Structure-Function Relationships at a Cellular Level in Choroideremia using Adaptive Optics Scanning Light Ophthalmoscopy

Awardee: Jessica I. W. Morgan

Institution: University of Pennsylvania

Grant Amount: $61,273.00

Funding Period: February 1, 2025 - January 31, 2026

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Summary:

Choroideremia (CHM) is an X-linked retinal degeneration affecting approximately 1 in 50,000 worldwide. Patients with CHM experience progressive degeneration of photoreceptors, retinal pigment epithelium (RPE) and choroid resulting in night blindness, loss of visual fields, and ultimately loss of central acuity. On retinal images, diffuse atrophy of the choriocapillaris and RPE can often be observed in peripheral areas, which gradually enlarges towards the central retina as the disease progresses. Subtle changes in retinal structure and function within the centrally retained retinal island often remain undetected using standard clinical evaluations. In addition, there is no clinical method to assess the structure or function of individual photoreceptors though gene therapy approaches attempt to restore function to individual cells that remain structurally preserved. The need for more sensitive biomarkers of photoreceptor structure and function is clear. The overall goal of this project is to understand photoreceptor structure and function at the cellular scale within the centrally remaining photoreceptor mosaic in CHM. To do this, our lab utilizes adaptive optics scanning light ophthalmoscopy (AOSLO) which allows non-invasive, single-cell level visualization of the human retina. We have further equipped our AOSLO with tools for measuring photoreceptor function including (1) optoretinography (ORG) and (2) AO-microperimetry. ORG measures an optical signal that arises from the photoreceptors when presented with visual stimuli, while AO-microperimetry enables measurements of visual thresholds for small stimuli, including for single cones. None of these measurements is achievable using conventional clinical devices. Using the AOSLO, we have previously observed patches of hyper- and hypo-reflective cones within the centrally preserved retina as a common CHM retinal feature. This project aims to study the relationship between this structural phenotype and functional measurements made through ORG and AO-microperimetry. The outcome of this project will help us understand the correlation of retinal function with local variations in structure throughout the photoreceptor mosaic, which will ultimately be helpful for monitoring disease progression and assessing treatment efficacy. Our long-term goal is to provide the field with novel, sensitive and non-invasive biomarkers for assessing individual cone function in CHM to aid in disease assessment and treatment design.

To Study the potential for Collagen Mimetic Peptides to reduce progressive damage to the Bruch's-RPE-Photoreceptor Complex in Choroideremia.

Awardee: Malia Edwards

Institution: Johns Hopkins University

Grant Amount: $64,735.00

Funding Period: February 1, 2024 - January 31, 2025

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Summary:

Collagen is the most common protein in the human. It is found in all organs in either its structural form or as a major component of the extracellular matrix. The source of newly formed collagen arising during tissue growth and remodeling is the nearby cells, often mesenchymal but also epithelial. A healthy body undergoes collagen remodeling on a constant basis, but aging or gene deficiencies can cause the ability to produce replacement collagen to decrease. In certain disease states collagen-producing cells are often involved and may become damaged as well, leading to a reduction in collagen replacement which slows the tissue healing process. A therapeutic with the ability to repair damaged collagen can facilitate recovery and halt progressive damage to critical tissues and organs, like the eye, when it is subjected to such diseases. CMPs are vastly different from denatured collagen supplements, which are highly advertised nutraceutical products and which do not have the direct collagen repairative activities associated with CMPs. CMPs have been shown to be efficacious and safe in humans when applied topically as eyedrops and systemically in animals under FDA regulated toxicity studies.

Targeting Metabolic Homeostasis in Dysfunctional CHM Retinal Pigment Epithelia

Awardee: Kathleen Boesze-Battaglia

Institution: University of Pennsylvania

Grant Amount: $61,760.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

Loss of vision due to choroideremia (CHM), a progressive retinal degenerative disease affects 1 in 50,000 males. Advanced imaging modalities have recently documented sub-clinical changes in the retinal pigment epithelia (RPE) of CHM patients. While metabolomic studies demonstrate dysfunctional metabolism in CHM patients characterized by a disruption of lipid homeostasis. Collectively, these observations implicate RPE-mediated metabolic dysregulation resulting from loss of Rab Escort Protein-1 (REP1) as an etiological factor in CHM. The Boesze-Battaglia lab has extensive experience with lipid homeostasis in models of human retinal degenerations. To explore the potential of metabolic pathways as therapeutic targets for CHM, we have analyzed induced pluripotent stem cell (iPSC)-derived retinal cell from CHM patients. Treatment strategies for CHM are limited albeit clinical trials for gene augmentation strategies are underway. The efficiency of such treatments may not be truly appreciated or fully assessed for nearly a decade due to the slow progressive nature of the disease. Therefore, there remains an unmet need to explore other options to preserve the health and integrity of the retina prior to noticeable degeneration of the eye. Our goal is to define metabolic imbalance in CHM RPE in an effort to restore metabolic homeostasis and RPE function using CHM-patient specific cell models.

Ace-tRNA readthrough therapy for choroideremia caused by nonsense mutations

Awardee: David M. Gamm

Institution: University of Wisconsin-Madison

Grant Amount: $64,360

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

Choroideremia is a devastating eye disease that leads to progressive loss of vision in 1 in 50,000 males. Currently, there are no approved treatments available for individuals affected by choroideremia. While several research laboratories are working on identifying effective therapies, such work is challenged by the lack of appropriate disease models that would allow clear assessment of the efficacy of a potential therapy. To overcome this impediment, the Gamm lab has developed induced pluripotent stem cell (iPSC)-derived retinal cell and organoid models, which provide a powerful platform for therapeutic testing. As in many other inherited disorders, choroideremia is commonly caused by “nonsense” mutations that prevent formation of full-length functional proteins. The Ahern lab has designed a specialized molecule that allows read-through of many types of these mutations, resulting in full-length protein production. Our goal is to test these read-through molecules in iPSC-derived retinal pigmented epithelial cells and photoreceptors affected by choroideremia in order to advance a new type of therapy for a significant portion of choroideremia patients.

Pharmacological induction of autophagy to treat CHM

Awardee: Ivan Conte

Institution: University of Naples Federico II

Award Amount: $64,990

Funding Period: February 1, 2021 - January 31, 2022

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Final Report Lay Summary:

The main goal of this project was to characterize at fine scale the contribution of molecular network regulating the autophagy pathway in the Retinal Pigment Epithelial ce ls. We demonstrated that impairment of ce l clearance in the RPE may affect visual system in the Choroideremia. Interestingly, we put the basis for developing a new therapeutic strategy to treat CHM, which stil represents a cha lenge, Remarkably, the therapy described herein was safe and wel tolerated showing no adverse effects associated with pharmacological treatment up to 3 months of treatment, the longest time for which the drug was tested on CHM mice. Lately, in vitro studies using hiPSC-derived RPE ce l sheet give us the opportunity to move forward with regulatory studies prerequisite to clinical trials for choroideremia patients.

Adaptive Optics imaging in follow-ups of choroideremia patients after gene therapy

Awardee: Katarina Stingl

Insitutional: University Eye Hospital Tübingen, Germany

Awarded Amount: $61,079

Targeting phagosome maturation to restore dysfunctional retinal pigmented epithelium in CHM

Awardee: Kathleen Boesze-Battaglia

Institution: University of Pennsylvania

Award Amount: $101,740

Funding Period: February 1, 2019 - January 31, 2020