal manifestations, as a model for genetic therapy of human MPS I.