Retinal tissue derived from human pluripotent stem cells for vision restoration

Abstract from the original SBIR Phase II This project will test human embryonic stem cell derivedD retinal tissue transplanted in subretinal space ofanimal models with photoreceptorPRdegeneration in a longitudinal study lasting for up tomonthsWe will use a large eye animal model of early onset RD with a Crx mutationRdy Abyssinian catsand immunodeficient rats with PR degeneration SD FoxnTg SterLavRD nudeThe immediate goal is to demonstrate the survivallaminationmaturationand structural and synaptic integration of grafts with the recipient retinaand improvement in vision bymonthsand to generate standard operating procedures for transforming such technology into therapy to treat blindness caused by PR deathThe overarching goal is to evaluate this technology in pilot clinical trials in patients with retinitis pigmentosaRPan orphan disease with fast track FDA approvalBlindness is a major health concern among Americansaffecting quality of life and with a high financial and heavy emotional burdenThe two major retinal diseases associated with photoreceptor degeneration are RP and dry age related macular degenerationAMDThere is a critical and urgent need to find new treatments of RP and AMD based on photoreceptor replacementThe research in the pastyears indicates that a piece of degenerating mammalian retina can be replaced with healthy fetal retinal tissuewhich can improve visionThe research shows that grafted fetal retina will complete differentiationsynapse on the recipient retinal ganglion cell neuronsand re establish connectivity with the visual cortexHuman fetal derived retinal tissue supply is very limitedand its clinical use in therapy is ethically not acceptableBioTime hypothesizes thatweek old human embryonic stem cell derivedD retinal tissue will integrate structurally and synaptically into the degenerating recipient retina and improve vision in animals with advanced RDWe predict that demonstrating positive therapeutic impact of hESCD retinal tissue grafting in alarge eyeanimal model with RD will enable us to move this technology to pilot clinical trials in RP patientsWe have already developed hESCD retinal tissue and demonstrated that it carries a layer of RPEPRssecond order neurons and ganglion cellsis capable of axonogenesissynaptogenesis and becomes progressively electrically activeWe also reported that it improves vision in a rat animal model with RP and blindness and activates superior colliculusWe propose to do in vivo testing in alarge eyeanimal model of RDRdy catswith blindnessand in a large cohort of SD FoxnTg SterLavRD nuderats with RD to statistically evaluate the feasibility of this therapy in RP patientsIn AimBioTimewe will scale up production of hESCD retinal tissue from cGMP grade hESCs andevaluate several lots using FDA criteriaIn AimUCIwe will do subretinal grafting into blind rats and evaluate vision improvements and grafthost connectivityIn AimMSUwe will do subretinal grafting into Rdycats and also evaluate vision improvements andgraft host connectivityThe results and procedures will be integrated into clinical protocols to enable clinical trials of blindness caused by PR degeneration Narrative from original Phase II SBIR Blindness is a major health fear among Americansand is a costly burden on our societyWe will test human embryonic stem cell derivedDimensional retinal tissueretinal patch grown as neural retinaRPE togetherin the subretinal space of a large eye animal model of RDAbyssinian cats with Crx mutation Rdyand blind immunodeficient rats with photoreceptor degenerationThe immediate goal is to demonstrate the survivalstructural and synaptic integration of grafts in the subretinal spaceand improvement in vision in two models of human RDThe ultimate goal is to delineate standard operating procedures for transforming such technology into cell therapy to treat blindness caused by PR degeneration and to test retinal patch technology in pilot clinical trials in patients with RPan orphan class disease with fast FDA approval