Retinal-adhesive thermoresponsive gel for AAV-mediated gene delivery to the outer retina

用于将 AAV 介导的基因传递至外视网膜的视网膜粘附热敏凝胶

基本信息

项目摘要

Project summary Until recently, there have been no effective treatments for retinal degenerations. FDA approval of Luxturna, the first gene therapy for bi-allelic mutations in RPE65, has opened the field for application to a broader range of retinal diseases. The rapidly growing number of clinical trials and emerging companies reflect the impact of this success and indicate the high expectations for retinal gene therapy. However, there is a significant need to develop new approaches for the many remaining forms of retinal degenerations, as RPE65-related dystrophies affect a very small population of patients. Moreover, the combination of the vector and surgical approach used for this disease is suboptimal for targeting the fovea in retinas with significant structural alterations. The major obstacles that must be addressed to improve clinical outcomes and extend the application of gene therapies to numerous retinopathies at various disease stages are: 1) efficient vector delivery to the central retina without damaging remaining photoreceptors, a significant, documented concern with sub-retinal injections in conditions where the retina is structurally compromised, 2) efficiently targeting gene delivery to affected cells, especially photoreceptors and RPE across the retina and 3) limiting the inflammatory/immune responses associated with intravitreal injections. These issues are relevant to all current and future retinal gene therapy programs. Here, we address each of these obstacles through development of an innovative new epiretinal gene therapy approach for NPHP5-LCA and RPE65-LCA2, in which a novel, biocompatible, retinal adhesive gel developed by our team releases high efficiency AAVs directly to the retina. We have created a comprehensive and efficient development plan that allows for rapid translation, drawing on the complementary skill sets of a team of experts with a track record of successful translational development. We will further develop the tunable, biocompatible gel and injection system to deliver these vectors directly to the retina, and we will incorporate a backing layer into the implant that allows for directionality of vector release for increased efficiency. We will determine the most efficient implant-compatible photoreceptor and RPE-targeting AAV vectors by utilizing our recently developed single cell RNA-Seq paradigm. We will fully validate this new gene therapy platform in two well-studied naturally occurring canine models of LCA that affect primarily the photoreceptors (NPHP5-LCA) and RPE (RPE65-LCA2), and we will characterize immune response and toxicity. The innovative approach developed herein will result in a new platform for direct, non-invasive and efficient AAV delivery to the retina, reducing diffusion and required dosage as well as the related immune response. This novel gene delivery platform has direct applicability to all outer retinal disease targets, paving the way forward for a safer, more efficient and targeted approach to treat a wide spectrum of disorders.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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William A. Beltran其他文献

Canine Best disease as a translational model
犬类最佳疾病作为转化模型
  • DOI:
    10.1038/s41433-024-03578-0
  • 发表时间:
    2025-01-07
  • 期刊:
  • 影响因子:
    3.200
  • 作者:
    Gustavo D. Aguirre;William A. Beltran
  • 通讯作者:
    William A. Beltran
A case of orbital hemangiopericytoma in a dog.
犬眼眶血管外皮细胞瘤一例。
  • DOI:
    10.1111/j.1463-5224.2001.00194.x
  • 发表时间:
    2001
  • 期刊:
  • 影响因子:
    1.6
  • 作者:
    William A. Beltran;M.;Lilia Boulouha;Arnaud Daude;Pierre Moissonnier;Bernard Clerc
  • 通讯作者:
    Bernard Clerc
Metabolic stress and early cell death in photoreceptor precursor cells following retinal transplantation
  • DOI:
    10.1186/s13287-025-04509-w
  • 发表时间:
    2025-07-25
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    Raghavi Sudharsan;Natalia Dolgova;Jennifer Kwok;Alexa Gray;Yu Sato;Agustin Luz Madrigal;Praveen Joseph Susaimanickam;Emil Kriukov;Petr Baranov;John H. Wolfe;Gustavo D. Aguirre;David M. Gamm;William A. Beltran
  • 通讯作者:
    William A. Beltran

William A. Beltran的其他文献

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{{ truncateString('William A. Beltran', 18)}}的其他基金

Retinal-adhesive thermoresponsive gel for AAV-mediated gene delivery to the outer retina
用于将 AAV 介导的基因传递至外视网膜的视网膜粘附热敏凝胶
  • 批准号:
    10453146
  • 财政年份:
    2022
  • 资助金额:
    $ 71.98万
  • 项目类别:
Retinal disease models for translational photoreceptor replacement
用于平移感光器替代的视网膜疾病模型
  • 批准号:
    10477226
  • 财政年份:
    2018
  • 资助金额:
    $ 71.98万
  • 项目类别:
Retinal disease models for translational photoreceptor replacement
用于平移感光器替代的视网膜疾病模型
  • 批准号:
    10006534
  • 财政年份:
    2018
  • 资助金额:
    $ 71.98万
  • 项目类别:
Equipment Supplement on NEI U24 EY-029890
NEI U24 EY-029890 设备补充
  • 批准号:
    10453170
  • 财政年份:
    2018
  • 资助金额:
    $ 71.98万
  • 项目类别:
Retinal disease models for translational photoreceptor replacement
用于平移感光器替代的视网膜疾病模型
  • 批准号:
    10063767
  • 财政年份:
    2018
  • 资助金额:
    $ 71.98万
  • 项目类别:
Retinal disease models for translational photoreceptor replacement
用于平移感光器替代的视网膜疾病模型
  • 批准号:
    10238820
  • 财政年份:
    2018
  • 资助金额:
    $ 71.98万
  • 项目类别:
Translational Gene Therapy for Rhodopsin Autosomal Dominant Retinitis Pigmentosa
视紫红质常染色体显性遗传性色素性视网膜炎的转化基因治疗
  • 批准号:
    8634788
  • 财政年份:
    2012
  • 资助金额:
    $ 71.98万
  • 项目类别:
Large animal therapy studies
大型动物治疗研究
  • 批准号:
    8384956
  • 财政年份:
    2012
  • 资助金额:
    $ 71.98万
  • 项目类别:
Translational Gene Therapy for Rhodopsin Autosomal Dominant Retinitis Pigmentosa
视紫红质常染色体显性遗传性色素性视网膜炎的转化基因治疗
  • 批准号:
    8420488
  • 财政年份:
    2012
  • 资助金额:
    $ 71.98万
  • 项目类别:
Translational Gene Therapy for Rhodopsin Autosomal Dominant Retinitis Pigmentosa
视紫红质常染色体显性遗传性色素性视网膜炎的转化基因治疗
  • 批准号:
    8213979
  • 财政年份:
    2012
  • 资助金额:
    $ 71.98万
  • 项目类别:

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I-Corps:肽整体作为新型生物粘合剂的转化潜力
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