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Targeting the Root Cause of Mucopolysaccharidosis IIIA with a New scAAV9 Gene Replacement Vector.

ABSTRACT: No treatment is available to address the unmet needs of mucopolysaccharidosis (MPS) IIIA patients. Targeting the root cause, we developed a new self-complementary adeno-associated virus 9 (scAAV9) vector to deliver the human N-sulfoglucosamine sulfohydrolase (hSGSH) gene driven by a miniature cytomegalovirus (mCMV) promoter. In pre-clinical studies, the vector was tested at varying doses by a single intravenous (i.v.) infusion into MPS IIIA mice at different ages. The vector treatments resulted in rapid and long-term expression of functional recombinant SGSH (rSGSH) enzyme and elimination of lysosomal storage pathology throughout the CNS and periphery in all tested animals. Importantly, MPS IIIA mice treated with the vector at up to 6 months of age showed significantly improved behavior performance in a hidden task in the Morris water maze, as well as extended lifespan, with most of the animals surviving within the normal range, indicating that the vector treatment can prevent and reverse MPS IIIA disease progression. Notably, 2.5 × 10¹² vector genomes (vg)/kg was functionally effective. Furthermore, the vector treatment did not lead to detectable systemic toxicity or adverse events in MPS IIIA mice. These data demonstrate the development of a safe and effective new gene therapy product for treating MPS IIIA, which further support the extended clinical relevance of platform recombinant AAV9 (rAAV9 gene delivery for treating broad neurogenetic diseases.

SUBMITTER: Bobo TA

PROVIDER: S-EPMC7704409 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Targeting the Root Cause of Mucopolysaccharidosis IIIA with a New scAAV9 Gene Replacement Vector.

Bobo Tierra A TA Samowitz Preston N PN Robinson Michael I MI Fu Haiyan H

Molecular therapy. Methods & clinical development 20201022

No treatment is available to address the unmet needs of mucopolysaccharidosis (MPS) IIIA patients. Targeting the root cause, we developed a new self-complementary adeno-associated virus 9 (scAAV9) vector to deliver the human <i>N</i>-sulfoglucosamine sulfohydrolase (hSGSH) gene driven by a miniature cytomegalovirus (mCMV) promoter. In pre-clinical studies, the vector was tested at varying doses by a single intravenous (i.v.) infusion into MPS IIIA mice at different ages. The vector treatments re ...[more]

PMID: 33313335

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Project description:Mucopolysaccharidosis (MPS) IIIA, also known as Sanfilippo syndrome type A, is a severe, progressive disease that affects the central nervous system (CNS). MPS IIIA is inherited in an autosomal recessive manner and is caused by a deficiency in the lysosomal enzyme sulfamidase, which is required for the degradation of heparan sulfate. The sulfamidase is produced by the N-sulphoglucosamine sulphohydrolase (SGSH) gene. In MPS IIIA patients, the excess of lysosomal storage of heparan sulfate often leads to mental retardation, hyperactive behavior, and connective tissue impairments, which occur due to various known missense mutations in the SGSH, leading to protein dysfunction. In this study, we focused on three mutations (R74C, S66W, and R245H) based on in silico pathogenic, conservation, and stability prediction tool studies. The three mutations were further subjected to molecular dynamic simulation (MDS) analysis using GROMACS simulation software to observe the structural changes they induced, and all the mutants exhibited maximum deviation patterns compared with the native protein. Conformational changes were observed in the mutants based on various geometrical parameters, such as conformational stability, fluctuation, and compactness, followed by hydrogen bonding, physicochemical properties, principal component analysis (PCA), and salt bridge analyses, which further validated the underlying cause of the protein instability. Additionally, secondary structure and surrounding amino acid analyses further confirmed the above results indicating the loss of protein function in the mutants compared with the native protein. The present results reveal the effects of three mutations on the enzymatic activity of sulfamidase, providing a molecular explanation for the cause of the disease. Thus, this study allows for a better understanding of the effect of SGSH mutations through the use of various computational approaches in terms of both structure and functions and provides a platform for the development of therapeutic drugs and potential disease treatments.

Dataset Information

Targeting the Root Cause of Mucopolysaccharidosis IIIA with a New scAAV9 Gene Replacement Vector.

Publications

Targeting the Root Cause of Mucopolysaccharidosis IIIA with a New scAAV9 Gene Replacement Vector.

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