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Application of iPSC Technology in Orphan Drug Development

May 28, 2019

CENTOGENE’s Orphan Drug Development Initiative

Patient-derived induced Pluripotent Stem Cells (iPSCs) as an approach to facilitate drug development for rare diseases

Challenges in Orphan Drug Development

One of the major challenges in orphan drug development for rare genetic diseases is the lack of predictive high-throughput compound screening systems. While the underlying pathophysiology may be easier to investigate in monogenic diseases, in-vivo animal-based disease models often cannot recapitulate the full human phenotype due to substantial species differences1. Primary cells from patients are also limited in their use – in particular hard-to-access cells from neuronal and cardiac tissues2. Furthermore, lack of genetically relevant predictive toxicology assays during the preclinical phase create additional hurdles. While these limitations hinder the traditional drug discovery process more broadly, they pose a bigger challenge regarding rare diseases, where information on the clinical spectrum of the disease is often limited and the number of patients available for clinical trials is by definition small. These obstacles contribute, among other factors, to the significant cost and the many years it takes an orphan drug to reach the market and provide benefit to rare disease patients.

Improved Disease Models

Such a pharmaceutical development challenge could be mitigated by having disease models that represent the actual human diseases more precisely, so that the underlying mechanism can be better understood and used as a basis to develop effective and safe therapies. Human induced pluripotent stem cells (iPSCs), first reported in 2007, are reprogrammed from somatic cells, and are self-renewal cells that can produce different types of cells4. Yamanaka and colleagues have introduced just 4 transcription factors (OCT3/4, SOX2, KLF4 and c-MYC) by retroviral transduction, which induce the pluripotency in somatic cells4. In other words, human iPSCs are an unlimited source from which to generate almost any disease-specific cell types in the laboratory. iPSC technology has enabled us to study each disease-affected cell type alone, or together with other cell types in a mixed environment called 3D organoids5. In addition, iPSCs also offer a reliable and cost-effective alternative for preclinical toxicity screening6.

iPSC – An Alternative Model for Drug Discovery

The advent of iPSC technology has created new therapeutic opportunities concerning a wide range of diseases including neurodegenerative, metabolic and cardiovascular diseases in a dish for cheaper and faster drug discovery. This may be particularly important in the context of monogenic rare hereditary diseases, where iPSCs can provide an alternative model system to compensate for the lack of a predictive in-vitro human model for drug discovery (Figure 1).

Some iPSC-based drug candidates are currently, in clinical trials. RG7800 is one of the small molecules that demonstrated an increased survival of motor neurons derived from iPSCs as a model for Spinal Muscular Atrophy (SMA). This compound has advanced into clinical trials by Roche 7,6. Ezogabine is an FDA-approved anti-epileptic drug that has also demonstrated efficacy in an iPSC model of the motor neuron disease Amyotrophic Lateral Sclerosis(ALS) and it is undergoing a clinical trial by GlaxoSmithKline as a repurposed drug8,6. Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare genetic disease in which bones are formed in muscle and other soft tissues. Recently a group of the researchers in CiRA (Japan) conducted a screening of seven thousands chemical compounds on patient-derived iPSCs and came up with rapamycin, a well characterized drug as a candidate to treat FOP patients9. At Kyoto University, rapamycin is currently in a clinical trial to investigate its effectiveness for FOP patients.

Driving Orphan Drug Discovery and Development

Over the past 13 years, CENTOGENE has fully curated over 300,000 individual patients with a wide range of rare genetic diseases. Each individual case analyzed has fully documented information including: associated phenotypes, analyses performed, results, diagnosis, and Human Phenotype Ontology(HPO) terms. The blood samples from these patients have been collected using CentoCard®- a proprietary CE marked paper that allows the stabilization of the sample for additional testing, and is supported by the patient’s consent. Based on this extensive experience, CENTOGENE is emerging as a leader in iPSC-based disease modelling field to support our pharmaceutical partners in the development of new orphan drugs. CENTOGENE scientists have already collected more than 500 skin biopsies from patients with rare diseases and are reprogramming many of them into iPSC for a number of metabolic rare diseases such as Gaucher, and Niemann Pick Type A and C, Polycystic kidney disease, Fabry disease, Metachromatic leukodystrophy, and Mucopolysaccharidosis type 2. These iPSC lines are now available as a unique enabling tool for orphan drug discovery and development. Additional iPSC can be created by specific requests.

Figure 1: iPSCs provide a unique human model for less expensive, faster, and safer orphan drug development. The discovery of iPSCs has provided a platform to create disease-specific iPSC lines from a wide spectrum of the human population. Then, these iPS cells can be differentiated into any disease-affected cell type to provide a platform to test certain drug candidates in a high-throughput system, and to assess the possible side effects of the orphan drug under development.

CENTOGENE’s iPSC target picture

  1. Patient Selection: CENTOGENE has an extensive data depository of epidemiologic, phenotypic and genetic information to identify rare disease patients; it contains analyzed samples from more than 420,000 patients across an ethnically diverse dataset from over 115 countries. Genotype and phenotype information in this database will be the source criteria for cohort selection using clinical subgroups, consent/accessibility, and genotypes (inclusion and exclusion). A trained fly-out team with nurses and physicians is available for sample collection at a high standard.
    • Up to date, CENTOGENE experts successfully collected over 500 skin biopsies to reprogram some of them into iPSC for three rare metabolic diseases: Gaucher, and Niemann Pick Type A and C, Polycystic kidney disease, Fabry disease, Metachromatic leukodystrophy, and Mucopolysaccharidosis type 2.. First quality-control passed iPSC lines from those patients are anticipated to be available by mid of 2019.

  2. iPSCs production: CENTOGENE’s laboratories are using latest technologies to perform high-standard iPS cell culture and differentiation. iPSC production is a joint venture with CENSO Biotechnologies (Edinburgh, UK), a renowned expert in the field. Starting sources for iPSC reprogramming are mostly fibroblasts or in some cases blood cells. The process is the utmost quality with a defined turnaround time of maximum six months - from the date of collection to delivery of iPSCs.
    • The first cohort of iPSC are in the production pipeline and anticipated to be available by the second quarter of 2019.

  3. iPSC expansion/differentiation: With the current advent in the stem cell field, it is possible to differentiate iPSC into almost any desired disease-specific cell type by using already established protocols. The quality of differentiated cells is constantly monitored to ensure that the process is robust and efficient.
    • CENTOGENE scientists continue to work on establishing in-house, reproducible and high-quality differentiation protocols by taking advantage of available knowledge in the field. Additionally, we are exploring academia and industry partnerships to develop and enhance CENTOGENE’s strength in iPSC field.

  4. High-throughput compound screening: Depending on the experimental setup, CENTOGENE offers high-throughput screening resources for biomarker discovery in differentiated iPSCs. Standard commercial compound libraries will be used in medium throughput screenings. Alternatively, CENTOGENE is also establishing partnerships with a number of companies that provide drug-screening platforms.
    • Since efficient commercial suppliers are already available for neurodegeneration and metabolic compound screening; instead of building-up new facilities, CENTOGENE will launch new partnerships with leading screening companies in the field. Nonetheless, our huge biomarker screening knowledge will allow us to connect external high-throughput compound screening providers using our proprietary biomarker readouts and thereby adding further value to each element.

  5. Read-out analysis/target identification: State of the art bioinformatics including machine-learning algorithms and big data tools for patterning recognition are now being employed for data analysis. CENTOGENE’s facilities allow us to engage in a wide variety of technologies for orthogonal target validation and as well as biomarker discovery.
    • Since this activity clearly drives the value of CENTOGENE’s iPSC business, internal recruitment is directed towards experienced experts in drug development, preclinical target validation, and multi-omics bioinformatics. These tasks will also be offered in a service-based model for big pharma companies engaged in orphan drug development.


1. Uhl,E.W. and Warner, N.J. (2015) Mouse models as predictors of human responses: evolutionary medicine. Curr. Pathobiol. Rep., 3, 219–223. Lin, J.H. (2008) Applications and limitations of genetically modified mouse models in drug discovery and development. Curr. Drug Metab., 9, 419–438.

2. Maqsood, M.I., Matin, M.M., Bahrami, A.R. and Ghasroldasht, M.M. (2013) Immortality of cell lines: challenges and advantages of establishment. Cell Biol. Int., 37, 1038–1045.

3. Giri, S., Bader, A., 2015. A low-cost, high-quality new drug discovery process using patient-derived induced pluripotent stem cells. Drug Discov. Today 20, 37–49.

4. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., Yamanaka, S., 2007. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872.

5. Dutta, D., Heo, I. and Clevers, H. (2017) Disease modeling in stem cell-derived 3D organoid systems. Trends Mol. Med., 23, 393–410.

6. Shi, Y., Inoue, H., Wu, J. C. & Yamanaka, S. Induced pluripotent stem cell technology: a decade of progress. Nat. Rev. Drug Discov.16, 115–130 (2017).

7. Naryshkin, N. A. et al. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science 345, 688–693 (2014).

8. McNeish, J., Gardner, J. P., Wainger, B. J., Woolf, C. J. & Eggan, K. From dish to bedside: lessons learned while translating findings from a stem cell model of disease to a clinical trial. Cell Stem Cell 17, 8–10 (2015).

9. Hino, K., Horigome, K., Nishio, M., Komura, S., Nagata, S., Zhao, C., Jin, Y., Kawakami, K., Yamada, Y., Ohta, A. et al.(2017). Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva. J. Clin. Invest. 127, 3339-3352. doi:10.1172/JCI93521.