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Principal Investigator: Kathleen R Chirco
Organization: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2023
Award: $249,000
Funding agency: National Eye Institute
As the leading cause of inherited retinal degeneration, retinitis pigmentosa (RP) affects about 1.5 million
people worldwide. Bardet-Biedl syndrome (BBS) is the second most common causes of syndromic RP,
and is characterized as an autosomal recessive ciliopathy with severe photoreceptor degeneration
occurring by the first or second decade of life. BBS has been linked to variants in 21 genes, with those in
BBS7 accounting for roughly 2% of all BBS cases. The overall goal of this proposal is to overcome two
major hurdles in vision research: 1) the ability to accurately recapitulate disease mechanisms and
progression for BBS7 in a translatable model system, and 2) the ability to permanently correct
disease-causing variants and restore photoreceptor cell function with high efficiency and specificity. In
Aim 1, disease mechanisms responsible for the onset of BBS7 will be examined by generating a retinal
organoid model system from human induced pluripotent stem cells harboring disease-causing mutations
in the BBS7 gene. In Aims 2 and 3, BBS7 variants will be corrected using prime editing tools and a lipid
nanoparticle (LNP)-based delivery strategy within the human retinal organoid model to study timing and
efficiency of disease rescue. Furthermore, the therapies found to be most effective in vitro will be tested in
nonhuman primates to determine dose, immunogenicity, and efficiency of Cas9 delivery into
photoreceptor cells in vivo. Successful completion of these aim will 1) contribute to our basic
understanding of the pathophysiological mechanisms underlying photoreceptor dysfunction in BBS7, 2)
provide the field with a thorough evaluation of a targeted gene editing strategy to treat BBS7 in the retina,
and 3) establish LNPs as an ideal delivery system to limit cytotoxic and immunologic side effects
commonly observed with AAV-based delivery methods. Taken together, this work will establish a pipeline
for testing and optimization of therapies to treat BBS7 and other inherited retinal diseases, including
additional forms of BBS as well as RP.
Terms: <Accounting><Affect><Bardet Biedel syndrome><Bardet-Biedl Syndrome><Biologic Models><Biological Models><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Body><Cell Function><Cell Process><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cilia><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Complex><Defect><Development><Disease><Disease Progression><Disease model><Disorder><Dose><Dysfunction><Evaluation><Formulation><Functional disorder><Future><Generalized Growth><Genes><Genetic Alteration><Genetic Change><Genetic defect><Goals><Growth><Hereditary><Human><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><In Vitro><Individual><Inherited><Investigation><Knowledge><Lead><Life><Link><Measures><Mediating><Membrane><Mentors><Methods><Model System><Modeling><Modern Man><Morphogenesis><Mutation><Organoids><Pb element><Persons><Phenotype><Photoreceptor Cell><Photoreceptors><Photosensitive Cell><Physiopathology><Pigmentary Retinopathy><Protein Trafficking><Retina><Retinal Degeneration><Retinal Diseases><Retinal Disorder><Retinitis Pigmentosa><Safety><Specificity><Subcellular Process><System><Tapetoretinal Degeneration><Testing><Therapeutic><Tissue Growth><Training><Translational Research><Translational Science><Validation><Variant><Variation><Vision research><Visual Receptor><Work><autosome><ciliopathy><clinic ready><clinical ready><cytotoxic><degenerative retina diseases><developmental><disease phenotype><disease-causing mutation><disorder model><effective therapy><effective treatment><experience><experiment><experimental research><experimental study><experiments><gene therapeutics><gene-based therapeutic><gene-based therapeutics><genes therapeutic><genes therapeutics><genome editing><genome mutation><genomic editing><heavy metal Pb><heavy metal lead><iPS><iPSC><iPSCs><immunogenicity><improved><in vivo><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><inherited retinal degeneration><lipid based nanoparticle><lipid nanoparticle><membrane structure><morphogenetic process><nano particle delivery><nanoparticle delivered><nanoparticle delivery><non-human primate><nonhuman primate><novel><ontogeny><optimal therapies><optimal treatments><pathophysiology><photoreceptor degeneration><postmitotic><prevent><preventing><prime editing><prime editor><protein transport><retina degeneration><retina disease><retina disorder><retinal degenerative><retinal degenerative diseases><retinopathy><rod and cone dystrophy><rod-cone dystrophy><side effect><therapeutic gene><therapy optimization><timeline><tool><translation research><translational investigation><translational model><treatment optimization><validations>