In vitro disease modeling

In vitro disease modeling involves generating disease-specific induced pluripotent stem cells (iPSCs) from patient somatic cells carrying disease genes. These iPSCs are then differentiated into disease-related functional cells, such as neurons, allowing the replication of the genotypic and phenotypic characteristics of the disease within a culture dish. This process enables the study of the underlying mechanisms of disease occurrence, offering novel insights for identifying effective treatment strategies and developing new therapeutic drugs.

Application of Disease-Specific iPSC Cell Lines

Due to the scarcity of available human cells for experimentation and the inherent individual differences, drug development and testing globally heavily depend on animal experiments, cancer cell lines, and a limited supply of donated human tissues. This approach directly contributes to the high failure rate of new drugs during clinical trials. The advent of iPSC technology has made industrial-scale production of various human cells feasible. Establishing an iPSC cell bank encompassing diverse disease types, particularly those with genetic factors, and differentiating it into various functionally defective or pathological cell types will significantly enhance the efficiency of new drug development, substantially reducing research and development costs.

Since 2008, there has been a substantial increase in research on disease-specific iPSC cell lines, spanning various human tissues and organs such as nervous tissue, blood, heart, pancreas, liver, etc. The covered disease types include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Parkinson's disease (PD), Huntington's disease (HD), schizophrenia, progeria syndrome, Fanconi anemia, familial dysautonomia syndrome, type 1 diabetes mellitus, congenital ichthyosis, liver metabolic diseases, among others.

Applications

(1) Drug Screening

Preparing disease-specific iPSC cell lines derived from patients and differentiating these iPSCs into functional cells relevant to the disease offer a more intuitive and straightforward representation of the disease's pathophysiological conditions, providing significant advantages for drug screening. Large-scale drug screening often demands a substantial quantity of cells. Since iPSCs can proliferate indefinitely in vitro, disease-specific iPSCs and their differentiated adult functional cells can be supplied indefinitely to meet these demands. Industrialized preparation ensures consistency and stability in cell quality between batches.

(2) Drug Safety Evaluation

Utilizing iPSCs to simulate clinical phase I trials for in vitro testing of drug toxicity serves as a partial replacement for the current practice of directly testing on normal human bodies during clinical phase I trials. This approach helps to mitigate the harm caused by drug toxicity during the clinical phase I stage, significantly enhancing the protection of subjects' rights.

(3) Disease Pathogenesis Research

The in vitro differentiation of disease-specific iPSCs into functional human cells effectively replicates the onset of diseases. This proves particularly advantageous for studying the developmental processes of diseases like neurodegenerative diseases and neurodevelopmental abnormalities, as well as for developing early disease prevention and intervention methods.

(4) Gene Therapy

Leveraging gene editing technology, researchers can rectify gene defects in disease model iPSCs or introduce therapeutic genes into iPSCs to achieve therapeutic goals.

Application Examples

(1) In 2014, the Woolf research team at Harvard University published an article in Cell Reports. They used adult cells from specific amyotrophic lateral sclerosis (ALS) patients to construct an ALS-iPSC in vitro disease model. Through differentiation of ALS-iPSCs into motor neurons, they identified retigabine, a small molecule activating Kv7 ion channels, as a personalized treatment for specific ALS patients. Their findings received rapid approval from the US FDA for clinical application through the expedited green channel.

Reference: Wainger, B. J. et al. (2014). Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Reports, 10; 7(1): 1-11.

(2) In 2009, Dr. Yu Junying's research group published an article in Nature, marking the first instance of using skin cells from children with spinal muscular atrophy (SMA) to establish an SMA-iPSC in vitro disease model. The neurons derived from SMA-iPSCs accurately replicated the phenotype characteristics of SMA.

Reference: Ebert, A. D., Yu, J., et al. (2009). Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature,457(7227), 277-80.

(3) In 2012, a collaborative research result between Liu Guanghui, a researcher at the Institute of Biophysics, Chinese Academy of Sciences, and researchers at the Salk Institute was published in Nature. They used iPSC technology for the first time to unveil the mechanism of degenerative changes in neural stem cells in the brains of Parkinson's disease (PD) patients during the aging process, presenting new potential targets for the diagnosis, prevention and treatment of PD.

Reference: Liu, G. H., Qu, J., et al. (2012). Progressive degeneration of human neural stem cells caused bypathogenic lrrk2. Nature, 491(7425), 6037.

(4) In 2015, Joseph Wu's research team at Stanford University School of Medicine published an article in the journal Cell Stem Cell. Utilizing cardiomyocytes derived from iPSCs (iPSC-CMs) of patients with familial dilated cardiomyopathy (DCM), they discovered that the upregulation of phosphodiesterases (PDEs) 2A and 3A expression in DCM patient iPSC-CMs led to weakened β-adrenergic signaling by norepinephrine. This implies that drug inhibition of PDE2A and PDE3A expression can restore β-adrenergic signaling in cardiomyocytes of DCM patients, achieving the goal of treating DCM disease.

Reference: Wu, H., Lee, J., et al. (2015). Epigenetic regulation of phosphodiesterases 2a and 3a underliescompromised β - adrenergic signaling in an ipsc model of dilated cardiomyopathy. Cell Stem Cell, 17(1), 89.