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Principal Investigator: David M Gamm
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $2,008,538
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY/ABSTRACT – FOLLOWER PROJECT 2
Best Disease (BD) is a prevalent, primarily autosomal dominant, macular degenerative disorder that results in
retinal pigment epithelium (RPE) dysfunction and progressive loss of central vision. BD results from >200 known
missense mutations in the BEST1 gene. Whereas there are currently no viable treatment options for autosomal
dominant BD, genome editing could offer a promising therapeutic strategy. The goal of this Follower Project
2 is to develop a safe and effective genome editing treatment for BD using Spotlight Therapeutics’
proprietary Targeted Active Gene Editors (TAGE) platform. TAGE is a novel, nonviral, non-nanoparticle
delivery system wherein a functional CRISPR-Cas effector is fused to antibody (Ab) and cell-penetrating
peptide (CPP) moieties, enabling in vivo cell-targeted delivery, intracellular trafficking to the nucleus and
subsequent gene editing. A TAGE-101 lead will be developed through identification and optimization of these
modular components and complexation with a human single guide RNA (sgRNA) that binds mutant Best1. A
preclinical data package will be generated demonstrating >10% editing/knockout of the R218C mutant BEST1
allele, restored function, and acceptable off-target and genotoxicity profiles ex vivo, using patient iPSC-derived
RPEs, and in non-GLP nonhuman primate (NHP) toxicity studies. INTERACT and pre-IND meetings with the
FDA are planned to present a preclinical and upstream process development data package and a future
development plan and to explore whether additional BD mutants can be addressed with patient-specific guides
under a master IND for TAGE-101. At the end of the five-year grant horizon, the TAGE-101 development
candidate will be poised to initiate IND-enabling studies and, ultimately, clinically tested in BEST1 patients. This
Project and Project 3 aim to develop CRISPR-Cas-based gene editing therapies targeting a BEST1 mutant allele
employing different delivery platforms. Synergy will exist in areas such as sgRNA development, ex vivo
preclinical characterization studies in partnership with the Human Cell Assay Core, as well as a regulatory
strategy for BD in partnership with the Regulatory Core. This project will also have synergy with Project 1 around
pilot NHP studies, addressing RPE channelopathies via subretinal injection, in partnership with the Large Animal
Core. Successful completion of this project will provide a rigorous, stepwise approach to nominate a development
candidate poised to initiate IND-enabling studies for all individuals with BD resulting from a specific mutation. It
will also advance the utility of iPSC models as custom preclinical tools to rapidly develop somatic cell genome
editing strategies in conjunction with a novel cell-targeted CRISPR gene editing platform.
Terms: <3-D><3-Dimensional><3D><Academia><Address><Alleles><Allelomorphs><Animals><Antibodies><Area><Best Disease><Biodistribution><CLCA2 gene><CRISPR><CRISPR/Cas system><CaCC><Calcium><Cell Body><Cell Line><Cell Nucleus><CellLine><Cells><Cellular Assay><Chimera Protein><Chimeric Proteins><Chinese Hamster><Chloride Channels><Chloride Ion Channels><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Collaborations><Cristobalite><Custom><DNA editor><Data><Degenerative Disorder><Development><Development Plans><Disease><Disorder><Doppler OCT><Dysfunction><Elements><Engineering><Eye><Eyeball><Formulation><Functional disorder><Fusion Protein><Future><Genes><Genetic Alteration><Genetic Change><Genetic defect><Goals><Grant><Guide RNA><Hereditary><Hereditary Disease><Human><Inborn Genetic Diseases><Individual><Industry><Inherited><Inherited disorder><Investigational Drugs><Investigational New Drugs><Knock-out><Knockout><Lead><Mediating><Missense Mutation><Modality><Modeling><Modern Man><Molecular><Mutation><NGS Method><NGS system><Non-sense Mediated Decay><Nonsense-Mediated Decay><Nuclear><Nucleus><OCT Tomography><Optical Coherence Tomography><Organoids><Outer pigmented layer of retina><Ovary><Patients><Pb element><Penetration><Peptides><Photoreceptor Cell><Photoreceptors><Photosensitive Cell><Physiopathology><Pigment cell layer of retina><Pigmented layer of retina><Pre IND FDA meeting><Pre-IND mtg><Process><RNA Binding><RNA bound><Reporter><Retina><Retinal Pigment Epithelium><Retinal pigment epithelial cells><Ribonucleoproteins><Sand><Sight><Silica><Silicon Dioxide><Strains Cell Lines><Structure of retinal pigment epithelium><System><Testing><Therapeutic><Therapeutic Gene Editing><Toxic effect><Toxicities><Tridymite><Validation><Vision><Visual Receptor><Vitelliform MD><Vitelliform macular dystrophy><assay development><autosome><best macular dystrophy><cell assay><clinical development><cultured cell line><customs><degenerative condition><degenerative disease><developmental><functional restoration><gRNA><gene editing platform><gene editing system><gene editing technology><gene editing tools><gene editor><gene-editing therapy><gene-editing toolkit><genome editing><genome editing based therapy><genome editing therapy><genome editing treatment><genome editing-based therapeutics><genome editor><genome mutation><genomic editing><genotoxicity><heavy metal Pb><heavy metal lead><hereditary disorder><heritable disorder><iPS><iPSC><iPSCs><immunogenicity><improved><in vivo><inborn error><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cells derived from patients><induced pluripotent stem cells from patients><inducible pluripotent stem cell><inherited diseases><inherited genetic disease><inherited genetic disorder><lead candidate><lead optimization><lipid based nanoparticle><lipid nanoparticle><macula><macular><manufacture><meeting><meetings><mutant><nanocapsule><next gen sequencing><next generation sequencing><nextgen sequencing><non-human primate><nonhuman primate><novel><nuclease><nucleofection><optical Doppler tomography><optical coherence Doppler tomography><pathophysiology><patient derived human iPS><patient derived human iPSC><patient derived human induced pluripotent stem cell><patient derived iPS><patient derived iPSC><patient derived induced pluripotent cells><patient derived induced pluripotent stem cells><patient-derived pluripotent stem cells><pre-IND consultation><pre-IND discussion><pre-IND meeting><pre-Investigational New Drug meeting><pre-clinical><preclinical><programs><prototype><restore function><restore functionality><restore lost function><site targeted delivery><somatic cell gene editing><somatic cell genome editing><somatic gene editing><somatic genome editing><stable cell line><subretinal injection><synergism><targeted delivery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tech development><technology development><therapeutic agent development><therapeutic development><therapeutic editing><therapeutic genome editing><three dimensional><tool><trafficking><validations><visual function>