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Principal Investigator: Luiz Miguel Quinn Camargo
Organization: UBIQUITX, INC.
Fiscal Year: 2024
Award: $6,500
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY
Pharmacologically targeting intracellular proteins is a key challenge of modern drug development, requiring
innovation and the development of new technologies. This challenge is made more difficult by the fact that many
protein targets remain beyond the reach of established drug discovery technologies because they lack easy-to-
find and unique binding pockets, possess large, and flat contact areas. Indeed, ~85-90% of the human genome
is considered “undruggable,” encoding proteins that are deemed too challenging to bind with conventional
molecules. Hence, new approaches are needed for drugging intracellular protein targets. To address this unmet
need, this project seeks to develop a new class of computationally-designed mRNA therapeutics that encode
peptide-guided protein degraders, known as ubiquibodies (uAbs), for potent and selective degradation of
historically undruggable targets not addressable by conventional drugs. Specifically, uAbs are modular,
programmable proteins consisting of a genetically engineered fusion between an E3 ubiquitin ligase, linker, and
protein/peptide guide. Following ectopic expression in cells, these heterobifunctional chimeras direct the activity
of an E3 to a protein of interest (POI), leading to polyubiquitination and subsequent degradation of the POI by
the endogenous ubiquitin-proteasome pathway (UPP). The objective of this Phase I STTR is to design
customized uAbs against β-catenin and CCAAT/enhancer-binding protein homologous protein (CHOP), two
intracellular transcription factors that hold promise as drug targets for hepatocellular carcinoma (HCC), alpha-1
antitrypsin deficiency (AATD), and other liver diseases. The hypothesis of this project is that uAbs can be
designed to selectively remove cytosolic/nuclear β-catenin and CHOP, with the potential to inhibit the tumorigenic
and proteotoxic potential, respectively, of these drug targets while also limiting toxicity. The plan to address these
hypotheses includes first leveraging an artificial intelligence/machine learning (AI/ML)-powered platform to
create designer uAbs that selectively degrade cytosolic/nuclear β-catenin and CHOP (Aim 1) and then to develop
and evaluate a lipid nanoparticle (LNP)-based strategy for systemically delivering synthetic uAb-encoding
mRNAs in cultured cells and mice. The best performing mRNA-LNP formulations will then be evaluated in mice
to assess biodistribution, efficiency and duration of target degradation, and biological impacts. Overall, the
proposed studies will demonstrate a new paradigm for drugging the proteome based on computational design
of peptide-guided uAbs, with proof-of-concept studies in this Phase I proposal focused on accelerating the
removal of two key intracellular disease drivers through LNP-mediated delivery of mRNA encoding customized
uAbs. Successful completion of this project will lead to a future Phase II application that will explore the
therapeutic potential of uAbs following systemic delivery of optimized mRNA-LNP formulations in relevant animal
models of HCC and AATD. These studies will serve to advance the development and commercialization of
UbiquiTx’s proprietary therapeutic candidates towards an IND.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><AAT deficiency><AI system><APF-1><ATP-Dependent Proteolysis Factor 1><Abscission><Acceleration><Address><Advanced Development><Animal Model><Animal Models and Related Studies><Area><Artificial Intelligence><Basal Transcription Factor><Basal transcription factor genes><Beta Cadherin-Associated Protein><Beta-1 Catenin><Binding><Biodistribution><Biological><C-EBP Nuclear Protein><C-EBP Proteins><C/EBP><CAAT-Enhancer-Binding Proteins><CCAAT Sequence-Specific DNA-Binding Proteins><CCAAT-Enhancer-Binding Proteins><CUL-2><Cell Body><Cells><Chimera><Chimera organism><Computer Reasoning><Cultured Cells><Development><Disease><Disorder><Drug Targeting><Drugs><E3 Ligase><E3 Ubiquitin Ligase><Ectopic Expression><Evaluation><Excision><Extirpation><Formulation><Future><General Transcription Factor Gene><General Transcription Factors><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><HMG-20><Hepatic Disorder><Hepatocarcinoma><Hepatocarcinoma model><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatoma><High Mobility Protein 20><Homologous Protein><Human Genome><Liver Cells Carcinoma><Liver diseases><Machine Intelligence><Machine Learning><Macropain><Macroxyproteinase><Mediating><Medication><Messenger RNA><Metabolic Protein Degradation><Mice><Mice Mammals><Modernization><Molecular Interaction><Multicatalytic Proteinase><Murine><Mus><Nuclear><PRO2286><Pathway interactions><Peptides><Pharmaceutical Preparations><Phase><Polyubiquitination><Primary carcinoma of the liver cells><Prosome><Proteasome><Proteasome Endopeptidase Complex><Protein Homolog><Protein Turnover><ProteinHomolog><Proteins><Proteome><Proteosome><Recombinant DNA Technology><Regulatory Protein Degradation><Removal><STTR><Small Business Technology Transfer Research><Surgical Removal><Technology><Therapeutic><Toxic effect><Toxicities><Transcription Factor Proto-Oncogene><Transcription factor genes><Ubiquitin><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><a1-antitrypsin deficiency><alpha 1-Antitrypsin Deficiency><alpha-1-anti-trypsin deficiency><alpha1-antitrypsin deficiency><beta catenin><biologic><chimeras><commercialization><deliver mRNA><deliver messenger RNA><delivery system for mRNA><design><designing><developmental><drug development><drug discovery><drug/agent><genetically engineered><hepatic disease><hepatocellular carcinoma cancer model><hepatocellular carcinoma model><hepatopathy><human whole genome><innovate><innovation><innovative><interest><lipid based nanoparticle><lipid nanoparticle><liver cancer model><liver carcinoma><liver disorder><mRNA><mRNA delivery><machine based learning><messenger RNA delivery><model of animal><multicatalytic endopeptidase complex><new approaches><new technology><novel approaches><novel strategies><novel strategy><novel technologies><pathway><pharmacologic><protein degradation><proteotoxic><proteotoxicity><resection><therapeutic candidate><transcription factor><tumorigenic><ubiquitin-protein ligase><α-1 anti-trypsin deficiency><α-1-antitrypsin deficiency><α1-Antitrypsin Deficiency><β-catenin>