The Vagelos Precision Medicine Supplemental Funding for Models of Human Disease Award Announcement

Awarded by the Columbia Precision Medicine Initiative (CPMI), these Pilot Awards underscore Columbia’s commitment to supporting research targeting the promise of precision medicine, across multiple diseases. These awards are a cornerstone of the CPMI mission: to establish world class academic research centers of excellence to build precision medicine as a basic and applied science at Columbia.

The proposals reflect the high standard and the broad base of precision medicine basic science research being conducted and conceived at Columbia. They include an innovative lagomorph model with the potential to become a standard gene therapy tool; a zebrafish Alzheimer disease model to study the role of the blood brain barrier; and a mouse model to investigate the molecular mechanisms contributing to mitochondrial eye diseases.

Further details of the models are below.

“Precision Single Nucleotide Variant (SNV)-Mediated Ablation in an FDA-Compliant Humanized Lagomorph Model of Autosomal Dominant Disorder”
Lead Investigator: Stephen Tsang, MD, PhD

The development of an FDA-compliant humanized lagomorph model, engineered with patient-specific DNA, marks a significant advancement in preclinical testing for CRISPR-based therapeutic editing. This large animal model provides an alternative to non-human primates for Investigational New Drug-enabling studies. Specifically designed with patient-specific genetic mutations, the humanized lagomorph is ideal for evaluating CRISPR therapies that precisely target patient DNA sequences. The model adheres to FDA guidelines for pharmacokinetic, toxicological, and biodistribution studies, ensuring regulatory compliance while delivering critical data on systemic toxicity and therapeutic efficacy. By accelerating the transition from preclinical studies to human trials, this engineered lagomorph model improves the translatability of therapeutic findings, creating a streamlined path toward the implementation of precision medicine.

“Functional analyses of ADAMTS1 missense gene variant segregating in families with AD identified in the National Institute on Aging Alzheimer's disease family-based study (NIA-AD FBS)”
Lead Investigator: Caghan Kizil, PhD

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder characterized by cognitive decline and memory loss. Recent studies in large multiethnic AD cohorts in families have identified a rare missense variant in the ADAMTS1 gene, which segregates within families affected by AD in the National Institute on Aging Alzheimer’s Disease Family Based Study. ADAMTS1 is crucial for extracellular matrix organization, angiogenesis, and tissue remodeling, and has been implicated in amyloid-beta degradation and blood-brain barrier (BBB) integrity—key factors in AD pathology. This proposal aims to investigate the functional impact of the ADAMTS1 variant using a zebrafish model, given their genetic similarity to humans and suitability for in vivo studies. The gene is 94% conserved in humans and zebrafish, the mutated residue is identical. We will generate zebrafish carrying the precise ADAMTS1 point mutation identified in humans to explore its effects on brain function, BBB integrity, and amyloid-beta regulation through molecular, histological, and omics analyses. By leveraging zebrafish’s transparency and ease of genetic manipulation, we will conduct comprehensive in vivo imaging, behavioral assays, and transcriptomic, proteomic, and metabolomic profiling. Our research addresses the need for precision medicine approaches by focusing on ethnicity-dependent genetic variations and their contributions to AD. This study will provide insights into the mechanistic roles of ADAMTS1 in AD, identify potential therapeutic targets, and advance the development of tailored treatments for diverse populations. The anticipated outcomes include a deeper understanding of AD pathology and the establishment of zebrafish as a valuable model for studying genetic variants associated with neurodegenerative diseases.

“A mouse model with defective mtDNA maintenance”
Lead Investigator: Nan-Kai Wang, MD, PhD

This research focuses on the SSBP1 gene, essential for mitochondrial DNA (mtDNA) synthesis and protection. Mutations in this gene cause Optic atrophy-13 (OPA13), leading to vision loss due to optic atrophy and retinal degeneration. These mutations disrupt SSBP1 function, affecting mtDNA replication and causing mtDNA depletion. The study aims to determine if the disease mechanism is due to haploinsufficiency or a dominant-negative effect. Previous zebrafish studies were inconclusive, so mouse models are preferred for their similar eye anatomy to humans and genetic tool availability. Germline knockout of Ssbp1 results in embryonic lethality and reduced mtDNA in heterozygous mice, highlighting SSBP1’s critical role. Therefore, knock-in mouse models are needed to understand OPA13 mechanisms. A mouse model with a specific Ssbp1 mutation will be created and studied for pre-clinical treatment exploration. This research aligns with precision medicine by tailoring treatments to the genetic makeup of the disease, potentially leading to therapies that improve mitochondrial function and prevent vision loss.