There is an enormous need for therapeutics to prevent and treat Alzheimer's disease (AD). Adult HippocampalNeurogenesis (AHN) is critical for normal learning and memory, but it declines in patients with AD. Work inanimal 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 brainis widely considered a potential therapeutic modality for the treatment of AD as well as for other disease statescharacterized by diminished neurogenesis e.g., frontotemporal dementia, treatment-resistant depression, posttraumatic stress disorder, and stroke. However, drug development efforts to date have lacked sufficientspecificity to selectively increase AHN without perturbing other stem cell regulatory mechanisms. In this PhaseI effort, Bolden Therapeutics will test exon-skipping antisense oligonucleotides (ASOs) against an undisclosedtarget expressed in neural stem cells to increase AHN. These candidate exon-skipping ASOs successfully skipthe target region of interest in cultured cells and demonstrate favorable characteristics. We will use theseASOs 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, theexon-skipping ASOs will be ready for IND-enabling experiments and rapid preclinical development as we worktowards developing a safe and effective therapy for AD and other disorders of impaired cognition via increasingAHN.
Public Health Relevance Statement: Project narrative: There is a tremendous need for new approaches for treating neurological disease,
especially Alzheimer's disease. These experiments will test lead candidate antisense oligonucleotides for in
vivo efficacy in wild-type mice and two mouse models 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.
Project Terms: <21+ years old> | | | 