CRISPR and iPSCs: Recent Developments and Future Perspectives in Neurodegenerative Disease Modelling, Research, and Therapeutics

Abstract

Neurodegenerative diseases are prominent causes of pain, suffering, and death worldwide. Traditional approaches modelling neurodegenerative diseases are deficient, and therefore, improved strategies that effectively recapitulate the pathophysiological conditions of neurodegenerative diseases are the need of the hour. The generation of human-induced pluripotent stem cells (iPSCs) has transformed our ability to model neurodegenerative diseases in vitro and provide an unlimited source of cells (including desired neuronal cell types) for cell replacement therapy. Recently, CRISPR/Cas9-based genome editing has also been gaining popularity because of the flexibility they provide to generate and ablate disease phenotypes. In addition, the recent advancements in CRISPR/Cas9 technology enables researchers to seamlessly target and introduce precise modifications in the genomic DNA of different human cell lines, including iPSCs. CRISPR-iPSC-based disease modelling, therefore, allows scientists to recapitulate the pathological aspects of most neurodegenerative processes and investigate the role of pathological gene variants in healthy non-patient cell lines. This review outlines how iPSCs, CRISPR/Cas9, and CRISPR-iPSC-based approaches accelerate research on neurodegenerative diseases and take us closer to a cure for neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, and so forth.

Efficient correction of ABCA4 variants by CRISPR-Cas9 in hiPSCs derived from Stargardt disease patients

“…hiPSCs have revolutionized basic research on human diseases and have generated interest as a potential cellular resource for treating pathologies. 24 , 47 The combination of CRISPR and hiPSCs is an important tool for disease study, modeling, and therapeutic applications. 24 Nonetheless, precise genome-editing in hiPSCs remains inefficient.…”

“… 24 , 47 The combination of CRISPR and hiPSCs is an important tool for disease study, modeling, and therapeutic applications. 24 Nonetheless, precise genome-editing in hiPSCs remains inefficient. 48 …”

“… 9 In addition, human induced pluripotent stem cells (hiPSCs) constitute a readily available source of patient-derived cells that could potentially be used for curative strategies, which is crucial because of the lack of cell resources and cell transplant rejection. 23 , 24 …”

“… 25 Nonetheless, low gene editing efficiency, potential adverse effects, and off-target effects must be considered and evaluated. 24 …”

Induced pluripotent stem cell-derived and directly reprogrammed neurons to study neurodegenerative diseases: The impact of aging signatures

“…Obligatory access to patient cell lines is a limitation of these approaches, since NDDs modeling needs the generation of iPSCs or iNs from large cohorts of patients, to comprise the genetic heterogeneity with respect to the disease-causing mutations. This limitation has been expunged by CRISPR/Cas9-edited disease models, which allow to introduce or correct any desired mutation, and to obtain isogenic cell lines carrying one or multiple disease-relevant mutations from a single iPSC background ( Sen and Thummer, 2022 ). In this review, we describe in more detail the differences in the aging status of iN- and iPSC-derived neurons and discuss the impact of these features in the disease modeling of NDDs.…”