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Researchers Say Derived Spinal Atrophy iPS Cells Offer Model for Genetic Disease Studies

Scientists at the University of Wisconsin-Madison reported last week that they were able to generate induced pluripotent stem cells from skin fibroblasts taken from a child with spinal muscular atrophy — the first study to demonstrate that human iPS cells can be used to model the specific pathology seen in a genetically inherited disease.
As such, the study, published online last week in Nature, represents a potentially valuable resource to study disease mechanisms, screen new drug compounds, and develop new therapies, a university investigator told CBA News this week.
Patient population-specific iPS cells provide a better model system than animal or tumor cell lines for the study of genetic diseases because their properties are closer to those found in a patient’s system, explained Allison Ebert, an assistant scientist at the University of Wisconsin regenerative medicine and stem cell program and the corresponding author on the study.
She added that iPS cell technology could lead to research in which “we can study the mechanisms of cell death and screen drugs in a more relevant way.”
Using the iPS technology, scientists could generate large numbers of the appropriate cell types that are affected in various diseases. “Using the cells that are derived, which naturally have the mutations that cause the disease, we do not have to do any genetic manipulations to overexpress certain mutations or knock down particular genes, so the genetics behind this are already in place,” Ebert said.
She added that iPS cells provide researchers with a much more natural system, derived from human tissue, for screening compounds that will affect particular cell types.
Next Top (Disease) Model
Ebert and her colleagues took the fibroblasts from a type 1 SMA patient and his unaffected mother, genetically modified them with the OCT4, SOX2, NANOG, and LIN28 lentiviral constructs to generate the iPS cells, and then generated motor neurons from those iPS cells. “We then looked at characterizations of motor neurons to show that they are developing, at least based on markers, into motor neurons,” Ebert said.
The scientists saw that there was a selective death of the motor neurons among the SMA patient-derived cells. They also used these SMA iPS-derived motor neurons as a type of drug screening system.
In previous studies, researchers used fibroblasts from SMA patients to screen for possible therapeutic drugs. “What we have done is picked two of those drugs, valproic acid and tobramycin, which had been used in the literature, to see if our newly-derived iPS cells from the SMA patient could possibly be used for drug screening assays,” said Ebert. 
One of the hallmarks of SMA is the loss of nuclear aggregates called gems. Previously published studies showed that adding valproic acid and tobramycin to cultures of SMA patient fibroblasts increased the number of gems.

“Using the cells that are derived, which naturally have the mutations that cause the disease, we do not have to do any genetic manipulations to overexpress certain mutations or knock down particular genes.”

The University of Wisconsin investigators were able to show in their paper that this increase in gems also occurred in their iPS-SMA sample after treatment with valproic acid and tobramycin, so “we demonstrated that we could mimic what was done previously, but now we are using human-derived neural cells,” Ebert said.
She added that the iPS cells might be more relevant for drug screening and drug development assays than fibroblasts because “we can now specifically use motor neurons to look at drugs that affect the motor neurons, which are the cells that die in amyotrophic lateral sclerosis.”
With the publication of Thomson and Yu’s paper in Science at the end of 2007, describing the development of iPS cells, Ebert said that her lab started collaborating with Thomson’s lab to generate iPS cells from a patient sample. “Our lab focuses a lot on ALS research, and so we looked into SMA, because it’s a childhood disease, it has a known genetic component, and it has a relevance to ALS because motor neuron death also occurs,” she explained.
“We got fibroblasts from the Coriell Institute repository cell bank, and in collaboration with Thomson’s lab, we gave them the fibroblasts and they generated the iPS cells, and then we got them back and started developing the motor neurons in the dish,” Ebert said.
She also said that this current work began as a proof-of-principle paper based on the work from Kevin Eggan’s group published in Science in July and George Daley’s group published in Cell in August, which showed that iPS cells could be derived from patients with Mendelian or complex genetic diseases. However, neither of those groups had looked at SMA, a childhood disease, and neither of those papers had really developed iPS cells into a model system (see CBA News, 8/15/08).
Eggan’s group generated the motor neurons from an ALS patient, but they did not report on any phenotype or cell death that was occurring in the ALS-derived iPS cells. “What we did with the SMA patient cells is generate the iPS cells and make motor neurons, and then compared these SMA-derived motor neurons to those of the patient’s mother, who did not have the disease. We saw that the SMA-derived cells ended up having a cell death component that occurred later on in culture, so they were fewer in number and smaller in size,” Ebert said.
The investigators started to see a disease phenotype occurring in the cell dish. “Really it was one of the first validated disease models that has been published,” said Ebert.
The Wisconsin researchers will now look for the mechanism that causes the motor neurons to die. “We are trying to determine if cell death pathways are activated, or whether there are mitochondrial issues or glutamate toxicity, and things of that sort that might give us a clue as to what is specifically occurring within the motor neurons, which would be useful for drug screening and drug development,” Ebert said.
She added that her group is focused on two aspects of this work: studying the mechanism of neuronal death and how to prevent the neurons from dying, as well as using these cells as drug screening assays, “so we are trying to build up a drug screening system and collaborations for that work as well.
“We haven't really talked much about commercializing this, nor finding a corporate partner, but we are certainly interested in pursuing collaborations to use these cells as a drug screening model,” Ebert said.

Potentially, a multitude of genetic and sporadic disorders could be studied using the iPS cell technology. Other groups have derived iPS cells from patients with ALS, Huntington's disease, and muscular dystrophy. 

ALS is also a good example of a sporadic disease, because the overwhelming majority of ALS patients have no genetic cause. Therefore, Ebert said, iPS cells derived from a sporadic ALS patient could provide insight into the disease mechanism and vulnerability factors.

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