Gene therapy applications based on adeno-associated virus (AAV) have demonstrated promise in clinical applications for the treatment of diverse genetic diseases highlighted by the recent FDA approval of AAV vector formulations as new drugs for ocular and neurological diseases. In these instances, along with all applications of clinical AAV gene therapy to date, constitutive transcription of the therapeutic cassette is employed without any safeguards in place to modulate transgene production in the targeted tissue. At the mechanistic level, the AAV vector transduction pathway is not well understood. The episomal AAV vector genomes form circular monomers and concatemers and a limited number of studies have demonstrated their associations with histones, transcriptional activators and repressors implying an untapped level of control related to overall transgene production. These observations suggest that AAV episomes may be restricted for maximal expression and allude to the ability for targeted approaches for modulating their epigenetic composition to enhance and/or repress AAV vector transduction. We recently developed a technology that couples a dCas9-based protein targeting system at a promoter with a small bifunctional molecule to control gene expression. Spefically, the dCas9-FKBP system was used to successfully activate epigenetically-silenced endogenous loci (e.g., MyoD1 and CXCR4) in HEK293 cells. Epigenos Biosciences proposes adding a new functionality, referred as CEMtrol, to AAV modules that will be designed to mitigate epigenetic dampening of transgene expression to ensure the efficacy of gene therapies will not be subject to uncontrollable epigenetic regulation. In collaboration with Dr. Matthew Hirsch, who is developing therapies for ocular diseases, Phase I will focus on developing an AAV that maximizes transgene expression in cell culture and explant cornea models as a proof-of-concept feasibility study. Public Health Relevance Statement Narrative Gene therapy applications based on adeno-associated virus (AAV) have demonstrated promise in clinical applications for the treatment of diverse genetic diseases highlighted by the recent FDA approval of AAV vector formulations as new drugs for ocular and neurological diseases. Studies suggest that therapeutic genes contained in AAV vectors may be restricted for maximal expression via epigenetic silencing mechanisms. Epigenos Biosciences proposes adding a new functionality, referred as CEMtrol, to AAV modules that will be designed to mitigate epigenetic dampening of AAV therapeutic gene expression to ensure that the efficacy of gene therapies will not be subject to uncontrollable epigenetic regulation.
Project Terms: Dependovirus ; Adeno-Associated Viruses ; Dependoparvovirus ; adeno associated virus group ; inhibitor/antagonist ; inhibitor ; Competitive Binding ; competitively bound ; Biological Sciences ; Biologic Sciences ; Bioscience ; Life Sciences ; Biomedical Engineering ; bio-engineered ; bio-engineers ; bioengineering ; Cell Culture Techniques ; cell culture ; Cells ; Cell Body ; Cornea ; corneal ; Keratoplasty ; Cornea Transplantation ; Corneal Grafting ; Corneal Transplantation ; corneal keratoplasty ; corneal transplant ; Couples ; Disease ; Disorder ; Enzymes ; Enzyme Gene ; Episome ; Feasibility Studies ; Future ; Gene Expression ; gene therapy ; DNA Therapy ; Gene Transfer Clinical ; Genetic Intervention ; gene-based therapy ; genetic therapy ; genomic therapy ; Genome ; Graft Rejection ; Transplant Rejection ; Transplantation Rejection ; Histones ; Human ; Modern Man ; In Vitro ; Methods ; Nervous System Diseases ; Neurologic Disorders ; Neurological Disorders ; neurological disease ; nervous system disorder ; Production ; Proteins ; Technology ; Body Tissues ; Tissues ; Gene Transcription ; RNA Expression ; Transcription ; Genetic Transcription ; Zinc Finger Domain ; Zinc Finger Motifs ; Zinc Fingers ; FK-506-Binding Protein ; FK506 Binding Proteins ; FKBP ; FKBP Rotamase ; Tacrolimus Binding Proteins ; Mediating ; promotor ; promoter ; Chimera Protein ; Fusion Protein ; Chimeric Proteins ; base ; improved ; Phase ; Ensure ; Chemicals ; Licensing ; Collaborations ; Transgenes ; Therapeutic ; System ; monomer ; transgenic ; Transgenic Organisms ; novel ; Prevention ; FK 506 ; FK506 ; Regulation ; Modeling ; Gene Down-Regulation ; Transcription Repression ; Transcriptional Repression ; gene repression ; Transcription Regulation ; Transcriptional Control ; Transcriptional Regulation ; Molecular Interaction ; Binding ; small molecule ; CXC-R4 ; CXCR-4 ; CXCR4 ; D2S201E ; FB22 ; HM89 ; HSY3RR ; LAP3 ; LCR1 ; LESTR ; NPY3R ; NPYR ; NPYRL ; NPYY3R ; CXCR4 gene ; Transcription Activator ; Transcription Factor Coactivator ; Transcriptional Activator ; Transcriptional Activator/Coactivator ; Transcriptional Coactivator ; transcription co-activator ; transcriptional co-activator ; Transcription Coactivator ; Transcriptional Repressor ; genetic repressor ; Transcription Repressor ; Dose ; Epigenetic ; Epigenetic Change ; Epigenetic Mechanism ; Epigenetic Process ; Validation ; Gene Delivery ; pathway ; Pathway interactions ; vector ; design ; designing ; therapeutic gene ; gene therapeutics ; gene-based therapeutic ; gene-based therapeutics ; genes therapeutic ; genes therapeutics ; transgene expression ; adeno-associated viral vector ; AAV vector ; adeno-associated virus vector ; clinical application ; clinical applicability ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; vector genome ; therapy development ; develop therapy ; intervention development ; treatment development ; FDA approved ; epigenetic regulation ; Formulation ; experimental study ; experiment ; experimental research ; recruit ; Genetic Diseases ; genetic condition ; genetic disorder ; lead candidate ; Transplantation Surgery ; epigenetic silencing ; epigenetic gene silencing ;
