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Principal Investigator: Andrea L Kasinski
Organization: PURDUE UNIVERSITY
Fiscal Year: 2024
Award: $386,127
Funding agency: National Cancer Institute
PROJECT SUMMARY
Like the challenges and skepticism that faced the antibody therapeutics field over a decade ago, RNA
therapeutics is facing the same. And, like the antibody therapeutics field, we are beginning to realize the clinical
impact of RNA therapeutics amiss these challenges. This is most clearly highlighted with the recent approval of
two mRNA vaccines to prevent against SARS-CoV-2 and the first three FDA approved RNAi drugs targeted to
the liver. Unfortunately, RNA-based drugs targeted to cancer cells is lagging behind, even with countless years
of work that has revealed the power of using RNAi for treating oncological diseases. Lack of success in this
space is attributed to inability to deliver RNAi safely and effectively. A successful delivery agent requires multiple
features. First, the agent must deliver the RNA specifically to the intended cells. Second, the agent must have a
large therapeutic window, meaning that toxicity, if observed, should occur at doses that are orders of magnitude
higher than the therapeutic dose. Third, if delivery of the RNA is by way of a specific ligand and receptor pair, as
is the case herein, the RNA must successfully escape the endosome. Simply swelling the endosome is not
enough if noncovalent interactions between the ligand and the receptor cannot be disrupted. Fourth, the RNA
should include appropriate stabilizing modifications to increase intracellular half-life that will reduce dosing and
cost. Through hard work and dedication in this space, we have come up with an inclusive, easily synthesized,
intramolecular molecule that will achieve all of these essential features. Moreover, the ligand used to achieve
successful delivery is also being evaluated for imaging tumors localized in the central nervous system.
The premise for this work is based on conjugating the tumor suppressive microRNA, miR-34a to 5-
methyltetrahydrofolate (5-MTHF), a ligand that is superior for the intended needs, in this case, release from the
receptor when an endosomal escape agent is present. Our preliminary data and strong scientific premise
supports our objective to i) advance 5-MTHF as a specific and non-toxic therapeutic ligand for delivery of
therapeutic miRNAs to triple negative breast cancer (TNBC) and ii) to characterize and prepare 5-MTHF-nigericin
conjugated to a fully modified version of miR-34a for clinical trial. To support these objectives, the following Aims
will be conducted: 1) To test the hypothesis that both in vivo and intracellular biodistribution of 5-MTHF
conjugates are superior to folate conjugates, and 2) To evaluate activity, efficacy, toxicity, pharmacokinetics,
dynamics, and combinatorial effects of 5-MTHF-nigericin conjugated to fully modified miR-34a in vivo. At the
completion of this work we will have the first an all-encompassing RNAi delivery vehicle that can deliver a
stabilized RNA to the intended cells, into the correct subcellular location, with limited toxicity for the treatment of
TNBC.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Abscission><Affinity><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Anzatax><Asotax><B7-H1><B7H1><BBB crossing><Binding><Biodistribution><Breast Cancer Treatment><Bristaxol><CD274><CNS Nervous System><CNS Tumor><CNS neoplasm><COVID-19 virus><COVID19 virus><Cancer Drug><Cancers><Cell Body><Cells><Central Nervous System><Central Nervous System Neoplasms><Central Nervous System Tumors><Circulation><Clinical><Clinical Trials><CoV-2><CoV2><Complex><Coupled><Cytosol><Data><Dedications><Disease><Disorder><Dose><Drug Kinetics><Drug Targeting><Endosomes><Excision><Extirpation><FDA approved><Folate><Folic Acid><Funding><Generations><Goals><Half-Life><Image-Guided Surgery><Kinetics><Ligands><Liver><Location><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mediating><Micro RNA><MicroRNAs><Mission><Modification><Molecular Interaction><NIH><National Institutes of Health><Neoplastic Disease Chemotherapeutic Agents><Neuraxis><Nigericin><Non-Polyadenylated RNA><Oncology><Oncology Cancer><PD-L1><PD-L1 inhibitors><PDL-1><PDL1><PDL1 inhibitors><Paclitaxel><Paclitaxel (Taxol)><Pharmacokinetics><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Praxel><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Pteroylglutamic Acid><Public Health><RNA><RNA Gene Products><RNA Interference><RNA Silencing><RNA based therapeutics><RNA based therapy><RNA delivery><RNA therapy><RNA vaccine><RNA-based vaccine><RNAi><Receptor Protein><Receptosomes><Removal><Ribonucleic Acid><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sequence-Specific Posttranscriptional Gene Silencing><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Small RNA><Surgical Removal><Swelling><TNBC><Taxol><Taxol A><Taxol Konzentrat><Testing><Therapeutic><Therapeutic Agents><Therapeutic antibodies><Time><Toxic effect><Toxicities><Treatment-related toxicity><Tumor-Specific Treatment Agents><United States National Institutes of Health><Vitamin M><Work><Wuhan coronavirus><anti-cancer><anti-cancer drug><blood-brain barrier crossing><bloodbrain barrier crossing><cancer cell><cancer imaging><combinatorial><coronavirus disease 2019 virus><coronavirus disease-19 virus><cost><delivery vector><delivery vehicle><dietary><folate carrier><folate receptor><folate-binding protein><folate-methotrexate transporter><folic acid binding protein><folic acid receptor><hCoV19><hepatic body system><hepatic organ system><in vivo><intra-operative imaging><intraoperative imaging><mRNA vaccine><mRNA-based vaccine><malignancy><methotrexate-binding protein><miR therapy><miR-based therapeutic><miR-based therapy><miRNA><miRNA therapy><miRNA-based therapeutic><miRNA-based therapy><miRNAs><microRNA therapy><microRNA-based therapeutic><microRNA-based therapy><nCoV2><neoplasm/cancer><oncologic imaging><oncology imaging><overexpress><overexpression><prevent><preventing><programmed cell death ligand 1><programmed cell death ligand 1 inhibitors><programmed cell death protein ligand 1><programmed cell death protein ligand 1 inhibitors><protein death-ligand 1><receptor><receptor mediated endocytosis><resection><success><surgical imaging><synergism><therapeutic RNA><therapeutic miRNA><therapeutic miRs><therapeutic microRNA><therapeutic toxicity><therapy associated toxicity><therapy related toxicity><therapy toxicity><tool><treatment toxicity><treatment-associated toxicity><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor imaging><tumors in the central nervous system><vitamin Bc>