SBIR-STTR Award

Corneal blindness is a leading cause of global blindness, with allogeneic corneal transplantation (CT) being the most common form of tissue transplantation worldwide. Though approximately 180, 000 CT surgeries are carried out each year, around 12.7 million are currently awaiting a donor cornea to undergo the operation. Still, CT surgery is accompanied by a high failure rate: as many as 20–30% of corneal grafts are rejected within the first 5 years in the general population, and in high-risk cases, which represent over 20% of the population, almost all grafts are rejected within 3 years. CT failure puts a strain on the already-limited supply of donor corneas, for which there is approximately only one cornea available for every 70 needed. Whether by lack of access or unsuccessful intervention, the vast majority of cases of corneal blindness go untreated, leaving patients with limited mobility, an increased risk of falls, emotional distress, and an increase in mortality. Current approaches to mitigate corneal graft rejection involve topical and systemic corticosteroids and immunosuppressive agents, but these methods are all burdened with acute disadvantages; corticosteroids have been known to induce vision loss, and immunosuppressive agents, besides incurring serious potential side effects, also come at a high price. To address the critical need for methods to reduce graft failure and improve the long-term success of allogeneic human CT, Bedrock Therapeutics proposes to use adeno-associated virus (AAV)-mediated transduction to deliver HLA-G isoforms to donor corneal grafts to ultimately modulate the immunologic response of a human recipient and prevent rejection following CT. This Phase I proposal focuses on the ex vivo optimization of identified variables that affect AAV vector transduction of corneal explants. Treatment efficacy and feasibility will be targeted through the pursuit of two specific aims: 1) optimization of AAV-HLA- Gcombo ex vivo transduction variables (i.e., vector production, dose, and incubation time), and 2) evaluation of AAV-HLA-Gcombo ex vivo transduction efficacy in a high-risk rabbit allogenic CT model. Bedrock Therapeutics' previous studies have demonstrated the feasibility of using AAV8G9 to transduce HLA-G isoforms into donor corneas and the resulting successful prevention of graft rejection in animal models of allogeneic CT. Transduction of HLA-G into rabbit corneas prior to transplantation resulted in complete prevention of allogeneic graft rejection over an 80-day period vs. rejection at 10 days in control corneas. Successful application of this method will provide a platform for obtaining immune-tolerant corneas, addressing the high rate of corneal graft rejection and ameliorating current tissue shortage problems. Completion of the proposed work will pave the way for additional preclinical and clinical studies with an eventual goal of applying our platform to human CT in order to improve the quality of life of the thousands of patients that experience corneal rejection each year.

Public Health Relevance Statement:
Narrative Though corneal blindness is a leading cause of blindness worldwide, the high rejection rate of corneal grafts after corneal transplantation (CT) surgery leaves patients to suffer persistent vision loss and the accompanying symptoms of limited mobility, emotional distress, and heightened risk of falls and mortality. Bedrock Therapeutics proposes to develop an immunomodulatory treatment to prevent corneal graft rejection by delivering HLA-G isomers to the cornea using an engineered adeno-associated virus vector. Successful development of this therapy will boost the success rate of CT surgery, upholding patients' quality of life and ensuring that the limited supply of donor corneas are put towards positive patient outcomes.

Project Terms:
Accounting; Acute; Address; adeno-associated viral vector; Adrenal Cortex Hormones; Affect; Allogenic; Animal Model; Antigens; base; Blindness; Capsid; Clinical Research; Combined Modality Therapy; Cornea; Corneal Diseases; Cytotoxic T-Lymphocytes; Dependovirus; Disadvantaged; DNA cassette; Dose; economic impact; emotional distress; Engineering; Engraftment; Ensure; Evaluation; experience; experimental study; Failure; fall risk; General Population; Goals; graft failure; Graft Rejection; Graft Tolerance; Health Care Costs; high risk; HLA G antigen; Human; Immune; Immune response; Immune Tolerance; immunomodulatory therapies; immunoregulation; Immunosuppressive Agents; improved; Intervention; Isomerism; Keratoplasty; Mediating; Methods; Modeling; mortality; operation; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; outcome forecast; Patient-Focused Outcomes; Patients; Phase; Population; preclinical study; Preparation; prevent; Prevention; Price; Production; Productivity; Protein Isoforms; Proteins; Quality of life; RNA Splicing; side effect; success; Symptoms; Testing; Therapeutic; therapy development; Time; Tissue Transplantation; Tissues; transplant model; Transplantation; Transplantation Surgery; Treatment Efficacy; Up-Regulation; Vascularization; vector; Work

Description Corneal blindness is one of the leading causes of vision loss worldwide, with 10 million individuals having bilateral corneal blindness globally. Allogeneic corneal transplantation (CT) to treat genetic and acquired corneal blindness is the most common form of tissue transplantation worldwide, annually accounting for >50,000 surgeries in the United States and ~180,000 globally. In high-risk CT, which accounts for >20% of the 180,000 transplants performed worldwide annually, all grafts are rejected within 10 years of CT, despite the current standard of care, topical and systemic immunosuppressive agents which have dose-limiting adverse side-effects including vision loss. Bedrock Therapeutics' goal is the clinical translation of our single dose ex vivo adeno-associated virus (AAV) gene therapy approach of the corneal donor tissue to shield it from the host's immune response. Phase I STTR Milestones were successfully achieved; a novel lead candidate (BDRK-401) that demonstrates immunosuppression and anti-vascularization functions was selected and a protocol for efficient corneal graft gene transfer was optimized towards feasibility of application in a hospital setting. Furthermore, corneal grafts treated with AAV-BDRK-401 prior to high-risk CT were completely protected from acute immunological rejection in a rabbit model. The objective of this Phase II proposal is to advance the clinical development of BDRK-401 for prevention of CT rejection in humans by receiving FDA guidance, large scale AAV-BDRK-401 manufacturing, and by performing a long-term safety and efficacy study. Successful completion of these goals will generate a BDRK-401 data portfolio sufficient for IND application submission and, optimistically, attract significant investment for GMP AAV-BDRK-401 production and the execution of a Phase I/II clinical trial. While Bedrock's initial focus is on preventing high-risk corneal transplant rejection, our novel immunomodulatory technology is a single drug also applicable to other ocular and non-ocular diseases including the prevention of rejection in any solid organ transplantation, wet age-related macular degeneration, and type 1 diabetes.

Public Health Relevance Statement:
Narrative Corneal transplantation rejection in high-risk patients occurs at an alarming rate of 70% within 10 years of the surgery. Bedrock Therapeutics has developed a single dose gene therapy specifically for the corneal donor tissue that prevents high-risk acute rejection in an animal model. The work proposed here in seeks to de-risk this approach for applications in human that require corneal transplantation. Successful application of this approach in the corneas may also prevent rejection of other transplanted organs including heart, liver, lung, and kidney. Terms: