Platform Technology

I. Platform technologies using iPS cells

iPS cells are pluripotent stem cells that have acquired the ability to differentiate into all cell types in the body and almost unlimited proliferative capacity by introducing specific genes into cells such as skin and blood cells. We are using iPS cells to develop treatments for diseases in the kidney, pancreas, and liver area.

1. Cell therapy

Cells differentiated from iPS cells are transplanted into patients to treat their diseases.

2. Human disease models

We will search for novel therapeutics from disease models created from differentiated cells derived from patient-derived or disease-specific iPS cells.


II. Treatment of chronic kidney disease (CKD) with human iPS cell-derived nephron progenitor cells

The nephron progenitor cell, discovered by our scientific advisors, is the origin of the nephron, the smallest unit of renal function. Our Scientific advisors have successfully induced nephron progenitor cells from human iPS cells. We are developing multiple approaches to treat CKD using nephron progenitor cells.

More than 13 million people in Japan suffer from CKD, and more than 40,000 people are newly introduced to dialysis therapy each year due to end-stage renal disease. The current dialysis population exceeds 340,000. Its healthcare cost is about 1.6 trillion yen in Japan, accounting for 4% of all medical expenses, making it one of the most financially burdensome medical conditions. However, there is no fundamental cure other than kidney transplantation.

1. Cell therapy

Cell therapy using nephron progenitor cells(1) generated from human iPS cells has been shown to be effective in several renal disease models(2-4). We have succeeded in developing a technology to inhibit cell aggregation, which has been an issue in the formulation development of nephron progenitor cells (patent pending). We have also succeeded in developing a highly sensitive detection system for residual undifferentiated iPS cells, which has been an issue in the administration of nephron progenitor cells generated from human iPS cells (5) (patent pending).

1. Tsujimoto H, Kasahara T, Sueta S-I, Araoka T, Sakamoto S, Okada C, et al. A Modular Differentiation System Maps Multiple Human Kidney Lineages from Pluripotent Stem Cells. Cell Rep. 2020;31: 107476. doi:10.1016/j.celrep.2020.03.040 2. Toyohara T, Mae S-I, Sueta S-I, Inoue T, Yamagishi Y, Kawamoto T, et al. Cell Therapy Using Human Induced Pluripotent Stem Cell-Derived Renal Progenitors Ameliorates Acute Kidney Injury in Mice. Stem Cells Transl Med. 2015;4: 980–992. doi:10.5966/sctm.2014-0219 3. Hoshina A, Kawamoto T, Sueta S-I, Mae S-I, Araoka T, Tanaka H, et al. Development of new method to enrich human iPSC-derived renal progenitors using cell surface markers. Sci Rep. 2018;8: 6375. doi:10.1038/s41598-018-24714-3 4. Araoka T, et al., our scientific advisors group, international paper submission 5. Tsujimoto H, Katagiri N, Ijiri Y, Sasaki B, Kobayashi Y, Mima A, et al. In vitro methods to ensure absence of residual undifferentiated human induced pluripotent stem cells intermingled in induced nephron progenitor cells. Liu L-P, editor. PLoS One. 2022;17: e0275600. doi:10.1371/journal.pone.0275600

2. Renal tissue regeneration

Nephron progenitor cells, renal interstitial progenitor cells, and ureteroblasts are known as fetal progenitor cells of the kidney. Our scientific advisors have succeeded for the first time in highly efficient differentiation of ureteroblast tissue from human iPS cells that derives the lower urinary tract from the collecting duct to part of the bladder (6, 7). Furthermore, we have developed a technology for highly efficient induction of progenitor cells of the renal interstitium, which are cells that constitute the supporting tissue of epithelial cells in kidney tissue, from human iPS cells. Using these technologies, we are working with AstraZeneca to reproduce kidney tissue in vitro for use in the development of therapies.

6. Mae SI, Ryosaka M, Sakamoto S, Matsuse K, Nozaki A, Igami M, et al. Expansion of Human iPSC-Derived Ureteric Bud Organoids with Repeated Branching Potential. Cell Rep. 2020;32. doi:10.1016/j.celrep.2020.107963 7. Mae S, Ryosaka M, Toyoda T, Matsuse K, Oshima Y, Tsujimoto H, et al. Generation of branching ureteric bud tissues from human pluripotent stem cells. Biochem Biophys Res Commun. 2017; 1–8. doi:10.1016/j.bbrc.2017.11.105

3. Organ regeneration

We are working with Pol MedTech, a company with cloned and genetically engineered pig technology, to develop pigs with hypoplastic kidneys. We aim to produce kidneys derived from human cells in pigs by transplanting kidney progenitor cells produced from human iPS cells into the uterus of pigs whose kidneys are hypoplastic and reconstructing kidneys as organs in the uterus.

4. Cell therapy using next-generation nephron progenitor cells
i. Hypoimmunogenic iPS Cells

Our scientific advisors are also working with the iPS Cell Foundation to develop nephron progenitor cells that can survive longer and be used by a wider range of patients, as well as HLA genome-edited iPS cells to develop immune-resistant nephron progenitors.

ii. Trophic factor-enhanced cells

Our scientific advisors have identified that the pharmacological effects of nephron progenitor cells are due to a paracrine effect in which trophic factors secreted by the cells act on neighboring cells (2, 4). Using iPS cells that more strongly express these trophic factors, we are also developing nephron progenitor cells with enhanced therapeutic efficacy.


III. Autosomal dominant (overt) polycystic kidney disease (ADPKD) disease model to explore novel therapeutics


ADPKD is the most common inherited renal disease, characterized by the development and gradual enlargement of numerous cysts (fluid-filled sacs) in the kidneys. The progressive renal dysfunction often results in end-stage renal disease, requiring artificial dialysis or kidney transplantation in approximately half of patients by the age of 70. In recent years, tolvaptan has been used to control the growth of renal cysts; however, there is still no fundamental treatment available.
We have the technology to generate renal organoids (three-dimensional reproductions of organ parts) that recapitulate the pathology of ADPKD. This is achieved by using genome editing technology to generate human iPS cells with a mutation in the PKD1 gene, which is the causative gene of ADPKD, and subsequently inducing differentiation of these cells.
Until now, a disease model with characteristics of the kidney nephron, the tissue responsible for urine production, had been developed using gene-edited human iPS cells. However, our Chief Scientific Advisor’s research group has succeeded in creating a disease model with characteristics of a structure known as a collecting duct, which connects to the nephron(1). Cysts generally occur in the collecting ducts of individuals with ADPKD, and this novel disease model more precisely replicates the pathology of ADPKD.

1.Shin-Ichi Mae, et al. “Human iPSC-derived renal collecting duct organoid model cystogenesis in ADPKD” Cell Reports, 2023

2. Development of novel therapeutics

Using kidney organoids that replicate ADPKD cysts, we have identified the retinoic acid receptor (RAR) agonist as a new therapeutic candidate and initiated clinical trials in December 2023.

3. Drug discovery screening

Using this pathological model, high-throughput screening equipped with automated technology is used to select potential new therapeutics from tens of thousands of compounds with high efficiency.


IV. Research in the liver area

1. Cell therapy for cirrhosis using iPS-derived hepatocytes

Cirrhosis is a disease in which liver cells are destroyed by chronic hepatitis such as non-alcoholic steatohepatitis (NASH), and fibrosis and nodule formation progress, causing the liver to harden and shrink. It not only causes liver cancer, but also has many serious symptoms and complications, and about 17,000 people die annually in Japan. Our scientific advisors have succeeded in inducing hepatocytes from human iPS cells with high therapeutic efficacy against liver cirrhosis and are developing this as a new treatment for liver cirrhosis.

2. Development of new therapeutics using a pathological model of non-alcoholic steatohepatitis (NASH)

Fatty liver is a condition in which neutral fat accumulates in the liver, leading not only to hepatitis but also to cirrhosis and liver cancer. In the past, fatty liver was mainly caused by alcohol, but in recent years, the incidence of NASH, a form of hepatitis that occurs in people who do not drink a lot of alcohol, has been increasing due to worsening lifestyle habits, and there is a need to urgently develop therapeutics. We are developing drugs that inhibit liver fibrosis caused by NASH.

Differentiation of liver organoids from iPS cells established from NASH patients (Creation of a disease model) ↓ High-throughput screening to develop novel therapeutics to inhibit fibrosis

3. Disease model of citrin deficiency

Citrin deficiency (adult-onset type II citrullinemia) is a serious disease that causes hyperammonemia and hypercitrullinemia, resulting in psychiatric symptoms and liver failure. The incidence of this disease is about 1/17,000 in Japan, and it is not rare. SLC25A13 having been identified as the causative gene and the gene product, citrin, exists in the inner mitochondrial membrane of the liver and is involved in metabolism, liver transplantation is successful. However, there is a demand for the development of therapeutics due to the shortage of donors. We have developed a human model of citrin deficiency.

Novel therapeutics for citrin deficiency may be useful as a treatment for NASH, since the citrin deficiency presents with NASH when liver failure is reached.


V. Research in the pancreatic area

Diabetes mellitus is caused by dysfunction of pancreatic beta cells that secrete insulin in the pancreas, resulting in persistent hyperglycemia which promotes atherosclerosis and leads to CKD, cerebral infarction and myocardial infarction. We are developing new therapeutics for diabetes mellitus through 1. next-generation cell therapy and 2. drug discovery screening. 

1. Next-generation cell therapy

<Transplantation of pancreatic beta cells using hypoimmunogenic iPS cells>
Pancreatic β-cells are generated and transplanted using hypoimmunogenic iPS cells, which can escape from rejection. By suppressing rejection at the time of transplantation, the transplanted cells are expected to improve the engraftment rate and function, and the amount of immunosuppressive drugs taken by the patient is also expected to be reduced.

2. Drug discovery screening

<High-throughput screening using iPS cell-derived pancreatic beta cells>
This project is designed to screen therapeutic candidates using pancreatic β-cells generated from iPS cells and to search for new therapeutics. High-throughput screening using automated technology enables us to select useful compounds from tens of thousands of compounds with high efficiency.