iNDI-PD

ASAP is supporting iNDI-PD (an expansion to the original iPSC Neurodegenerative Disease Initiative (iNDI) and anchored within the NIH Center for Alzheimer’s and Related Dementias (CARD)) to make iPSC resources accessible to all researchers interested in understanding Parkinson’s disease (PD) to discover novel insights into the molecular biology of disease and to ensure that additional mutations relevant to PD research are also included in their efforts​. By incorporating PD data in the neurodegenerative resource bank, we are also enabling researchers to draw connections across diagnostic lines. These cell lines will allow researchers to attribute observed changes to specific mutations more quickly – cutting through the noise of genetic variation – and more confidently.

Induced pluripotent stem cells (iPSCs) are derived from adult cells such as skin or blood and reprogrammed back into pluripotent stem cells. These appealing research tools create the ability to study a disorder in disease-relevant cell types from real patients. However, donors who provide these cells carry innumerable genetic differences, making it hard to pinpoint whether an observation is due to a disease-causing mutation or something else in the patient’s genetic makeup.

iNDI introduces disease-causing mutations to a set of cell lines that all have the same genetic background (called isogenic lines). iNDI is led by Mark Cookson, Ph.D., of the National Institute on Aging, and Michael E. Ward, M.D., Ph.D., of the National Institute of Neurological Disorders and Stroke, both parts of the National Institutes of Health. The initiative was initially funded to model more than 100 mutations associated with Alzheimer’s disease and related dementias in isogenic iPSC lines.

“iNDI is the largest iPSC genome engineering initiative in research to date. The expansion of iNDI to include additional PD lines will allow us not only to discover novel insights into the molecular biology of disease but also to draw connections across diagnostic lines.”

–Mark Cookson, PhD, iNDI Principal Investigator

Overview of iNDI

iNDI is a large iPSC genome-engineering initiative, with more than 600 engineered daughter lines to be generated from each parental line. Companion lines will include revertants, Halo-tagged knockins, and knockouts.

[Courtesy of Ramos et al., Neuron, 2021.]

Phase 1:

iNDI will genetically engineer isogenic iPSC lines harboring many ADRD variants, knockouts, and endogenous tags across several deeply characterized parental lines from unaffected individuals. Following stringent quality control assays, each line will be available for distribution through The Jackson Laboratory (JAX).

Phase 2:

Using high-throughput robotic platforms, iNDI will differentiate mutation harboring iPSC lines into CNS-relevant cell types, such as neurons and microglia, followed by a series of phenotypic assays. These include transcriptomics, proteomics, imaging, and genetic interaction screens, yielding a rich multi-dimensional picture of how mutations disrupt cellular function. Open access datasets will enable the community to analyze these data in new ways.

Parkinson's Genes

iNDI already has some PD gene mutations of interest that are associated with dementia within its existing workflow.

Using CRISPR/Cas-mediated gene editing, iNDI-PD will:

  • Include a series of human isogenic iPSC lines expressing PD-associated mutations of interest that do not have dementia as a clinical phenotype. (See table for the list of potential mutations that the team is considering)
  • Create isogenic controls for genetic PD patient-derived iPSC lines (LRRK2p.G2019S, LRRK2p.R144G, GBA p.N370S, SNCA p.A53T) from the MJFF PPMI cohort
Genes

Mutations of Interest

SNCA

A53T 
A30P
E46K

LRRK2

G2019S
N2081D
R1441G
Y1699C
I2020T

GBA

L444P
N370S
E326K

PINK1

P399L
L347P
A217D

PRKN

R275W
P437L
T240M
R42P

TMEM175

M393T

Distribution of Tools

As PD cell lines become available, they will be characterized and deposited at JAX labs to ensure ease of distribution. Some cell lines may be available as early as the first quarter of 2022!
If you are interested in receiving alerts as new lines become available, click the button below.