Immunosuppression decreases inflammation and increases AAV6-hSERCA2a-mediated SERCA2a expression

Area of Science:

• Cardiology
• Gene Therapy
• Molecular Biology

Background:

• Decreased SERCA2a expression is a hallmark of heart failure (HF), impacting cardiac contraction.
• Restoring SERCA2a levels in HF models has shown promise for improving cardiac function.

Purpose of the Study:

• To evaluate the safety and efficacy of direct cardiac delivery of adeno-associated virus encoding human SERCA2a (AAV6-hSERCA2a) in canine models of HF.
• To investigate the impact of immunosuppression on transgene expression and immune responses to AAV6-hSERCA2a.

Main Methods:

• Canine models with induced heart failure underwent left ventricle (LV) wall injection of AAV6-hSERCA2a.
• Cardiac function, hSERCA2a expression, and immune responses (neutralizing antibodies, cellular infiltration) were analyzed at 2 and 6 weeks post-injection.
• A separate cohort received immunosuppression to assess its effect on immune response and transgene persistence.

Main Results:

• AAV6-hSERCA2a delivery led to transient cardiac expression of hSERCA2a, peaking at 2 weeks and declining by 6 weeks.
• LV dimensions improved in dogs treated with AAV6-hSERCA2a at 6 weeks compared to controls.
• Host immune responses, including neutralizing antibodies and cardiac inflammation, were observed, reducing hSERCA2a levels.
• Immunosuppression significantly reduced immune responses and sustained hSERCA2a expression.

Conclusions:

• Direct cardiac delivery of AAV6-hSERCA2a can enhance local SERCA2a expression and improve cardiac function in HF models.
• Host immune responses limit the duration of transgene expression.
• Immunosuppression is a critical factor for achieving sustained transgene expression and may be essential for clinical translation of this gene therapy approach.