AAV serotype IVDs for patient selection in gene therapy development: Technical and regulatory considerations by ARDAT consortium
11 affiliations
- 1Bayer AG, Pharmaceuticals R&D, 13353 Berlin, Germany
- 2Astellas Pharma Europe B.V., 2333 BE Leiden, the Netherlands
- 3Sangamo Therapeutics, Inc., Richmond, CA 94804, USA
- 4GenoSafe, 91002 Evry, France
- 5Asphalion S.L., 08014 Barcelona, Spain
- 6Bristol Myers Squibb, Princeton, NJ 08543, USA
- 7Astellas Pharma Global Development, Northbrook, IL 60062, USA
- 8Novartis, 4056 Basel, Switzerland
- 9Celerion (GB) Ltd., BT9 6AD Belfast, UK
- 10University of Sheffield, S102TN Sheffield, UK
- 11Asphalion SL, 08014 Barcelona, Spain
Abstract
Currently, most clinical trials for adeno-associated virus (AAV)-based gene therapy (GT) exclude patients with pre-existing anti-AAV antibodies (AAV Abs) due to potential impact on treatment efficacy and safety. Diagnostic regulations require sponsors to define pre-existing AAV Ab level cutoffs and validate patient selection assays before beginning clinical studies. In the absence of robust clinical outcome data early in development, sponsors often rely on thresholds derived from literature or preclinical studies, or default to assay detection limits. The transferability of these thresholds to actual clinical outcomes remains uncertain, leading sponsors to use conservative cutoffs to avoid costly revalidations and development delays. This may prevent some patients from accessing potentially beneficial treatments. We advocate for more flexible validation approaches based on current understanding of antibody characteristics and the commonly used assay formats. We propose an AAV serotype-specific in vitro diagnostic (IVD) assay, an “AAV serotype IVD,” with pragmatic analytical validations for single AAV serotypes. This approach would allow sponsors to establish clinically meaningful cutoffs through adaptive clinical trials that progressively include patients with escalating pre-existing AAV Ab levels by implementing multiple cutoffs during clinical development. These measures could expedite AAV GT development while expanding access for patients with elevated pre-existing AAV Ab levels.
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BibTeX
@article{braun2026serotype,
title = {{AAV serotype IVDs for patient selection in gene therapy development: Technical and regulatory considerations by ARDAT consortium}},
author = {Manuela Braun and Christel Ravesteijn-Verrijt and Philipp Schatz and Yanmei Lu and Sarra Seninet and Jon Giblin and John Millholland and Gurunadh Chichili and Fraser McBlane and Johannes Stanta and Mimoun Azzouz and Christopher Mann},
journal = {Molecular Therapy Advances},
year = {2026},
month = oct,
doi = {10.1016/j.omta.2026.201862},
url = {https://doi.org/10.1016/j.omta.2026.201862},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - AAV serotype IVDs for patient selection in gene therapy development: Technical and regulatory considerations by ARDAT consortium
AU - Manuela Braun
AU - Christel Ravesteijn-Verrijt
AU - Philipp Schatz
AU - Yanmei Lu
AU - Sarra Seninet
AU - Jon Giblin
AU - John Millholland
AU - Gurunadh Chichili
AU - Fraser McBlane
AU - Johannes Stanta
AU - Mimoun Azzouz
AU - Christopher Mann
PY - 2026
DA - 2026/10/08
JO - Molecular Therapy Advances
DO - 10.1016/j.omta.2026.201862
UR - https://doi.org/10.1016/j.omta.2026.201862
AB - Currently, most clinical trials for adeno-associated virus (AAV)-based gene therapy (GT) exclude patients with pre-existing anti-AAV antibodies (AAV Abs) due to potential impact on treatment efficacy and safety. Diagnostic regulations require sponsors to define pre-existing AAV Ab level cutoffs and validate patient selection assays before beginning clinical studies. In the absence of robust clinical outcome data early in development, sponsors often rely on thresholds derived from literature or preclinical studies, or default to assay detection limits. The transferability of these thresholds to actual clinical outcomes remains uncertain, leading sponsors to use conservative cutoffs to avoid costly revalidations and development delays. This may prevent some patients from accessing potentially beneficial treatments. We advocate for more flexible validation approaches based on current understanding of antibody characteristics and the commonly used assay formats. We propose an AAV serotype-specific in vitro diagnostic (IVD) assay, an “AAV serotype IVD,” with pragmatic analytical validations for single AAV serotypes. This approach would allow sponsors to establish clinically meaningful cutoffs through adaptive clinical trials that progressively include patients with escalating pre-existing AAV Ab levels by implementing multiple cutoffs during clinical development. These measures could expedite AAV GT development while expanding access for patients with elevated pre-existing AAV Ab levels.
SN - 3117-387X
ER -