Klinische studie met iPS-cellen voor de ziekte van Parkinson

Kugako Sugimoto, NOST Tokyo

Origineel gepubliceerd op de site van Agentschap NL

Samenvatting

Een onderzoeksgroep van de Kyoto University heeft een plan aangekondigd om in 2016 te beginnen met klinische studies van de behandeling van de ziekte van Parkinson met geïnduceerde pluripotente stamcellen. De behandeling start met het creëren van de iPS cellen afkomstig van de patiënt. Vervolgens worden deze cellen geïnduceerd tot precurors van dopamine gerelateerde neuronen. Deze precurors zullen daarna geïmplanteerd worden in de hersenen van de patiënt  In het protocol van de klinische studies zullen procedures voor effectieve creatie van dopamine gerelateerde neuronprecursors en de nauwkeurige selectie van deze precursors door het gebruik van Corin-antilichamen worden opgenomen. Eerder zijn met goed resultaat studies van autologe transplantaties gedaan bij primaten met een minimale immuunrespons. Deze klinische studies met mensen volgen op eerder door het onderzoeksinstituut RIKEN aangekondigde plannen voor klinische studies van stamcellen voor netvliesbehandelingen

Clinical test with iPS cells for Parkinson’s disease

Summary

A research team of Kyoto University announced a plan for a clinical study to treat Parkinson’s disease by using iPS cells in 2016. Treatment starts with the creation of iPS cells from patients followed by an induction into dopaminergic neuron precursors. Obtained dopaminergic neuron precursors would be transplanted into the brain of the patients. Effective culturing of dopaminergic neuron precursors by using synthetic laminins and accurate selection of dopaminergic neuron precursors by using anti-Corin antibody will be incorporated into the protocol for the clinical test. An animal study by using non-human primate has been completed with good results of autologous transplantation with minimum immune response. This clinical test would be the second human test following a study by RIKEN in Japan on retinal regeneration.

Details

The research team of Kyoto University led by Prof. Jun Takahashi announced a plan to start the clinical study how to treat Parkinson’s disease by using iPS cell technology in 2016 according to news from Kyoto University dated on March 7, 2014.

Parkinson’s disease¹ is caused by decrease of dopamine-generating² cells in the central nervous system. Symptoms are shaking, difficulty in walk, and others. The clinical onset of the disease occurs mostly in older people beyond the age of 50. It affects about one in every 200 people worldwide. Currently, there is not a fundamental treatment for this disease, though drugs to alleviate symptoms are available.

A transplantation test of dopaminergic neurons created from iPS cells to the brains in non-human primates has already been conducted.

In this study, iPS cells were created by the fibroblasts obtained from the oral mucosa of the non-human primate by using retroviral vectors. Midbrain dopaminergic neurons were induced from iPS cells by the addition of purmorphamine³, a molecule involved in bone growth and brain development, and FGF8, a fibroblasts growth factor, followed by FGF2 and FGF20. During the observation of the development into dopaminergic neurons, markers of pluripotency (OCT4⁴) decreased and markers for differentiated neurons, characteristic of midbrain dopaminergic neurons such as LMX1A, FOXA2, TH, and TITX3, started to express.

Then, the suspension from the culture was prepared for the injection to one of the putamen⁵ of non-human primates. No immunosuppressant was used to compare the effect between the autologous and allogeneic transplantation.

The immune response and survival of transplanted cells were observed for the recipient primates of allografts and autografts for 3-4 months. Autografts caused a minimum immune response in the recipient brains, while allografts might trigger immune response. Grafted cells survived in both types of transplantation without immunosuppressant. The volume of the developed dopaminergic neurons of two types of transplants did not show significant differences. However, the number as dopaminergic neuron were higher in autografts than allografts.

Based on the preliminary test on nonhuman primates, clinical trials to treat Parkinson’s disease will use the patient’s own cells probably from the blood to create iPS cells for autografts. The clinical test will be conducted at the Center for iPS Cell Research and Application (CiRA) and Kyoto University Hospital including the observation of post transplantation to secure safety of the technology. Goals of this test are to improve symptoms and suppress the progression of the disease.

Osaka University and private companies also helped to establish a protocol for the clinical trial to produce ample and high quality of dopaminergic neuron precursors. The team will use synthetic laminin（recombinant laminin 511E8 fragments created by Osaka University）instead of mouse-derived feeder cells for adherent culturing. Laminin is a protein to hold cells together. Then, the cultured dopaminergic neuron precursors will be selected and concentrated by the cell sorting machine. Dopaminergic neuron precursors that have corins are picked up through the reaction with the fluorescence attached anti-Corin antibody in a cell sorting machine. Unwanted cells that might cause tumors due to proliferative ability would be excluded from the cultured grafts.

Prior to conducting clinical test, several approvals are required. First, the research team will submit the application to the third-party review panel (Certification Board) in Kyoto University in 2015. Then, the team needs an additional approval from the Ministry of Health, Labour and Welfare through the safety checks. Then the clinical test would start in 2016.

This trial would be the second clinical study using iPS cells in Japan. The first clinical study is being conducted by the research team of RIKEN lead by Dr. Masayo Takahashi for regeneration of retinas by iPS cells.

1. Parkinson’s disease (Wikipedia)
2. dopamine (Wikipedia)
3. purmorphamine (Wikipedia)
4. OCT4 (Wikipedia)
5. putamen (Wikipedia)

Source

1. Asuka Morizane, et al., (2013) Stem Cell Reports (1) 283-292
2. Bao-Yang Hu, et al. (2010) PNAS (107) 9, 4335-4340)
3. News from Kyoto University
4. Yomiuri Online (Feb. 27, 2014), Parkinson’s disease treatment by iPS, clinical trial by Kyoto University