Establishing Noonan and Leopard syndrome patient-specific iPS cell lines

Funding Type: 
New Cell Lines
Grant Number: 
RL1-00647
Investigator: 
ICOC Funds Committed: 
$0
oldStatus: 
Closed
Public Abstract: 
As a biomedical researcher, I firmly believe that many diseases that are incurable today could be treated effectively using human embryonic stem (ES) cell technology, the so-called cell replacement therapy or regenerative medicine. However, one ethical hurdle is the need to use human embryos in the classical way of establishing human ES cell lines. Also, patients may experience tissue rejection upon receiving transplantation of donor stem cell-derived functional cells. In 2007, scientists in Japan and the United States demonstrated that human ES cell-like stem cells can be created by reprogramming adult somatic cells with defined transcription factors, proteins that control gene expression in cells. This exciting result of establishing human inducible pluripotent stem (iPS) cells from somatic cells offers an alternative way to establish human stem cells without the need to use (destroy) human embryos. More importantly, this new technology raises the possibility for establishment of patient-specific human ES-like stem cells for research and therapeutic purposes. We will use this newly developed technology to create novel human iPS cell lines using dermal fibroblast cells derived from Noonan syndrome (NS) and LEOPARD syndrome (LS) patients. The objective of this project is to provide proof of principle in establishment of patient-specific iPS cell lines for dissection of the pathogenesis for complex human diseases and also for drug screening. NS and LS are developmental diseases with many common features. NS is an autosomal dominant disorder affecting 1 in 2500 live births, characterized by facial dysmorphia, typically ocularhypertelorism, cardiac defects, most commonly pulmonary valve stenosis, and proportionate short stature. LS (LEOPARD syndrome) is a rare, autosomal dominant disorder characterized by Lentigines, Electrocardio-gramabnormalities, Ocular hypertelorism, Pulmonic valvular stenosis, Abnormalities of genitalia, Retardation of growth, and Deafness. Both NS and LS patients exhibit increased risk of malignancy including myelogenous leukemia and neuroblastoma. We will use the established patient-specific iPS cell lines to investigate the molecular and cellular mechanisms underlying the developmental defects of the patients. We will identify and test small molecules that correct the cellular disorders associated with the diseases. We will also improve and optimize the technology to minimize the risky factors in use of iPS cell-derived functional cells for cell therapy on patients. Therefore, success of this project will provide fundamental insights into the pathogenesis and suggest novel therapeutic strategies for Noonan and LEOPARD syndrome patients. This project will set up an example of how the stem cell research can be beneficial to many otherwise hopeless human patients. However, this type of research is currently not fundable by NIH, and thus we are applying for CIRM award.
Statement of Benefit to California: 
The goal of this project is to establish new human pluripotent stem cell lines by reprogramming human somatic cells with defined transcription factors. As a biomedical researcher, I firmly believe that many diseases that are incurable today could be treated effectively using functional cells differentiated from human ES cells, the so-called cell replacement therapy or regenerative medicine. However, one ethical hurdle to the stem cell biology research field is the need to use human embryos in the classical way of establishing human ES cell lines. Also, a practical problem in clinical treatment is that patients may experience tissue rejection upon receiving transplantation of donor stem cell-derived functional cells. The recent success of establishing human iPS cells from somatic cells offers the feasibility for establishment of patient-specific human ES-like stem cells for diagnostic and therapeutic purpose. We will create novel human iPS cell lines using dermal fibroblast cells derived from Noonan syndrome (NS) and LEOPARD syndrome (LS) patients. Success of this project will benefit California citizens in the following ways. A) Success of this project will put California in the leading position in regenerative medicine. The objective of this project is to provide proof of principle for establishment of patient-specific iPS cell lines for dissection of pathogenesis for complex human diseases and also for drug screening. Therefore, the technology and the model system established will be applicable for stem cell therapy of many diseases, such as spinal cord injury, alzheimer’s disease, diabetes and leukemia. B) This project will directly benefit the NS and LS patients in California and other states in the country. NS is an autosomal dominant disorder affecting 1 in 2500 live births, characterized by facial dysmorphia, typically ocularhypertelorism, cardiac defects, most commonly pulmonary valvestenosis, and proportionate shortstature. LS (LEOPARD syndrome) is a rare, autosomal dominant disorder characterized by Lentigines, Electrocardio-gramabnormalities, Ocular hypertelorism, Pulmonic valvular stenosis, Abnormalities of genitalia, Retardation of growth, and Deafness. Both NS and LS patients exhibit increased risk of malignancy including myelogenous leukemia and neuroblastoma. Therefore, success of this project will provide fundamental insights into the pathogenesis and offer novel therapeutic strategies for Noonan and LEOPARD syndrome patients who are otherwise hopeless in their life. During the course of this research project, we will improve and optimize the technology to minimize the risky factors in use of iPS cell-derived functional cells for cell therapy on patients. In essence, success of this project will put us on the driver’s position in the competitive stem cell research field, which will benefit tremendously California’s biomedical research and industry.

© 2013 California Institute for Regenerative Medicine