Effective gene therapy of Stargardt disease with PEG-ECO/pGRK1-ABCA4-S/MAR nanoparticles

Da Sun; Wenyu Sun; Song-Qi Gao; Jonathan Lehrer; Amirreza Naderi; Cheng Wei; Sangjoon Lee; Andrew L. Schilb; Josef Scheidt; Ryan C. Hall; Elias I. Traboulsi; Krzysztof Palczewski; Zheng-Rong Lu

Molecular Therapy: Nucleic Acids (Sep 2022)

Effective gene therapy of Stargardt disease with PEG-ECO/pGRK1-ABCA4-S/MAR nanoparticles

Da Sun,
Wenyu Sun,
Song-Qi Gao,
Jonathan Lehrer,
Amirreza Naderi,
Cheng Wei,
Sangjoon Lee,
Andrew L. Schilb,
Josef Scheidt,
Ryan C. Hall,
Elias I. Traboulsi,
Krzysztof Palczewski,
Zheng-Rong Lu

Affiliations

Da Sun: Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
Wenyu Sun: Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
Song-Qi Gao: Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
Jonathan Lehrer: Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
Amirreza Naderi: Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
Cheng Wei: Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
Sangjoon Lee: Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
Andrew L. Schilb: Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
Josef Scheidt: Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
Ryan C. Hall: Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
Elias I. Traboulsi: Department of Pediatric Ophthalmology and Center for Genetic Eye Diseases, Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44106, USA
Krzysztof Palczewski: Gavin Herbert Eye Institute, Department of Ophthalmology, Departments of Physiology and Biophysics, Chemistry, and Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA 92697, USA
Zheng-Rong Lu: Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Corresponding author Zheng-Rong Lu, PhD, Department of Biomedical Engineering, Case Western Reserve University, Wickenden 427, Mail Stop 7207, 10900 Euclid Avenue, Cleveland, OH 44106, USA.

Journal volume & issue: Vol. 29
pp. 823 – 835

Abstract

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Stargardt disease (STGD) is the most common form of inherited retinal genetic disorders and is often caused by mutations in ABCA4. Gene therapy has the promise to effectively treat monogenic retinal disorders. However, clinically approved adeno-associated virus (AAV) vectors do not have a loading capacity for large genes, such as ABCA4. Self-assembly nanoparticles composed of (1-aminoethyl)iminobis[N-(oleoylcysteinyl-1-amino-ethyl)propionamide (ECO; a multifunctional pH-sensitive/ionizable amino lipid) and plasmid DNA produce gene transfection comparable with or better than the AAV2 capsid. Stable PEG-ECO/pGRK1-ABCA4-S/MAR nanoparticles produce specific and prolonged expression of ABCA4 in the photoreceptors of Abca4−/− mice and significantly inhibit accumulation of toxic A2E in the eye. Multiple subretinal injections enhance gene expression and therapeutic efficacy with an approximately 69% reduction in A2E accumulation in Abca4−/− mice after 3 doses. Very mild inflammation was observed after multiple injections of the nanoparticles. PEG-ECO/pGRK1-ABCA4-S/MAR nanoparticles are a promising non-viral mediated gene therapy modality for STGD type 1 (STGD1).

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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