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Research Programs

iPSC Neurodegenerative Disease Initiative (iNDI)

Computer generated graphic of immature stem cells sitting on a strand of DNA.

Researchers have identified more than 50 regions of the genome (called loci) that contain variants that may increase the risk for the disease. To develop effective treatments for Alzheimer’s and related dementias, we must identify how individual mutations impact cellular pathways and contribute to Alzheimer’s and related dementias pathology. However, this requires readily available, disease-relevant cellular models of Alzheimer’s and related dementias and phenotypic datasets of the effects of gene mutations on cellular pathways, which are not currently available in the field.

We will create a foundational repository of isogenic-induced pluripotent stem cell (iPSC) lines using CRISPR/Cas9-based genetic engineering. Our target goals are 132 variants across 72 AD/ADRD genes, eight of which are known AD-related genes, 15 are genes linked to dementia with Lewy bodies/Parkinson’s disease, 28 genes are associated with frontotemporal dementia/amyotrophic lateral sclerosis, and 21 are genes associated with other neurodegenerative disorders.

For each gene variant, we will engineer:

  • Heterozygous clones for the disease-associated single nucleotide variant
  • Homozygous clones for the disease-associated single nucleotide variant
  • Revertant clones
  • Gene knockout clones
  • Halotag gene and variant knock-in clones

Each of these lines will undergo rigorous quality control and be made publicly available to the research community.

The iNDI cell lines are now available on the Jackson Laboratories website. New lines will continue to be added in the coming months.

Overview of the iNDI Project

Graphic showing the flow of the iNDI project, including the scope: gene and mutant identification, phase 1: identify iPSC and CRISPR, and phase 2: cell culture to break down and identify mutants and add to them data repository.
From Ramos DM et al., Tackling neurodegenerative diseases with genomic engineering: A new stem cell initiative from the NIH, Neuron,109 (7), 2021, 1080-1083, DOI: https://doi.org/10.1016/j.neuron.2021.03.022