June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Suprachoroidally delivered DNA nanoparticles produce human Myosin7A protein in RPE-choroid in rabbits
Author Affiliations & Notes
  • Viral Kansara
    Clearside Biomedical Inc, Alpharetta, Georgia, United States
  • Mark J Cooper
    Copernicus Therapeutics Inc., Ohio, United States
  • Leroy Muya
    Clearside Biomedical Inc, Alpharetta, Georgia, United States
  • Robert Moen
    Copernicus Therapeutics Inc., Ohio, United States
  • Thomas A Ciulla
    Clearside Biomedical Inc, Alpharetta, Georgia, United States
  • Footnotes
    Commercial Relationships   Viral Kansara, Clearside Biomedical (E); Mark Cooper, Copernicus Therapeutics (E); Leroy Muya, Clearside Biomedical (E); Robert Moen, Copernicus Therapeutics (E); Thomas Ciulla, Clearside Biomedical (E)
  • Footnotes
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Investigative Ophthalmology & Visual Science June 2021, Vol.62, 1200. doi:
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    • Get Citation

      Viral Kansara, Mark J Cooper, Leroy Muya, Robert Moen, Thomas A Ciulla; Suprachoroidally delivered DNA nanoparticles produce human Myosin7A protein in RPE-choroid in rabbits. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1200.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : Adeno-associated viral vectors (AAV) cannot accommodate large genes such as Myosin7A, limiting investigational gene therapy for Usher syndrome. A prior preclinical study demonstrated that non-viral DNA nanoparticles (DNPs), which can accommodate large genes, yield similar marker gene activity when administered suprachoroidally or subretinally, suggesting the potential for office-based gene therapy. This study evaluated ocular tolerability and transfectability of DNPs encoding human Myosin7A (hMyo7A) after either suprachoroidal (SC) or intravitreal (IVT) injection in rabbits.

Methods : The DNPs consisted of a single copy of plasmid DNA encoding hMyo7A. Dutch-Belted pigmented rabbits (N=4 per group) received a single SC (0.1 mL) or IVT injection (0.05 mL) of DNPs (either 4 or 8 mg/mL of DNA). Ocular tolerability, with or without prophylactic steroids, was assessed via slit lamp, indirect ophthalmoscopy, intraocular pressure (IOP), optical coherent tomography (OCT), electroretinography (ERG) and fundus photography (FP) for up to 3 months. Protein and RNA levels were measured in ocular tissues via ELISA and qRT-PCR, respectively at 3 months.

Results : OCT imaging confirmed reversible opening of the suprachoroidal space after SC injection of DNPs. The SC injection of DNPs was much better tolerated than IVT injection of DNPs. During the 3- month study, IVT injected DNPs resulted in signs of severe ocular inflammation as assessed by slit lamp, indirect ophthalmoscopy, OCT, FP, and ERG testing. Prophylactic steroid treatment showed no clinically meaningful improvement in ocular inflammation after IVT injections. The hMyo7A protein was detected in the RPE-choroid (68-105 ng/gm) at 3 months after SC or IVT injection with no statistically significant difference between the routes of administration. The hMyo7A protein levels were detected in sporadic retina samples. The RT-PCR data indicate that DNPs produce mRNA levels in the RPE-choroid that is in the range of 45%-160% of the endogenous rabbit Myo7A.

Conclusions : Suprachoroidally administered DNPs produced hMyo7 protein in RPE-choroid in rabbits. Given the potential for repeatable office-based large gene therapy, further studies are warranted to improve transfection of photoreceptor cells, and to evaluate efficacy and safety in higher species

This is a 2021 ARVO Annual Meeting abstract.


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