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.
Public Health Relevance Statement: There is a tremendous need for new approaches for treating neurological diseases, especially Alzheimer's disease. The experiments set forth in this Entrepreneurial Development application will test lead candidate antisense oligonucleotides for in vivo efficacy in wild-type mice and a widely used mouse model of Alzheimer's disease. If successful, these experiments will enable rapid preclinical development of a first-in-class therapeutic targeting adult hippocampal neurogenesis for the treatment or prevention of Alzheimer's disease and also serve to support the training of the PI towards a career as an entrepreneur.
Project Terms: <21+ years old>| <Ï Proteins> | | | 