Method to improve Adeno-Associated Virus (AAV) gene delivery by evading breakdown by the immune system

Unmet Need

Adeno-Associated Virus (AAV) vectors are a safe and effective way to deliver gene therapies to patients. However, one limitation of AAV-based therapies is caused by the patient’s immune system. About 30-60% of patients have pre-existing neutralizing antibodies specific to AAV, which target the vectors for degradation by the immune system before they can reach their target and deliver their gene therapy. This humoral immune response decreases the effectiveness of the treatment by preventing delivery of the therapeutic, and may cause an enhanced immunogenic response to the therapy. Therefore, there is a clinical need for methods that help AAV vectors avoid this humoral immune response, prolonging the amount of time they have to reach their target cells and deliver their gene therapy.

Technology

Duke inventors have developed a reagent that helps break down immunoglobulins or antibodies that target AAV, preventing neutralization of the vectors. Specifically, the reagent is an IdeZ polypeptide that targets IgG against the AAV capsid or virions. This reduces the humoral immune response to AAV during treatment, allowing the AAV to circulate for longer periods of time and improving efficiency of gene transfer. This reagent can reduce the interactions between immunoglobulins and their cognate receptors on cell surfaces or directly degrade antibodies that recognize and target the AAV vectors. The transient effect of this method means that it will not interfere with future immune responses to AAV-like antigens. Researchers have demonstrated the safety and effectiveness of this reagent through multiple experiments. Specifically, they have shown that the IdeZ polypeptide is effective at cleaving recombinant mouse IgG and serum IgG from multiple species, including mice, primates, and humans, and that in vivo the IdeZ polypeptide effectively targets and cleaves human Intravenous Immunoglobulin (IVIG) in mice.

Other Applications

This method is applicable to many clinical areas. Ongoing clinical research is developing AAV-based therapies across neuroscience, gastrointestinal, cardiovascular, ocular, muscular, hematological, and rare diseases applications.

Advantages

• Improves circulation time of AAV vectors, enhancing gene delivery efficiency
• Applicable across a wide variety of therapeutic areas
• Proven efficacy at cleaving serum immunoglobulins in multiple species, including humans
• Effective at targeting human immunoglobulin in vivo in mouse experiments