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Tolerability and Potency of Sequential and Repeated AAV Corneal Gene Therapy

序贯和重复 AAV 角膜基因治疗的耐受性和效力

基本信息

批准号：
10481334
负责人：
Matthew Louis Hirsch
金额：
$ 36.76万
依托单位：
RAINBIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10481334
关键词：
Address Adverse effects Anatomy Animal Model Anterior Antibodies Antibody Response Bilateral Birth Blindness Canis familiaris Capsid Cells Child Clinic Clinical Clinical Protocols Collagen Fibril Complementary DNA Containment Contralateral Cornea Corneal Diseases Corneal Opacity Corneal Stroma DNA DNA cassette Data Dependovirus Disease Dose Dwarfism Engineering Enzymes Extracellular Matrix Eye Failure Family Foundations Gene Delivery Genes Genome Glycosaminoglycans Graft Rejection Grant Hepatosplenomegaly Human Immune response Incidence Inflammatory Response Injections Intention Investigation Investigational Therapies Keratoplasty L-Iduronidase Life Lysosomal Storage Diseases Mental Retardation Modeling Monitor Mucopolysaccharidosis I Mutation Nature Neuropathy Operative Surgical Procedures Organ Oryctolagus cuniculus Patients Penetrating Keratoplasty Pharmaceutical Preparations Phase Phase I Clinical Trials Physiology Positioning Attribute Prevention Procedures Production Proteoglycan Protocols documentation Quality of life Rare Diseases Reporting Retina Safety Severities Symptoms Technology Therapeutic Therapeutic Effect Transgenes Transplantation United States Validation Viral Vector Vision Work adeno-associated viral vector canine model cell stroma clinical application clinically relevant design effective therapy efficacy validation experience experimental study gene therapy high risk human subject improved meetings ocular surface patient population phase 3 study phase I trial pre-clinical prevent safety study sight restoration standard of care success sugar therapeutic gene therapeutically effective transgene expression vector genome

项目摘要

Abstract Mucopolysaccharidosis I (MPS I) is an autosomal recessive monogenetic disorder caused by mutations in the gene encoding alpha-L-iduronidase (IDUA), a ubiquitous enzyme that breaks down large sugar molecules called glycosaminoglycans (GAGs). In the absence of IDUA, intra- and extra-cellular GAG accumulation results in enlarged cells/organs resulting in a multifactorial and potentially lethal disease depending upon the nature of the mutation and the correlative severity [1, 2]. MPS I afflicts approximately 3,000-8,000 patients worldwide, and symptoms include clouding of the cornea occurring in 70% of MPS I patients which is the leading cause of blindness. Currently, no therapeutics exist to address MPS I corneal clouding and penetrating keratoplasty is not a current standard of care due to transplant rejection (>70%) in this high-risk patient population. To address this blinding disorder, over the past 5 years we have optimized adeno-associated virus (AAV) gene delivery to the cornea, including the engineering and validation of RainBIO-1 (RBIO-1), an optimized IDUA cDNA genetic cassette amenable to AAV gene therapy. In several reports, RBIO-1 has demonstrated the ability to restore IDUA activity to MPS I patient cells, elevate IDUA activity in WT human corneas >10-fold, and most remarkably, prevent and reverse MPS I corneal opacity in a canine model following a single corneal intrastromal injection. Rigorous safety studies of RBIO-1 in WT rabbit corneas (n=20), demonstrate complete tolerability, even at doses 10-fold higher than the lowest effective dose, and strict vector genome containment to the injected cornea and retina was observed. These optimistic safety and efficacy data have positioned RBIO-1 as the likely first-in-class AAV therapeutic for any anterior ocular disease. Regarding a clinical protocol for RBIO-1, administration to a single cornea, initially, is most prudent to evaluate safety and efficacy in MPS I patients. If RBIO-1 alleviates MPS I corneal storage disease similar to results obtained from MPS I canines, sequential administration to the contralateral cornea would be desired for bilateral vision. This clinically relevant question of sequential AAV gene delivery to the cornea will be answered by the execution of the experiments proposed in Aim 1 using a rabbit model. Although, we have reported strong IDUA production and therapeutic success out nearly 1 year in MPS I canines (n=10) and 6 months in rabbits, the durability of AAV transgene expression in the cornea remains unknown, and perhaps redosing of RBIO-1 to a single cornea may be required for long-term sustained efficacy. The experiments in Aim 2 will determine the extent of AAV vector transduction following re-administration to a previously dosed rabbit cornea. The work herein will employ RBIO-1 to determine the feasibility of sequential AAV vector injections and repeat administration in the cornea and thereby provide critical data for Phase I protocol design to treat MPS I corneal clouding. More broadly, the relevance of the critical data obtained herein extends beyond MPS I to all corneal, and perhaps ocular surface, disorders which also may benefit from an AAV gene therapy approach.

摘要