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Mucopolysaccharidosis type IIIB: a current review and exploration of the AAV therapy landscape
Courtney J Rouse1, Victoria N Jensen1, Coy D Heldermon2
1Lacerta Therapeutics, Alachua, FL, USA.
Abstract:
Mucopolysaccharidoses type IIIB is a rare genetic disorder caused by mutations in the gene that encodes for N-acetyl-alpha-glucosaminidase. This results in the aggregation of heparan sulfate polysaccharides within cell lysosomes that leads to progressive and severe debilitating neurological dysfunction. Current treatment options are expensive, limited, and presently there are no approved cures for mucopolysaccharidoses type IIIB. Adeno-associated virus gene therapy has significantly advanced the field forward, allowing researchers to successfully design, enhance, and improve potential cures. Our group recently published an effective treatment using a codon-optimized triple mutant adeno-associated virus 8 vector that restores N-acetyl-alpha-glucosaminidase levels, auditory function, and lifespan in the murine model for mucopolysaccharidoses type IIIB to that seen in healthy mice. Here, we review the current state of the field in relation to the capsid landscape, adeno-associated virus gene therapy and its successes and challenges in the clinic, and how novel adeno-associated virus capsid designs have evolved research in the mucopolysaccharidoses type IIIB field.
Insights
Gene therapy using adeno-associated virus 8 effectively treats mucopolysaccharidoses type IIIB in mice. This approach restores enzyme levels, improves hearing, and extends lifespan, offering hope for a cure.
Area of Science:
- Genetics
- Neurology
- Biotechnology
Background:
- Mucopolysaccharidoses type IIIB (MPS IIIB) is a rare genetic disorder causing severe neurological dysfunction due to N-acetyl-alpha-glucosaminidase deficiency.
- Heparan sulfate accumulation in lysosomes leads to progressive debilitating symptoms, with limited and costly treatment options currently available.
- Adeno-associated virus (AAV) gene therapy presents a promising avenue for developing effective treatments for MPS IIIB.
Purpose of the Study:
- To review the advancements in AAV gene therapy for MPS IIIB.
- To discuss the role of AAV capsid design in improving therapeutic efficacy.
- To highlight the potential of AAV gene therapy as a curative approach for MPS IIIB.
Main Methods:
- Review of current literature on AAV gene therapy for MPS IIIB.
- Analysis of AAV capsid landscape and its evolution.
- Examination of preclinical and clinical successes and challenges of AAV gene therapy.
Main Results:
- A codon-optimized triple mutant AAV8 vector effectively restored N-acetyl-alpha-glucosaminidase levels in a murine model of MPS IIIB.
- The AAV8 gene therapy improved auditory function and extended lifespan in MPS IIIB mice.
- Novel AAV capsid designs have shown potential in enhancing gene therapy efficacy for MPS IIIB.
Conclusions:
- AAV gene therapy, particularly with optimized vectors like AAV8, demonstrates significant therapeutic potential for MPS IIIB.
- Continued research into AAV capsid engineering is crucial for overcoming challenges and advancing clinical applications.
- This gene therapy approach offers a promising path towards a potential cure for MPS IIIB, addressing a significant unmet medical need.
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