Macular Degeneration and Retinal Dystrophies

Over the past 10 years, the Ali lab has focused on developing gene therapy-based treatments for ocular disorders. His group has demonstrated proof-of-concept for a wide range of diseases, by effectively rescuing 10 animal models of retinal dystrophy, and demonstrating proof-of-concept for gene therapy of ocular angiogenesis and uveitis. In the process, he has also advanced the development of new viral vector systems, and optimized their efficiency and production process. These extensive pre-clinical studies have resulted in the establishment of a pipeline of therapies that are now being tested in clinical trials for safety and efficacy. Dr. Ali established the world’s first clinical trial of gene therapy for retinal dystrophy in 2007, and continues to initiate clinical trials to test gene therapy for numerous retinal dystrophies, including LCA caused by mutations in the RPE65 gene, achromatopsia caused by mutations in the CNGB3 gene, and retinitis pigmentosa caused by mutations in the RPGR gene.

Dr. Ali has established active collaborations with numerous researchers at the Kellogg Eye Center to investigate the possibility of using gene therapy to treat additional retinal diseases. He is collaborating with Dr. Debra Thompson on a gene therapy-based treatment for LCA associated with mutations in the RDH12 gene, and is also collaborating with  Drs. Thomas Gardner, David Antonetti, Steven Abcouwer, Patrice Fort to investigate gene therapy-based strategies for treating diabetic retinopathy. 

Identification of therapeutic targets to prevent cell death in photoreceptor neurons: 

Our ultimate goal in the Besirli Laboratory is to improve vision in patients with retinal disorders by translating our discoveries on retinal cell degeneration into novel therapies. We study the molecular mechanisms of energy metabolism and how this interacts with apoptotic and survival pathways during periods of retinal stress. We are actively working on identifying molecular regulators of cell death in photoreceptors. Many pediatric and adult ocular disorders, including retinal dystrophies, macular degeneration, and diabetic retinopathy, lead to irreversible vision loss secondary to photoreceptor degeneration.  Understanding the fundamental pathways essential for photoreceptor survival and death is critical for us to identify molecular targets for therapeutic intervention.  Our research led to the identification a small peptide inhibitor of Fas death receptor mediated photoreceptor apoptosis.  This small peptide is currently under development to become the first neuroprotective agent in the eye.  We also showed that autophagy is used by photoreceptors to prevent apoptosis after stress.  We recently described a novel neuroprotective agent, Faim 2, that is important for prolonging the survival of photoreceptors.  Targeting the activation of survival proteins like Faim2 after retinal injury may lead to better vision in patients.

Grant Support

• 5K08EY023982-03
  Besirli (PI)
  02/01/2014-01/31/2019
  Neuroprotection in pediatric retinal detachment
  The goal of this project is to develop neuroprotective agents to enhance photoreceptor survival and prevent vision loss in pediatric retinal disorders.
  Role: PI
• Research to Prevent Blindness
  Besirli (PI)
  02/01/2014-01/31/2018
  Stress-induced neuroprotection in the retina
  The goal of this project is to identify the key retinal proteins interacting with the Fas receptor complex death signaling, which will be critical targets for the development of neuroprotective agents.
  Role: PI

Patient-Centered Outcomes in Severe Peripheral Field Loss 

Vision rehabilitation may improve patients’ quality-of-life functional abilities through the use of assistive devices and educational strategies. However, the effectiveness of rehabilitation options for patients with peripheral vision loss is poorly known since most prior research has focused on patients with central vision loss. In order to evaluate and compare the effectiveness of low vision rehabilitation strategies for patients with peripheral vision loss, a valid and reliable method for measuring vision-dependent functioning is needed. The proposed research will use the insights of patients with glaucoma and retinal dystrophy, their caregivers and their vision care providers to develop a patient-reported outcome measure that assesses functioning in patients with severe peripheral vision loss. Our ultimate goal is to use this outcome measure in future work to determine the effectiveness of low vision services, rehabilitation strategies and models of care delivery. 

Grant Support

NIH/NEI 1K23EY027848
Role: PI
09/01/2017 – 08/31/2022
Addressing Low Vision due to Severe Peripheral Field Loss: Development and Validation of a Patient-Centered Outcome Measure

Head-Mounted Display Technology in Low Vision 

Few interventions exist to improve the vision-dependent functioning of patients with severe peripheral vision loss. For this reason, our team is exploring the potential benefits of head-mounted display technology for this low vision population. We are examining the effect of this technology on a host of clinical, gait, mobility and quality-of-life outcomes. We are also working to optimize this technology so that it will best meet the needs of our patients. 

GRANT SUPPORT

Michigan Institute for Clinical and health Research
Role: PI
12/1/2016-11/30/2017
Optical Head-Mounted Display Technology for Low Vision Rehabilitation

The goal of the Hughes laboratory is to understand how ion channels in the RPE operate in transport processes to maintain the appropriate extracellular environment required for photoreceptor health and integrity. The importance of ion transport is underscored by the fact that mutations in genes encoding ion channels expressed in the RPE cause inherited retinal degenerations. We are studying the biophysical properties of ion channels in isolated RPE cells to understand their normal function and complement this with immunohistochemical and molecular approaches to determine their membrane location and identify the genes that encode them. Our research has led to the discovery of a previously unrecognized ion channel that is highly permeable to thiocyanate, an anion that is present in most extracellular fluids and that can be beneficial or damaging, depending on the biological context. Our work indicates that this ion channel is part of a novel transport system that removes thiocyanate from the outer retina, where it might have toxic effects. Identification and characterization of this ion channel and other components of the transport pathway may lead to insight into their importance in retinal health and disease.

Grant support

R01 EY008850-23
Hughes (PI)
“Ion Conductances in the Retinal Pigment Epithelium”
The overall goal of this research is to understand how ion channels in the retinal pigment epithelium (RPE) function in salt and water transport so as to maintain the health and integrity of photoreceptors. The goals of this project are focused on identifying anion channels and transporters that transport thiocyanate and chloride across the RPE.  

We build primary human cell culture models of dry age-related macular degeneration (ARMD), utilizing this platform to screen for therapeutic leads for the disease. The post-mitotic retinal pigment epithelium (RPE) phagocytizes the shed lipid-rich outer segments of photoreceptors every day for a lifetime. As the RPE ages, intracellular lipid-predominant lipofuscin accumulates along with extracellular lipid-predominant drusen, and both of these waste products are abundant in dry ARMD. Lipofuscin deposition is a direct consequence of suboptimal phagocytic handling of outer segments by the RPE. The link between drusen and outer segment phagocytosis is less direct, but it is clear that the RPE's ability to carry out lipid metabolism directly affects both lipofuscin and drusen accumulation. We study the fate of lipid-rich outer segments in the RPE, how these outer segments affect the RPE's lipid metabolism, and how alterations in lipid metabolism may predispose the RPE to dry ARMD-like changes. Concurrently, we are manipulating lipid metabolic and cell degradative pathways, including lipid synthesis, beta-oxidation, ketogenesis, and autophagy, to determine which pathways may protect the RPE against lipofuscin and drusen buildup, or the toxic effects of these waste products.

Wet age-related macular degeneration (AMD) is the leading cause of irreversible blindness in adults in the developed world. By 2020, an estimated 196 million people will suffer from AMD worldwide. The US population with AMD will double by 2050. Even with the profound impact of anti-vascular endothelial growth factor (VEGF) therapy on wet AMD, choroidal neovascularization (CNV) remains the leading cause of blindness due to AMD. Early stage wet age-related macular degeneration (AMD) is characterized by molecular changes, which are precursors to choroidal neovascularization (CNV), bleeding, and permanent scarring.  Currently available diagnosis and treatment of macular degeneration is based on imaging anatomic changes in the retina, including bleeding and edema. Anatomic abnormalities are the end-product of complex molecular processes. A critical barrier to progress in dealing with the problem of AMD is that there are currently no methods for early detection of choroidal neovascularization, and earlier detection of wet macular degeneration improves visual outcomes. The Paulus Advanced Eye Imaging and Laser Laboratory focuses on developing novel imaging techniques, such as photoacoustic microscopy, for imaging of the eye. We also work on molecular imaging methods to probe the cellular and molecular changes taking place in real-time to better characterize and understand the molecular changes, particularly on the process of neovascularization and the role of avb3 and other integrins.

Grant Support

• 4K12EY022299
  National Institutes of Health, National Eye Institute
  PI: Thomas Gardner
  05/01/2016 – 04/30/2018
  Real-time In Vivo Visualization of the Molecular Processes in Choroidal Neovascularization
  Role: Scholar

• Fight for Sight – International Retinal Research Foundation FFSGIA16002
  PI: Yannis M. Paulus
  07/01/2016 – 12/31/2017
  Realtime In Vivo Visualization of the Molecular Processes in Retinal and Choroidal Neovascularization
  Role: PI

Dr. Debra Thompson studies the molecular basis of inherited forms of retinal degeneration, a constellation of diseases resulting in the death of the rod and cone photoreceptors, the light-sensing cells of the retina.  The long-term goal of her studies is to contribute to the development targeted therapies for these diseases.

Inherited retinal degeneration is caused by mutations in the genes necessary for critical aspects of the physiology of the rods and cones, as well as the retinal pigment epithelium (RPE) that supports their function.  Leber congenital amaurosis (LCA) is a particularly severe form of inherited retinal degeneration resulting in blindness in the first or second decade of life.  Dr. Thompson’s studies led to the identification of three LCA genes – RPE65, LRAT, and RDH12 – that impact vitamin A metabolism necessary for the synthesis and recycling 11-cis retinal that is used a chromophore by the rods and cones to absorb light.  Current efforts focus on defining the factors that regulate the efficiency of the vitamin A cycle, as well as the links between defects in this pathway and the resulting death of the rod and cones.  Another aspect of her research focuses on the phagocytic activity of the retinal pigment epithelium that is essential for the mechanism of photoreceptor cell renewal needed to maintain rod and cone function.  Current studies involve characterization of the signaling mechanism downstream of the phagocytosis receptor MERTK whose gene is mutated in some cases of retinitis pigmentosa.

Dr. Thompson is involved internationally in collaborative studies of small molecule and gene-therapy approaches for treating inherited retinal degeneration.  The ultimate goal of the work is to identify strategies for improving outcomes in individuals with retinal degeneration that can rescue both early- and late-onset forms of these blinding diseases. 

Alternative fuel sources for photoreceptor biomass, function, and survival

Photoreceptor cell death is the ultimate cause of vision loss in many retinal disorders, and there is an unmet need for neuroprotective therapies to improve their survival. To this end, mutations in enzymes important to energy and purine metabolism have been linked to retinal degenerations. Considering photoreceptors have little reserve capacity to generate energy and as a result, are adversely affected by small changes in energy homeostasis, disruption of nutrient availability and metabolic regulation has been postulated to be a unifying mechanism in PR cell death. Hence, an improved understanding of the metabolic pathways that support photoreceptor function and survival is expected to provide a framework for developing novel neuroprotective agents for many retinal diseases.

Glucose has been central to the study of photoreceptor metabolism as these cells utilize the phenomenon of aerobic glycolysis, or the conversion of glucose to lactate despite the presence of oxygen, for energy production and anabolic building blocks, similar to cancer cells. Yet, it has been recently shown that fuel sources other than glucose may be utilized to meet the metabolic needs of photoreceptors. Photoreceptors have prodigious energy and biosynthetic requirements to maintain phototransduction and neurotransmission, normal cellular functions, and biosynthetic processes in the outer segments, which are constantly undergoing turnover. The literature shows that 80-90% of the glucose delivered to the outer retina is converted to lactate, instead of pyruvate, via aerobic glycolysis. As a result of this limited pyruvate availability, PRs need to utilize alternative substrates to supply tricarboxylic acid (TCA) cycle metabolites, maintain mitochondrial function, and support energy production and biomass, similar to cancer cells. This project investigates the flexibility of photoreceptors to use substrates other than glucose, to maintain photoreceptor cell biomass, regulate redox balance, and boost survival during periods of metabolic stress through the use of state-of-the-art metabolomics methodologies and novel transgenic mouse models. A fundamental understanding of photoreceptor metabolism and its interconnection with photoreceptor cell survival during periods of stress could be transformative for preventing vision loss and photoreceptor degeneration.