Patients with late-onset Alzheimer’s disease and other dementias suffer the loss of memories, independence and ultimately life. No treatments have yet been found that stop or even slow the progression of these diseases, which take a major emotional and financial toll on patients’ families and communities.
Studying these diseases is also fraught with challenges for researchers and clinicians. While certain genetic risk factors have been associated with dementias, there is no specific gene that directly causes them, yet hundreds of genes, as well as various environmental factors, have been implicated. (A rare, early-onset form of Alzheimer’s does have a clear genetic component.) That means that to date there is no genetic test that can signal the presence of disease before symptoms of dementia develop late in life; in fact, Alzheimer’s can be definitively diagnosed only after the patient’s death.
A promising new approach to finding effective treatments is to study human brain cells that carry mutations found in Alzheimer’s patients. Thanks to human induced pluripotent stem cell (iPSC) and gene-editing technologies, it’s possible to derive every kind of brain cell type, insert dementia-related genes and study them in culture.
The National Institutes of Health has contracted with The Jackson Laboratory (JAX) to develop a collection of more than 400 engineered iPS cell lines representing Alzheimer's disease and related dementias (ADRD). These iPS cells will be available to the scientific community as an open resource and as a tool to characterize how mutations change fundamental biological properties of disease-relevant cell types.
JAX Professor leads the large-scale editing project in collaboration with Mark R. Cookson, Ph.D., senior investigator in the Laboratory of Neurogenetics at the National Institute on Aging (NIA), and Michael E. Ward, M.D., Ph.D., investigator in the Inherited Neurodegenerative Diseases Unit of the National Institute of Neurological Disorders and Stroke.
The new three-year contract, totaling $6,323,255, follows a five-year NIH contract with this team announced in October 2019 to establish a community resource of human disease models of neurodegenerative disease by engineering disease-causing mutations in a set of well-characterized, genetically diverse iPS cells. The new project is dubbed iNDI-Plus, generating additional alleles for the iPSC Neurodegeneration Initiative (iNDI) project.
“This second NIH contract will permit us to expand the resource of ADRD iPS cell models and provide additional quality control of the edited cell lines,” Skarnes says. And, to control for any unintended genetic changes that may have occurred during CRISPR-Cas9 editing of the cells, he says the team will create additional, revertant sets of cell lines in which the disease-causing mutations are canceled out.
Cookson notes that generating these revertant lines “is a critical way to control for off-target effects in the genome of iPS cell lines, and one that we hope will become a standard for these types of experiments in the future.”
The team will use other technologies — knockout and HaloTag knock-in — to generate additional cell lines, to provide researchers with a complete set of cellular tools for cell biological and biochemical studies of the disease process.
“In this extension to our prior work between NIA, NINDS and JAX,” Cookson comments, “we are promoting open science while making sure we provide the highest quality reagents to the field.”
iPSC NeuroDegeneration Initiative project (iNDI-Plus), National Institute on Drug Abuse, contract number 75N95020P00621