Patient-derived Induced Stem Cells Retain Disease Traits
ScienceDaily (Jan. 5, 2009) - When neurons started dying in Clive Svendsen's 
lab dishes, he couldn't have been more pleased.
The dying cells - the same type lost in patients with the devastating 
neurological disease spinal muscular atrophy - confirmed that the University 
of Wisconsin-Madison stem cell biologist had recreated the hallmarks of a 
genetic disorder in the lab, using stem cells derived from a patient. By 
allowing scientists the unparalleled opportunity to watch the course of a 
disease unfold in a lab dish, the work marks an enormous step forward in 
being able to study and develop new therapies for genetic diseases.
As reported this week in the journal Nature, Svendsen and colleagues at 
UW-Madison and the University of Missouri-Columbia created disease-specific 
stem cells by genetically reprogramming skin cells from a patient with 
spinal muscular atrophy, or SMA. In this inherited disease, the most common 
genetic cause of infant mortality, a mutation leads to the death of the 
nerves that control skeletal muscles, causing muscle weakness, paralysis, 
and ultimately death, usually by age two.
Genetic reprogramming of skin cells, first reported in late 2007 by 
UW-Madison stem cell biologists James Thomson and Junying Yu and a Japanese 
group led by Shinya Yamanaka, turns back the cells' developmental clock and 
returns them to an embryonic-like state from which they can become any of 
the body's 220 different cell types. The resulting induced pluripotent stem 
cells, known as iPS cells, harness the blank-slate developmental potential 
of embryonic stem cells without the embryo and have been heralded as a 
powerful potential way to study development and disease.
Just one year later, the new work is fulfilling that promise.
"When scientists study diseases in humans, they can normally only look at 
the tissues affected after death and then try to work out - how did that 
disease happen? It's a little like the police arriving at the scene of a 
road accident - the car's in the ditch, but they don't know how it got there 
or the cause of it," explains Svendsen, a professor of anatomy and neurology 
in the UW-Madison School of Medicine and Public Health and the Waisman 
Center, and co-director of the Stem Cell and Regenerative Medicine Center.
With iPS cells, he says, "Now you can replay the human disease over and over 
in the dish and ask what are the very early steps that began the process. 
It's an incredibly powerful new tool."
In the new study, the researchers created iPS cells from stored skin cells 
of a young SMA patient and his mother, who does not have the disease. The 
cells grew well in the lab, and the group developed a new method to 
efficiently drive them to make large numbers of motor neurons, the cells 
that control muscles and that are affected in SMA.
Initially, the motor neurons thrived in both samples. But after about a 
month, "the accident started happening," Svendsen says, and the motor 
neurons from the patient-derived cells began to disappear.
"The motor neurons we got started to die in culture, just like they do in 
the disease. This is the first validation of a human disease that we've 
modeled in a culture dish," he says.
They can now begin to dissect what kills the motor neurons and why these 
cells alone are targeted in the disease. Past studies to understand the 
effects of the SMA-causing mutation have often relied on the easy-to-obtain 
skin cells, which are not affected in SMA and offer limited insight into how 
and why motor neurons die, says UW-Madison researcher Allison Ebert, lead 
author on the new study.
"If we start to understand more of the mechanism of why the motor neurons 
specifically affected in the disease are dying, then potentially new 
therapies can be developed to intervene at particular times early in 
development," she explains. Current SMA treatment options are limited, and 
there is no cure.
Ebert points out that the patient-derived iPS cells can offer scientific 
advantages over other approaches, including embryonic stem cells, for 
studying disease. In effect, the researchers can watch the unfolding of an 
accident that has already occurred, and the known clinical outcome - the 
course and severity of the patient's disease - should help them understand 
how the changes they see in the cells fit into the bigger picture of the 
disease.
"The development of human-derived SMA motor neurons is an important step 
forward for the SMA field, especially as a variety of therapeutic avenues 
are being examined," agrees SMA expert Christian Lorson, a professor of 
veterinary pathobiology at MU and an author on the paper. "To be able to 
investigate therapeutic activity in these cells, whether it be novel drugs, 
viral vectors, oligonucleotides, or a better understanding of disease 
pathology, the iPS SMA motor neurons represent an excellent disease-related 
context."
While complex and late-hitting disorders like Alzheimer's and Parkinson's 
diseases will be harder to model with iPS cells, the researchers say the 
approach should pave the way for studies of other genetic disorders, such as 
Huntington's disease. "We have to find better ways to model complex human 
diseases that are difficult to reproduce in animals," Svendsen says. "iPS 
cells represent a promising new research tool to reach this goal."
He credits the UW-Madison Stem Cell and Regenerative Medicine Center with 
facilitating the work, especially by drawing on the expertise of Yu and 
Thomson, who pioneered the technique, to create the iPS cells used in this 
study. "This is an example of how the center is working to collaborate on 
campus and off campus to bring these kind of things to fruition," he says.

University of Wisconsin-Madison (2009, January 5). Patient-derived Induced 
Stem Cells Retain Disease Traits. ScienceDaily

Rayilyn Brown
Director AZNPF
Arizona Chapter National Parkinson Foundation
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