Bolden Therapeutics, Inc.

2024-07-31

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Department of Health and Human Services

PRECLINICAL CHARACTERIZATION OF SPLICE-MODIFYING ANTISENSE OLIGONUCLEOTIDES TARGETING NEUROGENESIS IN HUMAN AD NEURAL CELLS - PROJECT SUMMARY THERE IS AN ENORMOUS NEED FOR THERAPEUTICS TO PREVENT AND TREAT ALZHEIMER’S DISEASE (AD). ADULT HIPPOCAMPAL NEUROGENESIS (AHN) IS CRITICAL FOR NORMAL LEARNING AND MEMORY, BUT IT DECLINES IN PATIENTS WITH AD. WORK IN ANIMAL MODELS HAS UNDERSCORED THE ROLE OF AHN IN IMPROVING COGNITION IN THE FACE OF AD PATHOLOGY. AUGMENTING AHN REPRESENTS A PROMISING POTENTIAL AVENUE TO PROMOTE COGNITIVE FUNCTION IN THE SETTING OF MILD COGNITIVE IMPAIRMENT OR ALZHEIMER’S DISEASE, AS WELL AS IN OTHER NEUROLOGICAL CONDITIONS. IN THIS PHASE I EFFORT, WE WILL EVALUATE LEAD CANDIDATE EXON-SKIPPING ANTISENSE OLIGONUCLEOTIDES (ASOS) IN HUMAN NEURAL CELL CULTURE. OUR ASOS HAVE ALREADY DEMONSTRATED SUCCESSFUL TARGET MODULATION IN TWO HUMAN CELL TYPES AND IN VIVO EFFICACY STUDIES ARE ONGOING. THESE PROPOSED STUDIES REPRESENT AN IMPORTANT ADVANCEMENT IN OUR DEVELOPMENT EFFORTS AS THEY WILL GENERATE DATA ON OUR ABILITY TO MODULATE OUR TARGET IN CELLS THAT ARE PHYSIOLOGICALLY HIGHLY SIMILAR TO OUR ULTIMATE TARGET CELL OF INTEREST, AND MAY LEAD TO BIOMARKER IDENTIFICATION. WE WILL USE THESE ASOS IN VALIDATED PATIENT CELL LINES IN TWO “AD ENVIRONMENTS” TO STUDY THEIR ABILITY TO ACHIEVE SUCCESSFUL EXON SKIPPING, ALTER PROTEIN EXPRESSION, AND MODULATE SIGNALING AND FUNCTION. EXON-SKIPPING ASOS HAVE EMERGED AS EFFECTIVE AND SAFE AGENTS FOR REGULATING ALTERNATIVE SPLICING IN THE CNS, AND SIGNIFICANT ADVANCEMENTS ARE ONGOING WITH RESPECT TO NON-INVASIVE AND MINIMALLY INVASIVE ROUTES OF ADMINISTRATION THAT WOULD PERMIT BROAD CLINICAL IMPLEMENTATION. DETERMINING IN VITRO EFFICACY OF OUR CANDIDATE ASOS IS A CRITICAL STEP TOWARDS DEVELOPING A HIGHLY TARGETED, SAFE AND EFFECTIVE THERAPEUTIC FOR PROMOTING AHN AND IMPROVING COGNITION IN AD. IF SUCCESSFUL, THESE STUDIES WOULD PROVIDE SIGNIFICANT BIOLOGICAL VALIDATION OF THE THERAPEUTIC POTENTIAL OF OUR CANDIDATE ASOS FOR THE TREATMENT OR PREVENTION OF AD AND OTHER NEUROLOGICAL CONDITIONS, AND WILL ENABLE US TO BUILD ADDITIONAL SUPPORT AS WE WORKS TOWARDS AN INVESTIGATIONAL NEW DRUG APPLICATION WITH FDA.

504505.00

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0.00

2022-09-01

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Department of Health and Human Services

ENTREPRENEURIAL DEVELOPMENT AWARD FOR A NOVEL ALZHEIMER'S DISEASE THERAPEUTIC - THE AGING POPULATION IN THE US AND GLOBALLY HAS LED TO AN URGENT NEED FOR THERAPEUTICS TO PREVENT AND TREAT ALZHEIMER'S DISEASE (AD). ADULT HIPPOCAMPAL NEUROGENESIS (AHN) IS CRITICAL FOR NORMAL LEARNING AND MEMORY AND DECLINES IN PATIENTS WITH AD. WORK IN ANIMAL MODELS HAS UNDERSCORED THE ROLE OF AHN IN IMPROVING COGNITION IN THE FACE OF AD PATHOLOGY. THUS, RESTORING AHN HAS EMERGED AS AN ATTRACTIVE TARGET FOR AN AD THERAPY. BOLDEN THERAPEUTICS HAS DISCOVERED A NEW PATHWAY TO PROMOTE AHN. CRITICALLY, THIS PATHWAY CAN BE TARGETED BY EXON-SKIPPING ANTISENSE OLIGONUCLEOTIDES (ASOS), A THERAPEUTIC MODALITY THAT IS ON THE MARKET AND HAS EMERGED AS EFFECTIVE AND SAFE FOR REGULATING ALTERNATIVE SPLICING IN THE CNS. DR. VALAT LED THE EFFORT TO IDENTIFY SEVERAL LEAD ASOS THAT SUCCESSFULLY SKIP OUR TARGET REGION IN CULTURED CELLS. IN THIS PHASE I EFFORT, THESE ASOS WILL BE TESTED IN VIVO. WE WILL EVALUATE THEIR SAFETY AS WELL AS THEIR ABILITY TO PROMOTE AHN AND IMPROVE COGNITION IN AGING WILD-TYPE MICE (AIM 1), AND IN A MOUSE MODEL WITH ENTRENCHED AD PATHOLOGY (AIM 2). EVALUATING THE SAFETY AND EFFICACY OF THESE CANDIDATES IS A CRITICAL STEP THAT WOULD SUPPORT THE ADVANCEMENT OF THESE ASOS TO IND-ENABLING EXPERIMENTS AND RAPID PRECLINICAL DEVELOPMENT. DR. VALAT HAS EXTENSIVE EXPERIENCE IN THE TECHNICAL AND THE SCIENTIFIC MANAGEMENT OF IN VITRO EXPERIMENTS, AS PROVEN BY THE WORK THAT SHE HAS DONE AT BOLDEN THERAPEUTICS IN IDENTIFYING THE LEAD ASOS. IN THE WORK PROPOSED SHE WILL NOW TAKE A LEADING ROLE IN DIRECTING THE KEY IN VIVO PRECLINICAL PHASE OF THERAPEUTIC DEVELOPMENT - A CRITICAL STEP FOR ANY PHARMACEUTICAL COMPANY. DR. VALAT'S ENTREPRENEURIAL DEVELOPMENT WILL BE GUIDED BY THREE SEASONED CO- MENTORS WHO BRING SKILLS AND EXPERIENCE IN DISCOVERY SCIENCE, INTERACTING WITH THE FDA, CONDUCTING CLINICAL TRIALS, CARING FOR PATIENTS, STARTING COMPANIES, BUSINESS DEVELOPMENT, FUNDRAISING, AND INVESTING IN NOVEL SCIENTIFIC DISCOVERIES. THUS, THIS AWARD WILL ALLOW HER TO TRANSITION WITH SUCCESS FROM BENCH WORK TO AN ENTREPRENEURIAL POSITION. IN PARALLEL TO THIS HANDS-ON EXPERIENCE, DR. VALAT WILL ALSO BENEFIT FROM A RANGE ENTREPRENEURSHIP AND CAREER DEVELOPMENT PROGRAMS FROM LABCENTRAL, A PREMIER BIOTECH INCUBATOR WHERE SHE IS CURRENTLY PERFORMING BOLDEN'S RESEARCH, PROGRAMS OFFERED BY THE NIH SUCH AS I-CORPS, AND FROM AN INTENSIVE ENTREPRENEURSHIP DEVELOPMENT PROGRAM OFFERED AT MIT. OVERALL, THIS AWARD WILL COMPLEMENT DR. VALAT'S EXPERTISE AND ENABLE HER TO ADVANCE HER SKILLSETS BOTH AS A RESEARCH SCIENTIST AND AS A FUTURE LEADER IN THE BIOTECHNOLOGY INDUSTRY.

404707.42

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0.00

2022-06-14

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Department of Health and Human Services

PROMOTING ADULT HIPPOCAMPAL NEUROGENESIS USING ANTISENSE OLIGONUCLEOTIDES AS AN ALZHEIMER'S DISEASE THERAPY - PROJECT SUMMARY THERE IS AN ENORMOUS NEED FOR THERAPEUTICS TO PREVENT AND TREAT ALZHEIMER'S DISEASE (AD). ADULT HIPPOCAMPAL NEUROGENESIS (AHN) IS CRITICAL FOR NORMAL LEARNING AND MEMORY, BUT IT DECLINES IN PATIENTS WITH AD. WORK IN ANIMAL MODELS HAS UNDERSCORED THE ROLE OF AHN IN IMPROVING COGNITION IN THE FACE OF AD PATHOLOGY. THUS, RESTORING AHN HAS EMERGED AS AN ATTRACTIVE TARGET FOR AN AD THERAPY. AUGMENTING AHN IN THE DISEASED BRAIN IS WIDELY CONSIDERED A POTENTIAL THERAPEUTIC MODALITY FOR THE TREATMENT OF AD AS WELL AS FOR OTHER DISEASE STATES CHARACTERIZED BY DIMINISHED NEUROGENESIS E.G., FRONTOTEMPORAL DEMENTIA, TREATMENT-RESISTANT DEPRESSION, POST TRAUMATIC STRESS DISORDER, AND STROKE. HOWEVER, DRUG DEVELOPMENT EFFORTS TO DATE HAVE LACKED SUFFICIENT SPECIFICITY TO SELECTIVELY INCREASE AHN WITHOUT PERTURBING OTHER STEM CELL REGULATORY MECHANISMS. IN THIS PHASE I EFFORT, BOLDEN THERAPEUTICS WILL TEST EXON-SKIPPING ANTISENSE OLIGONUCLEOTIDES (ASOS) AGAINST AN UNDISCLOSED TARGET EXPRESSED IN NEURAL STEM CELLS TO INCREASE AHN. THESE CANDIDATE EXON-SKIPPING ASOS SUCCESSFULLY SKIP THE TARGET REGION OF INTEREST IN CULTURED CELLS AND DEMONSTRATE FAVORABLE CHARACTERISTICS. WE WILL USE THESE ASOS IN WILD-TYPE AND AD MOUSE MODELS TO EVALUATE THEIR EFFECT ON AHN, DISEASE PATHOLOGY, AND COGNITION. EXON-SKIPPING ASOS HAVE EMERGED AS EFFECTIVE AND SAFE AGENTS FOR REGULATING ALTERNATIVE SPLICING IN THE CNS. DETERMINING IN VIVO EFFICACY OF OUR CANDIDATE COMPOUNDS IS A CRITICAL STEP TOWARDS DEVELOPING A HIGHLY TARGETED, SAFE AND EFFECTIVE THERAPEUTIC FOR PROMOTING AHN AND IMPROVING COGNITION IN AD. FOLLOWING THESE STUDIES, THE EXON-SKIPPING ASOS WILL BE READY FOR IND-ENABLING EXPERIMENTS AND RAPID PRECLINICAL DEVELOPMENT AS WE WORK TOWARDS DEVELOPING A SAFE AND EFFECTIVE THERAPY FOR AD AND OTHER DISORDERS OF IMPAIRED COGNITION VIA INCREASING AHN.

496952.00

0.00

0.00

2021-09-13

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Department of Health and Human Services

PROMOTING ADULT HIPPOCAMPAL NEUROGENESIS IN ALZHEIMER'S DISEASE USING AN ANTIBODY-BASED THERAPY - PROJECT SUMMARY ALZHEIMER'S DISEASE (AD) IS A LOOMING PUBLIC HEALTH CRISIS THAT THREATENS MILLIONS OF PATIENTS' ABILITY TO EXPERIENCE HEALTHY AGING. IN ADDITION TO THE CHALLENGES THAT AD POSES TO PATIENTS, HEALTHCARE PROVIDERS AND CAREGIVERS, THERE IS ALSO TREMENDOUS ECONOMIC BURDEN ASSOCIATED WITH AD AND RELATED DEMENTIAS – ESTIMATED TO BE WELL OVER $200B/YEAR IN THE UNITED STATES ALONE. HUNDREDS OF ATTEMPTS TO DEVELOP THERAPIES TO HALT THE PROGRESSION OF OR REVERSE AD HAVE BEEN TRIED, BUT UNFORTUNATELY NONE HAVE BEEN SUCCESSFUL TO DATE. THE RESULTS OF THESE STUDIES STRONGLY SUPPORT THE PURSUIT OF NEW THERAPEUTIC MODALITIES AND MOLECULAR TARGETS. ADULT HIPPOCAMPAL NEUROGENESIS (AHN) HAS LONG BEEN APPRECIATED AS CRITICAL FOR NORMAL LEARNING AND MEMORY IN RODENTS, HOWEVER ITS ROLE IN HUMANS HAS HISTORICALLY BEEN LESS CLEAR. SEVERAL PRECLINICAL STUDIES HAVE UNDERSCORED THE ROLE OF AHN IN IMPROVING COGNITION IN AN AD ENVIRONMENT. CRITICALLY, SEVERAL RECENT STUDIES HAVE SUPPORTED THAT AHN IS ALSO ROBUST IN HUMANS AND PERSISTS THROUGHOUT LIFE IN HEALTHY ADULTS, BUT DECLINES DRAMATICALLY IN AD PATIENTS. THUS, RESTORING AHN HAS EMERGED AS AN ATTRACTIVE TARGET FOR EARLY INTERVENTION, AMELIORATING OR DELAYING THE ONSET OF AD SYMPTOMS. IN THE PROPOSED EXPERIMENTS, BOLDEN THERAPEUTICS WILL DEVELOP THERAPEUTIC MONOCLONAL ANTIBODIES (MABS) THAT REDUCE BONE MORPHOGENETIC PROTEIN (BMP) SIGNALING IN NEURAL STEM CELLS IN VIVO TO INCREASE AHN VIA TARGETING A NOVEL BMP CO-RECEPTOR. BMP SIGNALING IS AN IMPORTANT NEGATIVE REGULATOR OF ADULT NEUROGENESIS, AND INCREASES BOTH IN NORMAL AGING AND IN AD. INHIBITING BMP SIGNALING HAS BEEN SHOWN TO INCREASE NEUROGENESIS, AND THAT IS THE EXPECTED OUTCOME OF OUR PROJECT. THE MABS WILL BE GENERATED BY IMMUNIZING PROPRIETARY, KNOCK- IN MICE, WHICH ARE EXPECTED TO HAVE A MORE ROBUST IMMUNOLOGICAL RESPONSE AND WILL OVERCOME TOLERANCE. THE MOST PROMISING MAB CANDIDATE WILL BE ADMINISTERED USING BOTH DIRECT HIPPOCAMPAL STEREOTACTIC INJECTION AND SYSTEMIC DELIVERY IN AD MICE TO PROVIDE PROOF OF CONCEPT DATA FOR AUGMENTING AHN IN THE SETTING OF DISEASE PATHOLOGY. THESE STUDIES WILL SUPPORT FUTURE PHASE II STUDIES FOR FURTHER CHARACTERIZATION OF THE MAB, INCLUDING EVALUATING ITS EFFECT ON NOT ONLY NEUROGENESIS, BUT ALSO COGNITION AND ADDITIONAL PATHOLOGICAL HALLMARKS (E.G., AMYLOID, TAU, INFLAMMATION). ULTIMATELY, OUR GOAL IS THAT THESE STUDIES WILL ENABLE BOLDEN TO GENERATE THE REQUISITE DATA PACKAGE TO BEGIN CLINICAL DEVELOPMENT OF A PRO-NEUROGENIC THERAPEUTIC ANTIBODY FOR IMPROVING THE CLINICAL COURSE IN MCI/AD, AS WELL AS POTENTIALLY IN OTHER NEUROLOGICAL INDICATIONS.

896442.35

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