B-Cell Depletion is Protective Against Anti-AAV Capsid Immune Response: A Human Subject Case Study

Area of Science:

• Immunology
• Gene Therapy
• Neuromuscular Disorders

Background:

• Repeat adeno-associated viral (AAV) vector administration is crucial for congenital myopathies due to dosing limitations, muscle growth, and myofiber loss.
• Immune responses against AAV capsids and transgene products impede gene transfer efficacy and preclude re-administration.
• Previous studies show anti-capsid and anti-transgene responses in preclinical models and human subjects.

Purpose of the Study:

• To investigate the efficacy of immune modulation using Rituximab and Sirolimus prior to AAV vector administration in a Pompe patient.
• To assess the impact of B-cell depletion on immune responses to AAV vectors and transgene products.
• To determine the feasibility of repeat AAV vector administration following immune suppression.

Main Methods:

• A single Pompe patient received Rituximab and Sirolimus to modulate immune responses.
• The patient was subsequently dosed with an adeno-associated viral type 1-guanidinium N-acetyltransferase (AAV1-GAA) vector.
• Humoral and cell-mediated immune responses against the AAV capsid and GAA transgene were monitored.

Main Results:

• B-cell ablation with rituximab prior to AAV vector exposure resulted in non-responsiveness to both the capsid and transgene.
• This immune non-responsiveness allowed for the potential of repeat AAV vector administration in the future.
• The combined immunosuppressive therapy effectively blocked immune responses to gene therapy.

Conclusions:

• Pre-treatment with rituximab to deplete B-cells is a clinically relevant approach to block immune responses to AAV vectors.
• This strategy establishes a potential method for enabling repeat AAV gene therapy administrations in patients with congenital myopathies.
• Immune modulation prior to gene therapy holds promise for improving long-term treatment efficacy.