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Roland W Herzog

Publications and source records attributed to Roland W Herzog.

2 recordsLinked to original sources
PubMed2026

Mechanisms of and mitigating strategies for cellular immune responses to CRISPR-associated nucleases in genome editing therapy.

Immunogenicity of CRISPR-associated nucleases (Cas) is a critical barrier to the development of safe and effective genome editing therapies. These proteins inherently pose a risk of immune recognition due to their prokaryotic origins. A multitude of factors, such as the delivery vehicle, the route of administration, components of the therapeutics, tissue microenvironment, and pre-existing immunity, also contribute to the complexity of the host immune response to Cas proteins. As CRISPR-based therapies advance into clinical settings, it is imperative to elucidate and address the immunogenicity of Cas proteins. Here, using Cas9 as an example, we review the current understanding of Cas protein immunogenicity, the challenges it poses for therapeutic application, and strategies to mitigate cellular immune responses to Cas proteins.

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PubMed2025

Enhancing AAV9-UFμDys1 Gene Therapy Efficacy Through Immunosuppression in Mice with Pre-Existing Immunity and Enabling Redosing Strategies for Duchenne Muscular Dystrophy.

Significant progress has been made in gene therapy for Duchenne muscular dystrophy (DMD), a severe genetic disorder primarily affecting pediatric patients. However, the immune responses triggered by high-dose systemic delivery of adeno-associated virus (AAV) vectors remain a major challenge. These responses include the generation of long-lasting anti-capsid antibodies and potential immunity against the therapeutic transgene, rendering gene therapy ineffective. In addition, pre-existing anti-AAV antibodies exclude patients from eligibility for treatment. To address these limitations, we have developed an immunosuppression (IMS) strategy aimed at mitigating immune responses to the AAV capsid while enhancing microdystrophin expression. Using an optimized expression cassette (AAV9-UFµDys1) for sustained microdystrophin expression in striated muscle and heart, we observed a 40% improvement in muscle force compared with animals receiving a GFP-encoding control AAV9 vector. In mdx mice, a single-dose IMS regimen significantly increased microdystrophin expression in cardiac and skeletal tissues and repeat dosing further enhanced expression, an effect not observed in non-IMS-treated mdx mice. To model pre-existing immunity, we immune-challenged wild-type mice with empty AAV9 capsids and tracked antibody responses over time. The IMS regimen effectively reduced total anti-AAV antibody levels and increased microdystrophin expression in UFµDys1-treated mice. These findings highlight the potential of IMS to minimize immune barriers, facilitate repeat AAV administration, and expand the therapeutic window for DMD gene therapy. Our results support the further development of AAV-mediated approaches using either microdystrophin-expressing vectors or next-generation systems delivering full-length or near-full-length dystrophin.

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