Combined Stem Cell Gene Therapy Approach Cures Human Genetic Disease In Vitro

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Combined Stem Cell Gene Therapy Approach Cures Human Genetic Disease In Vitro

01 Jun 2009

A study led by researchers at the Salk Institute for Biological Studies, has

catapulted the field of regenerative medicine significantly forward, proving in

principle that a human genetic disease can be cured using a combination of gene

therapy and induced pluripotent stem (iPS) cell technology. The study, published

in the May 31, 2009 early online edition of Nature, is a major milestone on the

path from the laboratory to the clinic.

" It's been ten years since human stem cells were first cultured in a Petri

dish, " says the study's leader - Izpisúa Belmonte, Ph.D., a professor

in the Gene Expression Laboratory and director of the Center of Regenerative

Medicine in Barcelona (CMRB), Spain. " The hope in the field has always been that

we'll be able to correct a disease genetically and then make iPS cells that

differentiate into the type of tissue where the disease is manifested and bring

it to clinic. "

Although several studies have demonstrated the efficacy of the approach in mice,

its feasibility in humans had not been established. The Salk study offers the

first proof that this technology can work in human cells.

Belmonte's team, working with Salk colleague Inder Verma, Ph.D., a professor in

the Laboratory of Genetics, and colleagues at the CMRB, and the CIEMAT in

Madrid, Spain, decided to focus on Fanconi anemia (FA), a genetic disorder

responsible for a series of hematological abnormalities that impair the body's

ability to fight infection, deliver oxygen, and clot blood. Caused by mutations

in one of 13 Fanconi anemia (FA) genes, the disease often leads to bone marrow

failure, leukemia, and other cancers. Even after receiving bone marrow

transplants to correct the hematological problems, patients remain at high risk

of developing cancer and other serious health conditions.

After taking hair or skin cells from patients with Fanconi anemia, the

investigators corrected the defective gene in the patients' cells using gene

therapy techniques pioneered in Verma's laboratory. They then successfully

reprogrammed the repaired cells into induced pluripotent stem (iPS) cells using

a combination of transcription factors, OCT4, SOX2, KLF4 and cMYC. The resulting

FA-iPS cells were indistinguishable from human embryonic stem cells and iPS

cells generated from healthy donors.

Since bone marrow failure as a result of the progressive decline in the numbers

of functional hematopoietic stem cells is the most prominent feature of Fanconi

anemia, the researchers then tested whether patient-specific iPS cells could be

used as a source for transplantable hematopoietic stem cells. They found that

FA-iPS cells readily differentiated into hematopoietic progenitor cells primed

to differentiate into healthy blood cells.

" We haven't cured a human being, but we have cured a cell, " Belmonte explains.

" In theory we could transplant it into a human and cure the disease. "

Although hurdles still loom before that theory can become practice - in

particular, preventing the reprogrammed cells from inducing tumors - in coming

months Belmonte and Verma will be exploring ways to overcome that and other

obstacles. In April 2009, they received a $6.6 million from the California

Institute Regenerative Medicine (CIRM) to pursue research aimed at translating

basic science into clinical cures.

" If we can demonstrate that a combined iPS-gene therapy approach works in

humans, then there is no limit to what we can do, " says Verma.

Researchers who also contributed to the work include first author Ángel Raya, as

well as Ignasi Rodríguez-Pizà, Rita Vassena, María José Barrero, Antonella

Consiglio, Eduard Sleep, Federico González, Gustavo Tiscornia, Elena Garreta,

Trond Aasen, and Veiga of the Center for Regenerative Medicine in

Barcelona, Spain; Guillermo Guenechea, a Navarro, a Río, and

Bueren of the Hematopoiesis and Gene Therapy Division, Centro de Investigaciones

Energéticas, Medioambientales y Tecnológicas in Madrid, Spain; and

Castellà and Jordi Surrallés of the Department of Genetics and Microbiology,

Universitat Autonoma de Barcelona.

Source:

Kirchweger

Salk Institute

Article URL: http://www.medicalnewstoday.com/articles/152037.php