Aug 2026· Stem Cell Research· Vol 95, pp.
104073
· 0 citations· 36 references
Medicine
TL;DR
An integrated collection of genetically defined iPSC lines and associated clinical data provides a powerful platform for investigating disease mechanisms and advancing iPSC-based drug discovery for NDDs.
Abstract
In this manuscript, we report the development of a comprehensive resource designed to harness the transformative potential of patient-derived induced pluripotent stem cells (iPSCs) to advance the study of neurodevelopmental disorders (NDDs). Using CRISPR-Cas-mediated genome editing, the Human Neuron Core generated a repository comprising 29 isogenic iPSC pairs, two sex-matched parental control iPSC pairs, and one unmatched patient line representing six monogenic NDDs: Tuberous Sclerosis Complex, PTEN Hamartoma Tumor Syndrome, KCNQ2 Developmental and Epileptic Encephalopathy, FOXG1 Syndrome, Phelan-McDermid Syndrome, and SETBP1 Haploinsufficiency Disorder. In parallel, detailed clinical phenotyping data were collected to enable comparison of cellular phenotypes with clinical severity in future studies. This integrated collection of genetically defined iPSC lines and associated clinical data provides a powerful platform for investigating disease mechanisms and advancing iPSC-based drug discovery for NDDs.
We report the generation and characterization of a human induced pluripotent stem cell (iPSC) line derived from dermal fibroblasts of a patient with Skogholt’s disease, a rare maternally inherited neurodegenerative syndrome associated with choroid plexus dysfunction and impaired cerebrospinal fluid (CSF) homeostasis. Patient fibroblasts were reprogrammed using the non-integrating Repro-OSKGM kit. The resulting iPSC line exhibited typical pluripotent morphology, expressed canonical pluripotency markers, maintained a normal karyotype, retained the disease-associated genetic variant, was mycoplasma-free, and demonstrated trilineage differentiation potential. We also made choroid plexus (ChP) like organoids from the generated iPSCs. This patient-specific iPSC line provides a valuable resource for generating choroid plexus organoids and neurons to investigate disease mechanisms and develop therapeutic strategies.
DOK7-related Congenital Myasthenic Syndrome (CMS) is a rare genetic neuromuscular junction disorder. This is one of the most common of the recessive forms of CMS, often presenting with more static proximal weakness (hence also referred to as limb girdle CMS). Whole-genome sequencing of affected patients implicates frameshift duplication mutations in DOK7 as drivers of impaired neuromuscular-junction signaling. In this study, we generated a human induced pluripotent stem cell (hiPSC) line TRNDi045-A-38 from the KOLF2.1J reference line, engineered to carry homozygous DOK7 c.1124_1127dupTGCC mutation knock-in using CRISPR/Cas9. This iPSC line could be used for in vitro disease modeling to study disease pathophysiology and for therapeutic development.
B. M. Jones, Miao Xu, J. Zou et al.· Stem Cell Research· 0 citations
The YARS2 variant, harboring the compound heterozygous pathogenic mutations F185L/E264del, was identified in the gene for mitochondrial tyrosyl-tRNA synthetase in a proband that suffered a neonatal phenotype. To facilitate studies to better understand the severity of the mutations, we created a patient-derived inducible pluripotent stem cell (iPSC) model. We first derived iPSCs from fibroblasts of the patient Q1818, which contain two mutations, c.553T>C (p.F185L) and c.792_794delAGA (p.E264del) in the YARS2 gene. We then generated three isogenic control iPSC lines with one or both mutations corrected by using CRISPR-Cas9 technology. The correction of mutations in YARS2 was confirmed by Sanger sequencing. The stemness of iPSC lines was demonstrated by the expression of stem cell markers in the iPSCs, as determined using qPCR, immunostaining, and trilineage differentiation. Moreover, three positive clones of each iPSC line were extensively characterized, confirming that they originated from Q1818 fibroblasts, had normal karyotypes, and did not contain off-targets in the YARS2 coding sequence; genome wide off target effects were not a major concern. Subsequently, Q1818 iPSCs and the three isogenic control iPSCs were differentiated into clinically relevant motor neurons. In addition, we demonstrated that the patient fibroblasts and the derived iPSCs are heterozygous for either c. 553T>C or c.792_794delAGA, and that the two mutations are located on different alleles of the YARS2 gene, providing critical information for studying the mutation-associated disease. In conclusion, we have generated a set of four iPSC lines, which can be used as a model to study a clinically severe case of YARS2 disease.
Chen-Bo Zeng, Andrew Gray, R. Ganetzky et al.· International Journal of Ste...· 0 citations
Fabry disease is an X-linked lysosomal storage disorder caused by pathogenic variants in the α-galactosidase A (α-Gal A, GLA) gene. The disease exhibits substantial clinical heterogeneity, with renal injury representing one of its most prominent manifestations. Due to the scarcity of human renal specimens and the inability of conventional animal models to recreate patient-specific pathological features, the precise mechanism underlying renal-predominant Fabry disease remains poorly understood. In this study, we successfully established and comprehensively characterized a urine-derived induced pluripotent stem cell (iPSC) line from a 35-year-old male patient with classic Fabry disease with a typical renal-dominant phenotype. The patient carried the GLA c.1080_1082delTGG (p.Gly361del) variant. Non-integrating episomal reprogramming was used to generate monoclonal iPSCs, which were further validated for pluripotency, trilineage differentiation ability, genomic stability, and exogenous vector clearance. The established iPSC line stably retained the patient-specific pathogenic variant, exhibited full pluripotent properties, and showed no genomic abnormality or residual episomal integration. Therefore, this well-characterized renal-phenotype-specific iPSC line provides a reliable cellular platform for investigating the mechanisms of progressive Fabry disease nephropathy and can facilitate future targeted drug screening.
Guowei Li, Jing Luan, Zihan Li et al.· Intractable & Rare Diseases...· 0 citations
The development of new therapeutics and the validation of pathogenetic cancer mechanisms require representative laboratory models1,2. However, existing collections represent only a fraction of the diversity observed in human cancer2-4. Recent technologies have enabled efficient in vitro model derivation (for example, tumour organoids)5. However, whether these maintain essential properties of patient tumours during long-term expansion has not been systematically investigated. Here we present results of a large-scale international programme-the Human Cancer Models Initiative-which involved the generation of a resource of 665 next-generation models from 2,780 donors with 25 cancer types and integrated tumour-model whole genome, exome, methylome and transcriptome analyses. The resource provides 522 models with comprehensive clinical data, 153 models of rare cancers and 71 models from participants with non-European ancestry. Analyses of 421 matched tumour-model pairs reveal high genetic (97.8%) and epigenetic (95%) concordance and define correlates of model discordance. Single-nucleus RNA sequencing of tumour-model pairs reveals subsets of models in which culture conditions significantly influence cell states. Finally, we characterize model preservation of extrachromosomal DNA and post-treatment mutational signatures to provide opportunities to study therapeutic resistance. This model repository is being made available to the community-including multimodal molecular profiling, clinical information and integrative software tools-thus providing a valuable resource for preclinical investigation of cancer pathogenesis and treatment response.
Dina Elharouni, Mushriq Al-Jazrawe, Seongmin Choi et al.· Nature· 2 citations
Two human induced pluripotent stem cell lines from a female FD patient carrying a heterozygous c.644A > G missense mutation provide a valuable resource for studying FD mechanisms and developing therapeutic strategies.
Nick Heise, Carla Borisch, Christopher Jahn et al.· Stem Cell Research· 0 citations
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