Project Grant R44NS135792

TARGETED CEREBRAL SPINAL FLUID (CSF) DRUG DELIVERY - ENCLEAR PRECISION SYSTEM - ENCLEAR THERAPIES IS DEVELOPING NEW TECHNOLOGY FOR MORE EFFECTIVE DRUG DELIVERY TO THE BRAIN AND COMBINING OUR TECHNOLOGY WITH QURALIS WHO ARE DEVELOPING EXCITING GENE THERAPY APPROACHES FOR FRONTOTEMPORAL DEMENTIA (FTD). EXCITINGLY, RECENT RESEARCH HAS FUNCTIONALLY LINKED TDP-43 TO STATHMIN-2 (STMN2) IN FTD PATIENT TISSUE. IT IS KNOWN THAT THE LOSS OF NORMAL TDP-43 FUNCTION AS A REGULATOR OF RNA METABOLISM CAUSES INCORRECT SPLICING OF STMN2. STMN2 IS ESSENTIAL FOR AXONAL AND NEUROMUSCULAR JUNCTION MAINTENANCE AND REPAIR. WHEN STMN2 EXPRESSION IS LOST, AGE-INDUCED NEURODEGENERATION AND ASSOCIATED DEMENTIAS, LIKE FTD, ARE PROMOTED. THIS NEWLY DISCOVERED LINK BETWEEN STMN2 AND NEURONAL PLASTICITY, ALONG WITH STMN2'S INTERACTION WITH TDP-43, SUGGESTS THAT STMN2 TARGETING REPRESENTS A NOVEL AND EXCITING APPROACH FOR DEVELOPING A POTENTIAL THERAPY FOR FTD. QURALIS ANALYZED THE STMN2 RNA SEQUENCE TO IDENTIFY REGIONS FOR SPLICE REGULATION AND DEVELOPED SPLICE SWITCHING ANTISENSE OLIGONUCLEOTIDES (ASOS) THAT TARGET THESE SEQUENCES. THE ASO DOSE-DEPENDENTLY RESTORES STMN2 MRNA LEVELS. WE NOW AIM TO DELIVER THE QURALIS ASOS TO TARGET AFFECTED NEURONS IN FTD. GENE THERAPIES HAVE BEEN PLAGUED WITH POOR TISSUE DISTRIBUTION AND PENETRATION. A NUMBER OF GENE THERAPIES HAVE BEEN "SHELVED" OR FAILED CLINICAL TRIALS BECAUSE OF THE CHALLENGE OF REACHING BRAIN PARENCHYMA IN SUFFICIENT QUANTITIES. THE ENCLEAR SYSTEM IS CAPABLE OF CONTROLLING CSF FLOW PRECISELY BY UTILIZING OUR SENSOR ARRAY TO UNDERSTAND PATIENTS' PHYSIOLOGIC RESPONSES TO ADJUST DRUG INFUSION RATE, CSF FLOW RATE, FLOW DIRECTION AND TO "OSCILLATE" DRUG CONCENTRATION OVER SPECIFIC TISSUE TARGETS. THIS LEVEL OF CSF FLOW CONTROL IS FIRST-IN- CLASS AND MAKES THE ENCLEAR SYSTEM UNIQUE AND POTENTIALLY CAPABLE OF PERSONALIZED DRUG DELIVERY TO PATIENTS WITH CNS DISEASES. IN THIS FAST TRACK NIH/SBIR PROPOSAL, OUR AIMS IN PHASE 1 ARE TO GAIN UNDERSTANDING OF THE FLOW DYNAMICS OF OUR SYSTEM USING SHEEP AS OUR ANIMAL MODEL. EMPLOYING LIVE IMAGING WE WILL DEVELOP THE IDEAL ALGORITHM FOR PRECISION DRUG DELIVERY. AFTER IMAGING, THE DRUG METHOTREXATE USED FOR TREATING BRAIN CANCER, WILL BE ADMINISTERED. AT NECROPSY, CNS DRUG TISSUE CONCENTRATIONS WILL BE QUANTIFIED TO CONFIRM OUR ABILITY FOR PRECISION DRUG DELIVERY AND TO AVOID "OFF-TARGET" DRUG DELIVERY. THIS KNOWLEDGE GAINED IN PHASE 1 RELATED TO PRECISION DRUG TARGETING WILL BE APPLIED TO A LARGER COHORT WHERE WE WILL USE OUR INSIGHTS ON PRECISION DRUG DELIVERY INCORPORATED INTO OUR CSF FLOW ALGORITHM TO DOSE QURALIS' STMN2 ASO TO TARGET THE NEURODEGENERATIVE DISEASE FTD. IN PHASE 2, WE WILL CONFIRM DISTRIBUTION OF STMN2 ASO TO RELEVANT AREAS OF THE BRAIN. RESULTS WILL BE APPLIED TO THE DEVELOPMENT OF THE STMN2 ASO AS A THERAPY FOR FTD PATIENTS. RESULTS FROM THIS GRANT WILL GO TOWARDS FDA APPROVAL OF ENCLEAR'S DELIVERY TECHNOLOGY WITH DATA SUPPORTING BROAD APPLICATIONS TO BENEFIT DRUG DELIVERY FOR SMALL AND LARGE MOLECULES, AND GENE THERAPIES FOR MANY CNS DISEASES INCLUDING ALZHEIMER'S DISEASE (AD) AND ALZHEIMER'S DISEASE RELATED DEMENTIAS (ADRD) SUCH AS FTD.