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A Modular Polymer Enhancer Promotes AAV Transduction and Circumvents Preexisting Immunity in Nonhuman Primates
Lauren E Switala1,2,3,4, Afsana Mim Khandaker1,3,4,5, Sumita Dutta1,3,4
1Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA.
Human Gene Therapy
|July 30, 2026
Summary
Enhancer polymer (ePL) nanoparticles improve adeno-associated virus (AAV) gene therapy by enhancing AAV uptake and reducing neutralizing antibodies (nAbs). This novel approach shows promise for overcoming key challenges in AAV gene transfer for clinical applications.
Area of Science:
- Biotechnology
- Gene Therapy
- Nanomedicine
Background:
- Adeno-associated virus (AAV) gene therapy faces challenges including dose-limiting toxicities and pre-existing neutralizing antibodies (nAbs).
- Effective AAV gene transfer requires overcoming immune barriers and enhancing cellular uptake.
Purpose of the Study:
- To evaluate enhancer polymer (ePL), a novel nanoparticle, as a supporting agent to improve AAV gene therapy.
- To assess the biocompatibility, immunomodulatory effects, and AAV-enhancing capabilities of ePL.
Main Methods:
- Systemic administration of cargo-less poly(L-lactic-co-glycolic acid) nanoparticles (ePL) in nonhuman primates (NHPs).
- Proteomic analysis of human peripheral blood mononuclear cell-derived secretomes.
- Assessment of AAV uptake in human iPSC-derived cardiomyocytes.
- Mechanistic studies involving hepatic insulin receptor substrate 2 degradation and AKT inhibition in mouse hepatocytes.
- In vitro and in vivo evaluation of ePL's effect on neutralizing antibodies (nAbs) in NHPs and a mouse-NHP xenotransfusion model.
- Analysis of Immunoglobulin G (IgG) secretory capacity in splenic B cells.
Main Results:
- ePL demonstrated biocompatibility in NHPs and generated a protransduction serum secretome enhancing AAV uptake.
- Proteomic analysis revealed transient upregulation of AAV-entry factors (e.g., ITGB3) and downregulation of inflammatory pathways.
- ePL-stimulated macrophages induced transient degradation of hepatic insulin receptor substrate 2 and AKT inhibition.
- ePL attenuated NHP-derived nAbs in vitro and in vivo without depleting total immunoglobulins.
- ePL reduced IgG secretory capacity of splenic B cells, suggesting a mechanism for nAb attenuation.
Conclusions:
- ePL is a promising supporting agent for enhancing AAV gene transfer by improving cellular uptake and mitigating immune responses.
- ePL's ability to attenuate neutralizing antibodies (nAbs) and enhance AAV transduction warrants further optimization for clinical translation.
