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.

抽象的粘二糖I（MPS I）是一种由突变引起的常染色体隐性单基因遗传疾病编码α-l-二维醛酸酶（IDUA）的基因，一种无处不在的酶，可分解大糖分子称为糖胺聚糖（插科打）。在没有IDUA的情况下，细胞内和细胞外插入积累结果在扩大的细胞/器官中，导致多因素和潜在的致命疾病，具体取决于突变和相关严重程度[1，2]。国会议员一世在全球大约3,000-8,000名患者症状包括在70％的MPS患者中发生角膜的阴影，这是失明。目前，尚无治疗剂来解决MPS I角膜云和穿透性角膜造成术的问题在这个高危患者人群中，由于移植排斥反应（> 70％）而不是当前的护理标准。到解决这种盲目疾病，在过去的5年中，我们优化了与腺相关病毒（AAV）基因交付到角膜，包括Rainbio-1（RBIO-1）的工程和验证，一项优化的IDUA cDNA遗传盒适合AAV基因治疗。在几个报告中，RBIO-1证明了能够恢复MPS I患者细胞的IDUA活性，升高人角膜的IDUA活性> 10倍，并且最值得注意的是，在单个角膜之后，在犬模型中预防和反向MPS I Corneal Entacity 基质内注射。 wt兔角膜中RBIO-1的严格安全研究（n = 20），证明了完整耐受性，即使在剂量上也比最低有效剂量高10倍，并且严格的载体基因组遏制观察到注射的角膜和视网膜。这些乐观的安全性和功效数据已定位 RBIO-1可能是任何前眼病的第一类AAV治疗。关于临床方案对于RBIO-1，最初对单个角膜进行给药是评估MPS I的安全性和功效的最谨慎的患者。如果RBIO-1减轻了MPS I角膜储存疾病，类似于MPS I犬的结果类似双边视力将需要顺序给对侧角膜。这在临床上连续AAV基因传递到角膜的相关问题将通过执行使用兔模型在AIM 1中提出的实验。虽然，我们报告了强大的IDUA生产和在MPS I犬（n = 10）和兔子6个月的治疗成功中，AAV的耐用性将近1年（n = 10）和6个月角膜中的转基因表达仍然未知，也许将RBIO-1归为单个角膜可能长期持续功效所必需。 AIM 2中的实验将确定AAV矢量的程度重新服用到先前剂量的兔角膜后的转导。这里的工作将雇用 RBIO-1确定顺序AAV载体注射的可行性并在角膜中重复给药因此，为I期协议设计提供了关键数据，以治疗MPS I角膜云。更广泛的是本文获得的关键数据的相关性扩展到MPS I超过所有角膜表面，也许是眼表面也可能受益于AAV基因治疗方法的疾病。