Treatment of Skeletal and Non-skeletal Alterations of Mucopolysaccharidosis Type IVA by AAV-mediated Gene Therapy

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Sep 10

PMID 34504088

Citations 13

Authors

Joan Bertolin

Victor Sanchez

Albert Ribera

Maria Luisa Jaen

Miquel Garcia

Anna Pujol

Xavier Sanchez

Sergio Munoz

Sara Marco

Jennifer Perez

Gemma Elias

Xavier Leon

Carles Roca

Veronica Jimenez

Pedro Otaegui

Francisca Mulero

Marc Navarro

Jesus Ruberte

Fatima Bosch

Affiliations

Soon will be listed here.

Abstract

Mucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation. Patients develop severe skeletal dysplasia, early cartilage deterioration and life-threatening heart and tracheal complications. There is no cure and enzyme replacement therapy cannot correct skeletal abnormalities. Here, using CRISPR/Cas9 technology, we generate the first MPSIVA rat model recapitulating all skeletal and non-skeletal alterations experienced by patients. Treatment of MPSIVA rats with adeno-associated viral vector serotype 9 encoding Galns (AAV9-Galns) results in widespread transduction of bones, cartilage and peripheral tissues. This led to long-term (1 year) increase of GALNS activity and whole-body correction of KS levels, thus preventing body size reduction and severe alterations of bones, teeth, joints, trachea and heart. This study demonstrates the potential of AAV9-Galns gene therapy to correct the disabling MPSIVA pathology, providing strong rationale for future clinical translation to MPSIVA patients.

Citing Articles

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

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Adeno-Associated Virus Gene Transfer Ameliorates Progression of Skeletal Lesions in Mucopolysaccharidosis IVA Mice.

Herreno-Pachon A, Sawamoto K, Stapleton M, Khan S, Piechnik M, Alvarez J Hum Gene Ther. 2024; 35(23-24):955-968.

PMID: 39450470 PMC: 11659441. DOI: 10.1089/hum.2024.096.

CRISPR/Cas9 technology in the modeling of and treatment of mucopolysaccharidosis.

Reyhani-Ardabili M, Ghafouri-Fard S Biochem Biophys Rep. 2024; 39:101771.

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Consensus-based expert recommendations on the management of MPS IVa and VI in Saudi Arabia.

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