Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Patient’s Own Cells May Hold Therapeutic Promise After Reprogramming, Gene Correction

05.04.2011
Study shows patient’s own cells may hold therapeutic promise after reprogramming, gene correction

Scientists from the Morgridge Institute for Research, the University of Wisconsin-Madison, the University of California and the WiCell Research Institute moved gene therapy one step closer to clinical reality by determining that the process of correcting a genetic defect does not substantially increase the number of potentially cancer-causing mutations in induced pluripotent stem cells.

Their work, scheduled for publication the week of April 4 in the online edition of the journal Proceedings of the National Academy of Sciences and funded by a Wynn-Gund Translational Award from the Foundation Fighting Blindness, suggests that human induced pluripotent stem cells altered to correct a genetic defect may be cultured into subsequent generations of cells that remain free of the initial disease. However, although the gene correction itself does not increase the instability or the number of observed mutations in the cells, the study reinforced other recent findings that induced pluripotent stem cells themselves carry a significant number of genetic mutations.

“This study showed that the process of gene correction is compatible with therapeutic use,” says Sara Howden, primary author of the study, who serves as a postdoctoral research associate in James Thomson’s lab at the Morgridge Institute for Research. “It also was the first to demonstrate that correction of a defective gene in patient-derived cells via homologous recombination is possible.”

Like human embryonic stem cells, induced pluripotent stem cells can become any of the 220 mature cell types in the human body. Induced pluripotent stem cells are created when skin or other mature cells are reprogrammed to a pluripotent state through exposure to select combinations of genes or proteins.

Since they can be derived from a patient’s own cells, induced pluripotent stem cells may offer some clinical advantages over human embryonic stem cells by avoiding problems with rejection. However, scientists are still working to understand subtle differences between human embryonic and induced pluripotent stem cells, including a higher rate of genetic mutations among the induced pluripotent cells and evidence that the cells may retain some “memory” of their previous lineage.

Gene therapy using induced pluripotent stem cells holds promise for treating many inherited and acquired diseases such as Huntington’s disease, degenerative retinal disease or diabetes. The patient in this study suffers from a degenerative eye disease known as gyrate atrophy, which is characterized by progressive loss of visual acuity and night vision leading to eventual blindness.

While diseases such as genetic retinal disorders and diabetes offer attractive targets for induced pluripotent stem cell-based transplant therapies, concerns have been raised over the commonly occurring mutations in the cells and their potential to become cancerous.

Howden says that because gene targeting to correct specific genetic defects typically requires an extended culture period beyond initial induced pluripotent stem cell generation, researchers have been interested to learn whether the process would increase the number of mutations in the cells. The team set out to determine if it was possible to correct defects without introducing a level of mutations that would be incompatible with clinical applications.

In the study, the researchers used a technique called episomal reprogramming to generate the induced pluripotent stem cells. In contrast to techniques that use retroviruses, episomal reprogramming doesn’t involve inserting DNA into the genome. This technique allowed them to produce cells that were free of potentially harmful transgene sequences.

The scientists then corrected the actual retinal disease-causing gene defect using a technique called homologous recombination. The stem cells were extensively “characterized” or studied before and after the process to assess whether they developed significant additional mutations or variations. The results showed that the culture conditions required to correct a genetic defect did not substantially increase the number of mutations.

“By showing that the process of correcting a genetic defect in patient-derived induced pluripotent cells is compatible with therapeutic use, we eliminated one barrier to gene therapy based on these cells,” Howden says. “There is still much work to be done.”

David Gamm, an author of the study and an assistant professor with the Department of Ophthalmology and the Waisman Center Stem Cell Research Program, says the ability to correct gene defects in a patient's own induced pluripotent stem cells should increase the appeal of stem cell technology to researchers striving to improve vision in patients with inherited blinding disorders.

“Although further development certainly is needed before such techniques may reach the clinical trial stage, our findings offer reason for continued hope,” Gamm says. “Dr. Howden and our collaborative group have overcome an important hurdle which, when considered in the context of other recent developments, may lead to personalized stem cell therapies that benefit people with genetic visual disorders.”

In addition to primary author Howden, who holds joint appointments with the Morgridge Institute for Research, the Department of Cell and Regenerative Biology and the Genome Center of Wisconsin, co-authors of the study included: Thomson, who in addition holds an appointment with the Department of Molecular, Cellular & Developmental Biology, University of California-Santa Barbara; Gamm, who holds joint appointments with the UW-Madison School of Medicine and Public Health’s Department of Ophthalmology and Visual Sciences and the Waisman Center Stem Cell Research Program; Jeff Nie, Goukai Chen, Brian McIntosh, Daniel Gulbranson, Nicole Diol and David Vereide with the Morgridge Institute for Research; Athurva Gore, Zhe Li, Ho-Lim Fung and Kun Zhang, of the Department of Bioengineering at the University of California-San Diego; and Benjamin Nisler, Seth Taapken and Karen Dyer Montgomery of WiCell Research Institute.

Made possible with support from John and Tashia Morgridge, the Wisconsin Alumni Research Foundation and the state of Wisconsin, the interdisciplinary Morgridge Institute for Research aims to speed the process through which discoveries in the laboratory are delivered to the public to advance human health and well-being. The private, nonprofit Morgridge Institute for Research is located on the UW–Madison campus and works collaboratively with the public Wisconsin Institute for Discovery. For more, visit http://discovery.wisc.edu/morgridge.

Sara Howden | Newswise Science News
Further information:
http://www.wisc.edu

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>