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Disease-Specific iPS Cell Lines Could Be Useful Tools for Drug Screening

Scientists at the Children’s Hospital of Boston and the Harvard Stem Cell Institute last week announced that they have derived induced pluripotent stem cells from patients with 10 different Mendelian or complex genetic diseases using a reprogramming protocol similar to that used by Yamanaka and Thomson in their seminal papers last year in Cell and Science.
The diseases are adenosine deaminase deficiency-related severe combined immunodeficiency, Shwachman-Bodian-Diamond syndrome, Gaucher disease type III, Duchenne and Becker muscular dystrophy, Parkinson’s disease, Huntington’s disease, juvenile-onset type I diabetes mellitus, Down syndrome, and the carrier state of Lesch-Nyhan syndrome. 
The cell lines from these disorders represent an opportunity to recapitulate both normal and pathological tissue formation in vitro, thereby facilitating drug development, according to the researchers.
In a paper published online in Cell last week, the researchers describe how they made retroviruses expressing human versions of the OCT4, SOX2, KLF4, and c-MYC transcription factors and infected the dermal fibroblasts or bone marrow-derived mesenchymal cells from patients with these four retroviruses. 
The researchers then cultured the infected patient cells in conditions that support the growth of human embryonic stem cells. The infected cells that survived in conditions supporting the growth of hESCs would have very similar characteristics to hESCs, In-Hyun Park, a postdoctoral fellow at the Harvard Stem Cell Institute and the Children’s Hospital of Boston and lead author on the paper, told CBA News this week.  
“When we took those colonies and compared their characteristics with those of hESCs, we found that, in general, they are almost identical,” said Park.  
According to Park, one of the investigators’ ultimate goals is to use these cells to screen compound libraries. For example, “we can differentiate our Huntington’s disease iPS cell into neurons,” he said.

“We can differentiate the disease-specific iPS cells into certain lineages, and we can screen for a drug that can alleviate the phenotype of the disease.”

The Huntington’s disease iPS cells may form an aggregate of the huntingtin protein and cause apoptosis of the cell because of the presence of CA polyglutamate repeats. That could serve as an in vitro model of the disease.
“So we can differentiate the disease-specific iPS cells into certain lineages, and we can screen for a drug that can alleviate the phenotype of the disease,” Park explained.
“These [cell lines] are going to be great resources for understanding how these diseases progress, and will make great assay tools for targeting drug discovery and for use in compound screening,” said Marie Csete, chief scientific officer of the California Institute for Regenerative Medicine.
In June, CIRM awarded $23 million to California investigators to develop new iPS cell lines, many of which will be disease-specific.
“At the CIRM, we are really excited about [the research described in the Cell paper] because this means that stem cells can be used as drug discovery tools for a variety of diseases that really we had not anticipated that stem cells would be useful for, such as inherited metabolic disease, Alzheimer’s disease, and pretty much any disease you can name that has an inherited component and a cellular phenotype,” said Csete.   
New Field Emerging
Park and his colleagues published a paper on the derivation of iPS cells from normal fibroblasts in Nature this past January and, after that study appeared, the researchers “decided that it would be very important to show that we can derive iPS cells from the somatic cells of patients,” Park said. “We also knew that it is very important to show that iPS cells can be derived from various kinds of diseases.”
Park said that he and his team used the same reprogramming protocol that was used to derive iPS cells from normal fibroblasts, and that it worked very well for most of the patient-derived fibroblasts.  
iPS cells could even be used to better understand acquired diseases. For example, “getting stem cells from patients who have an adverse drug reaction and generating hepatocytes from them, and trying to understand the nature of the adverse drug reaction,” CIRM’s Csete said.
“My general comment is that the study reflects the characteristic high quality of the work of senior author George Daley and other members of his collaborative team,” said Thoru Pederson, a professor of biochemistry and molecular pharmacology at the University of Massachusetts Medical School.
They provide in the article “every bit as much characterization of these patient derived iPS cell lines as they did in their former study in Nature using the cells from healthy people,” Pederson told CBA News this week. In particular, they focus on demonstrating that the cell lines retain the genomic DNA mutations.
“The fact that the cell lines did retain the mutations is not surprising,” he said. “It would have been very surprising if they had NOT retained the original genetic mutations.”
Most definitively they show, as they did in their earlier study, that these cell lines not only have the genetic profile of pluripotentcy, but can also be induced to differentiate into specific cell lineages.
Park said that Daley’s group does not plan to commercialize or license these cell lines. “We want to support the research of any lab that wants to use our cells. We plan to distribute the cell lines to whoever would like to use them.”
Park said, however, that the HSCI may make an iPS cell core. “They will maintain and distribute our iPS cells, but there will be a fee, because we need to maintain these cells and ship them.“
“I think how this really sits in the context of the field is that it is very important for Daley and his team to show that they can replicate their findings from the January Nature paper using cells from people carrying these specific genetic diseases,” said Pederson. “A fair statement would be that a lot of different groups are now beginning to try to program the differentiation of iPS cells derived from patients.”
Although very little has actually been published on the topic of deriving iPS cells from patients, “I suspect that at this moment, a great deal of activity is going on prepublication,” Pederson said. “The paper by Dimos et al that was published in Science on July 31 is, to my knowledge, the first out of the gate, but it is certainly not the last.”  
That paper derived iPS cells from the ALS patient’s fibroblasts and also claims that these cells can be stimulated into motor neurons. To be sure, the question there is “whether these nerve cells have the attributes of ALS,“ Pederson said
It is a dynamic field and the real issue is that, ironically, in the case of the ALS patient in the Dimos paper, the nerve cells that are programmed in vitro are healthy, non-ALS-behaving neurons that could be used for transplantation or implantation therapy, said Pederson. The alternative is, in fact, they will have the defective qualities of the ALS-affected neurons, and in that case, the therapeutic promise will not be there, but they would serve as “a wonderful resource to study the pathogenesis of ALS,” Pederson said.

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