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

Autor:	Belur LR; Center for Genome Engineering, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA., Huber AK; Center for Genome Engineering, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA., Mantone H; Center for Genome Engineering, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA., Robertson M; Center for Genome Engineering, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA., Smith MC; Center for Genome Engineering, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA., Karlen AD; Center for Genome Engineering, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA., Kitto KF; Department of Pharmaceutics, University of Minnesota, Minneapolis MN, USA., Ou L; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA., Whitley CB; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA., Braunlin E; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA., Furcich J; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA., Lund TC; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA., Seelig D; Comparative Pathology Shared Resource, University of Minnesota, Minneapolis, MN, USA., Fairbanks CA; Department of Pharmaceutics, University of Minnesota, Minneapolis MN, USA., Buss N; REGENXBIO, Inc., Rockville, MD, USA., Kim KH; REGENXBIO, Inc., Rockville, MD, USA., McIvor RS; Center for Genome Engineering, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2024 Nov 04; Vol. 32 (4), pp. 101369. Date of Electronic Publication: 2024 Nov 04 (Print Publication: 2024).
DOI:	10.1016/j.omtm.2024.101369
Abstrakt:	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 10 7 to 10 10 vector genomes (vg) via intrathecal (IT), intravenous (IV), and intrathecal+intravenous (IT+IV) routes of administration. In mice administered doses ≤10 9 vg IT or ≤10 8 vg IV, there was no therapeutic benefit, while in mice administered 10 9 vg IV, there was a variable increase in IDUA activity with inconclusive neurocognitive and cardiac assessments. However, at the 10 10 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 10 10 vg (5 × 10 11 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. Competing Interests: The work detailed in this manuscript was sponsored by REGENXBIO, Inc. K.H.K. and N.B. are current or former employees of REGENXBIO, Inc. L.R.B., T.C.L., C.A.F., N.B., and R.S.M. are co-inventors on patents related to the contents of this manuscript. R.S.M. is also an employee of Immusoft Corp. (© 2024 The Authors.)
Databáze:	MEDLINE
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