Recreating A Nerve Disease In Order To Study It

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Recreating A Nerve Disease In Order To Study It - Patient-derived

Induced Stem Cells Retain Disease Traits

22 Dec 2008

Clive Svendsen, of the University of Wisconsin-Madison, could not

have been happier when neurons started dying in his lab dishes. Clive

and team had created the hallmarks of a genetic disorder in the

laboratory using stem cells derived from a patient. The dying cells

were the same type lost in patients with spinal muscular atrophy, a

devastating neurological disorder. In other words, a gene disease had

been recreated in the lab by scientists.

If researchers can watch the course of a disease unfurl in a lab

dish, they are much further along the way towards being able to study

and develop new treatments for genetic diseases.

You can read about this in the journal Nature.

Svendsen et al at UW-Madison and the University of Missouri-Columbia

genetically reprogrammed skin cells from a patient with SMA (spinal

muscular atrophy) and created disease-specific stem cells. SMA is the

most common genetic cause of infant mortality - a mutation causes the

death of nerves that control skeletal muscles, leading to muscle

weakness, paralysis, and ultimately death. Few patients live beyond

the age of two years.

Genetic reprogramming of skin cells, first reported in late 2007 by

UW-Madison stem cell biologists 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. (A pluripotent cell can create all

cell types except for extra embryonic tissue).

Svendsen, Professor of anatomy and neurology, UW-Madison School of

Medicine and Public Health and the Waisman Center, and Co-Director of

the Stem Cell and Regenerative Medicine Center, said " 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. 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 this study the scientists created iPS cells from stored skin cells

of a young patient with SMA, and also stored skin cells of his

mother. The mother does not have SMA. The cells were then grown in

the laboratory. The team developed a new method to effectively drive

them to produce large quantities of motor neurons. Motor neurons are

cells that control our muscles - the very cells that are affected in

SMA.

At first the motor neurons thrived in both samples. However, after a

month Svendsen explains that " the accident started happening " . The

motor neurons that had originated from the patient-derived cells

started 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, "

Svendsen explained.

The scientists can now dissect what destroys the motor neurons and

why just these cells are targeted in SMA.

Previous studies to identify the effects of the SMA-causing mutation

have generally relied on the easy-to-obtain skin cells, which are not

affected in SMA and don't offer much insight into how and why motor

neurons die, says UW-Madison researcher Ebert, lead author on

the new study.

Ebert explain " 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. " Existing 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. The researchers can now, in effect,

watch the unfolding of an accident that has already occurred, and the

known clinical outcome - the course and severity of the patient's

disease. This should help them understand how the changes they see in

the cells fit into the bigger picture of the disease.

SMA expert Christian Lorson, Professor of veterinary pathobiology at

MU and an author on the paper, said " 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. 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. "

Whilst complex and late-hitting disorders, such as Alzheimer's and

Parkinson's diseases will be more difficult to model with iPS cells,

the scientists 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 kinds of

things to fruition, " he says.

Source - University of Wisconsin-Madison

Article URL: http://www.medicalnewstoday.com/articles/133905.php