Clinical Development for Gaucher Disease Types 1 and 3: Gene Therapy

A Novel Approach to Gaucher Disease

The investigational gene therapy program (AVR-RD-02) for Gaucher disease type 1 sought to offer a curative approach by addressing the root genetic cause, not just managing symptoms. Unlike standard enzyme replacement therapy (ERT), this approach involved:

• Autologous Hematopoietic Stem Cell (HSC) Modification: Using the patient’s own stem cells, reducing the risk of rejection.
• Lentiviral Vector Technology: Delivering a functional copy of the GBA1 gene, which is defective in Gaucher patients.
• Enduring Enzyme Expression: The modified stem cells were designed to produce the needed enzyme (GCase) over the patient’s lifetime, potentially offering a long-term solution.

Overcoming Challenges in Design and Development

Leading the clinical development and regulatory strategy for this program required navigating significant challenges:

• Regulatory Hurdles: The use of lentiviral vectors and the autologous HSC approach presented complex safety and efficacy questions for regulators. Crafting a robust regulatory strategy involved:
  • Extensive dialogue with regulatory bodies.
  • Designing trials to generate the specific data needed to demonstrate the therapy’s safety and efficacy.
  • Ensuring compliance with evolving gene therapy guidelines.
• Clinical Trial Design: As the program leader, I designed and oversaw the Phase 1/2 GUAR13 trial, focusing on:
  • Establishing appropriate endpoints for a novel therapy, such as changes in liver/spleen volume and Gaucher biomarkers.
  • Managing the logistics of a complex, multi-site trial involving cell collection, modification, and re-infusion.
• Translational Development: Translating promising preclinical data into a viable clinical program was a major challenge. My role involved:
  • Bridging the gap between lab research and clinical practice.
  • Developing and validating assays to monitor GCase expression and biomarker levels in treated patients.

Expertise in AAV Gene Therapy

While the Gaucher program utilized a lentiviral vector, my broad expertise extends to AAV (adeno-associated virus) gene therapy, which could also be instrumental for Gaucher disease or other genetic disorders. My experience allows me to:

• Assess Feasibility: Evaluate whether AAV or other vectors are the most appropriate approach for different patient populations or disease types.
• Develop Strategies: Design effective and efficient clinical and regulatory strategies for AAV-based programs, considering specific manufacturing, dosing, and safety considerations.
• Address Key Considerations: Anticipate and address the critical regulatory, clinical, and logistical issues unique to AAV gene therapy, such as potential immunogenicity and dose optimization.

Disclaimer: The AVR-RD-02 program was terminated by AVROBIO for strategic reasons in 2023. This webpage details my role in the early development of that program and highlights broader expertise in gene therapy