Indiana University Receives $11.3 Million NIH Grant to Advance SHIP1 Inhibitor for Alzheimer's Disease
核心洞察
Indiana University School of Medicine researchers received a five-year, $11.3 million NIH grant to develop SHIP1 (搜索) inhibitors targeting the INPP5D (搜索) gene, which acts as a brake on microglia (搜索) function in Alzheimer's disease (搜索).
The TREAT-AD (搜索) drug discovery center has narrowed down hundreds of potential drug targets to five promising candidates, with SHIP1 (搜索)/INPP5D (搜索) leading as the most advanced therapeutic target.
Researchers aim to optimize small molecules that block SHIP1 (搜索) protein, potentially making microglia (搜索) more effective at clearing harmful amyloid plaques (搜索) in the brain.
A team of researchers from Indiana University School of Medicine has secured a five-year, $11.3 million grant from the National Institute on Aging to advance a promising new therapeutic approach for Alzheimer's disease (搜索). The funding, awarded in December 2024, will support the development of small molecule inhibitors targeting SHIP1 (搜索), a protein that regulates microglia (搜索) function in the brain.
The research focuses on the INPP5D (搜索) gene, which encodes the SHIP1 (搜索) protein and has been identified as a risk gene for Alzheimer's disease (搜索). Timothy Richardson, senior research professor of medicine and lead investigator, explained that SHIP1 acts like a brake on microglia (搜索) function. "We believe inhibitors will make these immune cells more effective at cleaning up harmful proteins, like taking the foot off the brake of a snowplow and stepping on the gas to clear snow from the road more quickly," Richardson said.
TREAT-AD Center Identifies Key Therapeutic Targets
The grant builds on foundational work from the TREAT-AD (搜索) (Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (搜索)) drug discovery center, led by Richardson and co-principal investigators at IU School of Medicine. The center, which received a separate five-year, $41.6 million grant renewal in December 2024, has systematically evaluated hundreds of potential drug targets and narrowed the focus to a portfolio of five novel targets, with INPP5D (搜索)/SHIP1 (搜索) leading the way.
TREAT-AD (搜索) represents a partnership between researchers at IU School of Medicine, Purdue University, the Indiana Biosciences Research Institute, Lgenia Inc., and the University of Pittsburgh. The center initially focused on proteins related to microglia (搜索) function that may contribute to and protect against Alzheimer's disease (搜索), narrowing down hundreds of potential targets to 30 before selecting the five most promising candidates.
Targeting Brain Immune Function
Microglia (搜索) serve as the brain's primary immune cells, acting as the first line of defense against viruses, neurotoxins, and damaged neurons. These cells have been found to clear amyloid plaques (搜索), a hallmark of Alzheimer's disease (搜索) that contributes to its progression. The research team aims to optimize small molecules into drug candidates that block SHIP1 (搜索), potentially enhancing microglia's ability to remove harmful proteins from the brain.
Adrian Oblak, associate professor of radiology and imaging sciences and co-principal investigator, spearheaded research to uncover molecular mechanisms of INPP5D (搜索). "Our lab realized that TREAT-AD (搜索)'s infrastructure and expertise would allow us to delve deeper into the druggable aspects of INPP5D," Oblak said. "We saw this partnership as a way to access cutting-edge drug discovery platforms, advanced molecular tools and the collective expertise of a collaborative network."
Comprehensive Research Approach
The grant will enable researchers to develop better inhibitors of SHIP1 (搜索)/INPP5D (搜索) by studying and optimizing compounds that block the protein and allow microglia (搜索) to work more effectively in the brain to clear plaques. The team will test these inhibitors in Alzheimer's disease (搜索) mouse models, evaluating how they inhibit SHIP1, activate microglia, and whether they slow cognitive decline and improve brain health.
Richardson and his team will focus on developing the most promising compounds for clinical studies in humans. They will also identify biomarkers measurable using blood and cerebrospinal fluid that can track a potential drug's activity and effectiveness in clinical trials.
Alternative Therapeutic Strategy
In addition to the main grant, Richardson and Oblak received a separate five-year, $4 million grant in June from the National Institute on Aging to explore an alternative approach to inhibiting SHIP1 (搜索). Working with Travis Johnson, assistant professor of biostatistics and health data science, they found that certain forms of INPP5D (搜索) are differentially expressed in Alzheimer's patients compared to cognitively normal, age-matched control patients.
Richardson's lab is designing small interfering RNAs (siRNAs) that harness the cell's natural machinery for regulating gene expression. The siRNAs will be tested using animal models of Alzheimer's disease (搜索) to investigate whether microglia (搜索) can reduce amyloid plaques (搜索) and improve brain health, with results compared to the small-molecule research.
Clinical Context and Future Outlook
Alzheimer's disease (搜索) impacts more than 6 million Americans and is projected to affect nearly 13 million by 2050, according to the Alzheimer's Association. Over the past few years, the FDA has approved two disease-modifying antibody drugs for Alzheimer's disease—lecanemab in 2023 and donanemab in 2024—that reduce amyloid plaques (搜索) in the brain.
With these antibodies establishing a new baseline for clinical management of select patients in early stages of Alzheimer's disease (搜索), Richardson noted there's an opportunity to study the potential efficacy and safety of next-generation drugs and how they could be used individually or in combination with existing treatments.
"There is still a need for more effective, safer and less expensive treatments," Richardson said. "We are looking forward to a future when Alzheimer's disease (搜索) is a preventable and treatable disease like diabetes and cardiovascular diseases."
The TREAT-AD (搜索) center plans to expand its scope over the next five years, investigating additional drivers of neuroinflammation in the brain and broadening its toolbox to include antibodies and oligonucleotides. The center will also place greater emphasis on biomarkers through the work of Jeff Dage, who led the discovery and development of phosphorylated tau (搜索) 217 as a novel blood biomarker for Alzheimer's disease (搜索) clinical trials.