. Tackling neurodegenerative diseases with genomic engineering: A new stem cell initiative from the NIH. Neuron. 2021 Apr 7;109(7):1080-1083. PubMed.


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  1. This is an extremely helpful initiative that will have a huge impact on iPSc research in relation to AD and other neurodegenerative disorders. There are many advantages to studying human neurons and glial cells as models for these disorders. Rodent models may be incapable of capturing some of the properties of mammalian neurons, for example, and certainly do not display the pathological phenotypes of the neurodegenerative diseases.

    To date, iPSc studies have used fibroblasts, lymphoblasts, or other cells to derive pluripotent cells and then differentiate them. Almost every laboratory uses its own cell lines, however, hence factors such as variability of genetic backgrounds of donors, limited phenotyping of differentiated cells, and failure to use isogenic controls, can make findings difficult to interpret.

    Knocking in a host of different pathogenic mutations that cover AD, FTD, DLB, and ALS against a background of a few standard cell lines originating from healthy donors is a marked improvement in standardization. The multi-omic characterization of differentiated neurons, astrocytes, and microglia from such well-controlled cell lines will provide a remarkably rich reference database. This project will enable data from iPSc to be integrated into large-scale, systems-biology efforts such as AMP-AD, AMP-PD, and others. The cell lines that result from this initiative will be invaluable for researchers.

    View all comments by Douglas Galasko
  2. The iPSC Neurodegenerative Disease Initiative (iNDI) is a herculean effort led by Mark Cookson and Michael Ward at the NIH to provide well-characterized hiPSC lines that harbor hundreds of mutations and/or variants that contribute to Alzheimer’s disease and related dementias (ADRD). The data and cell lines generated in this resource will be incredibly useful to both individual labs, such as my own, and the larger research community, especially those who want to analyze human data without the burden of setting up a cell culture program.

    The quality-control measures proposed for this project are impressive, and they are necessary to ensure experimental reproducibility. It is also good that these mutations will be generated in several donor cell lines, taking into account human genetic background. Indeed, I look forward to more information on the genetic backgrounds to be chosen, including ethnicity.

    However, many cases of ADRD cannot be mapped to a single polymorphism or mutation but are possibly the accumulation of multiple “low-risk” variants that interact with the environment. While it is, of course, very challenging to incorporate all the factors that lead to ADRD in a cellular model, we should not discount the value of well-characterized hiPSC lines from well-studied populations, from whom clinical and neuropathologic data can also be incorporated into the datasets.

    View all comments by Jessica Young

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  1. iNDI Aims to Standardize Human Stem Cell Research