Phase II year
2017
(last award dollars: 2019)
Phase II Amount
$2,230,814
This project will test human embryonic stem cell-derived 3-D retinal tissue transplanted in subretinal space of 2 animal models with photoreceptor (PR) degeneration in a longitudinal study lasting for up to 12 months. We will use a large-eye animal model of early-onset RD with a Crx mutation (Rdy Abyssinian cats) and immunodeficient rats with PR degeneration SD-Foxn1 Tg(S334ter)3Lav (RD nude). The immediate goal is to demonstrate survival, lamination, maturation, and structural and synaptic integration of grafts with the recipient retina, the and improvement in vision by 6-12 months, and to generate standard operating procedures for transforming such technology into therapy to treat blindness caused by PR death. The overarching goal is to evaluate this technology in pilot clinical trials in patients with retinitis pigmentosa (RP), an orphan disease with fast track FDA approval . Blindness is a major health concern among Americans, affecting quality of life and with a high financial and heavy emotional burden. The two major retinal diseases associated with photoreceptor degeneration are RP and dry age-related macular degeneration (AMD). There is a critical and urgent need to find new treatments of RP and AMD based on photoreceptor replacement. The research in the past 15-20 years indicates that a piece of degenerating mammalian retina can be replaced with healthy fetal retinal tissue, which can improve vision. The research shows that grafted fetal retina will complete differentiation, synapse on the recipient retinal ganglion cell neurons, and re-establish connectivity with the visual cortex. Human fetal-derived retinal tissue supply is very limited, and its clinical use in therapy is ethically not acceptable. BioTime hypothesizes that 6-8- week old human embryonic stem cell-derived 3-D retinal tissue will integrate structurally and synaptically into the degenerating recipient retina and improve vision in animals with advanced RD . We predict that demonstrating positive therapeutic impact of hESC-3D retinal tissue grafting in a large eye animal model with RD will enable us to move this technology to pilot clinical trials in RP patients. We have already developed hESC-3D retinal tissue and demonstrated that it carries a layer of RPE, PRs , second order neurons and ganglion cells, is capable We also reported that it improves vision in a rat animal model with RP and blindness and activates superior colliculus . We propose to do in vivo testing in a large eye animal model of RD (Rdy cats) with blindness, and in a large cohort of SD-Foxn1 Tg(S334ter)3Lav (RD nude) rats with RD to statistically evaluate the feasibility of this therapy in RP patients. In Aim 1 (BioTime), we will scale-up production of hESC-3D retinal tissue from cGMP-grade hESCs and evaluate several lots using FDA criteria. In Aim 2 (UCI), we will do subretinal grafting into blind rats and evaluate vision improvements and graft-host connectivity. In Aim 3 (MSU), we will do subretinal grafting into Rdy/+ cats and also evaluate vision improvements and graft-host connectivity. The results and procedures will be integrated into clinical protocols to enable clinical trials of blindness caused by PR degeneration of axonogenesis, synaptogenesis and becomes progressively electrically active. .
Public Health Relevance Statement: NARRATIVE Blindness is a major health fear among Americans, and is a costly burden on our society. We will test human embryonic stem cell-derived 3-Dimensional retinal tissue ( retinal patch grown as neural retina + RPE together ) in the subretinal space of a large-eye animal model of RD (Abyssinian cats with Crx mutation Rdy + /) and blind immunodeficient rats with photoreceptor degeneration . The immediate goal is to demonstrate t he survival, structural and synaptic integration of grafts in the subretinal space, and improvement in vision in two models of human RD. The ultimate goal is to delineate standard operating procedures for transforming such technology into cell therapy to treat blindness caused by PR degeneration and o test retinal patch technology in pilot clinical t trials in patients with RP, an orphan class disease with fast FDA approval.
Project Terms: 3-Dimensional; Affect; Age; Age related macular degeneration; American; Animal Model; Animals; Antibodies; base; behavior test; bevacizumab; Biological; Biological Preservation; Biology; Biotechnology; blind; Blindness; Blood Vessels; Cell Therapy; cell type; Cells; Cessation of life; Clinical; Clinical Protocols; Clinical Trials; cohort; cost; Cyclic GMP; Data; Derivation procedure; Diabetic Retinopathy; Disease; drug market; early onset; Electron Microscopy; Electrophysiology (science); Electroretinography; Emotional; Endotoxins; Ethics; Euthanasia; Eye; Felis catus; fetal; Fetal Tissues; Fright; Future; ganglion cell; gene therapy; Genetic Fingerprintings; Glaucoma; Goals; Graft Survival; Health; Histology; Human; human embryonic stem cell; human pluripotent stem cell; Immunohistochemistry; improved; in vivo; Injection of therapeutic agent; Karyotype; Life Expectancy; Longitudinal Studies; Macular degeneration; Modeling; Mutation; Mycoplasma; Neural Retina; Neuroanatomy; Neurons; Nude Rats; Operative Surgical Procedures; ophthalmic drug; Ophthalmology; Optical Coherence Tomography; optical imaging; Organoids; Orphan; Patients; Pharmaceutical Preparations; photoreceptor degeneration; Photoreceptors; Population; Prevalence; Procedures; Production; Quality of life; Rare Diseases; Rattus; regenerative; relating to nervous system; repaired; Reporting; Research; restoration; Retina; Retinal; retinal damage; Retinal Degeneration; Retinal Diseases; Retinal Ganglion Cells; Retinitis Pigmentosa; safety testing; scale up; Societies; sterility testing; Structure of retinal pigment epithelium; superior colliculus Corpora quadrigemina; Synapses; synaptogenesis; Technology; Testing; Therapeutic; Time; Tissue Grafts; Tissues; transcriptome sequencing; transcriptomics; Transplantation; Transplanted tissue; Tumorigenicity; Vision; Visual Cortex
