Potential to repair any genetic defect offered by new gene repair technique

Main Category: Genetics
Article Date: 14 Aug 2013 - 1:00 PDT Current ratings for:
Potential to repair any genetic defect offered by new gene repair technique

Using human pluripotent stem cells and DNA-cutting protein from meningitis bacteria, researchers from the Morgridge Institute for Research and Northwestern University have created an efficient way to target and repair defective genes.

Writing in the Proceedings of the National Academy of Sciences, the team reports that the novel technique is much simpler than previous methods and establishes the groundwork for major advances in regenerative medicine, drug screening and biomedical research.

Zhonggang Hou of the Morgridge Institute's regenerative biology team and Yan Zhang of Northwestern University served as first authors on the study; James Thomson, director of regenerative biology at the Morgridge Institute, and Erik Sontheimer, professor of molecular biosciences at Northwestern University, served as principal investigators.

"With this system, there is the potential to repair any genetic defect, including those responsible for some forms of breast cancer, Parkinson's and other diseases," Hou said. "The fact that it can be applied to human pluripotent stem cells opens the door for meaningful therapeutic applications."

Zhang said the Northwestern University team focused on Neisseria meningitidis bacteria because it is a good source of the Cas9 protein needed for precisely cleaving damaged sections of DNA.

"We are able to guide this protein with different types of small RNA molecules, allowing us to carefully remove, replace or correct problem genes," Zhang said. "This represents a step forward from other recent technologies built upon proteins such as zinc finger nucleases and TALENs."

These previous gene correction methods required engineered proteins to help with the cutting. Hou said scientists can synthesize RNA for the new process in as little as one to three days - compared with the weeks or months needed to engineer suitable proteins.

Thomson, who also serves as the James Kress Professor of Embryonic Stem Cell Biology at the University of Wisconsin-Madison, a John D. MacArthur professor at UW-Madison's School of Medicine and Public Health and a professor in the department of molecular, cellular and developmental biology at the University of California, Santa Barbara, says the discovery holds many practical applications.

"Human pluripotent stem cells can proliferate indefinitely and they give rise to virtually all human cell types, making them invaluable for regenerative medicine, drug screening and biomedical research," Thomson says. "Our collaboration with the Northwestern team has taken us further toward realizing the full potential of these cells because we can now manipulate their genomes in a precise, efficient manner."

Sontheimer, who serves as the Soretta and Henry Shapiro Research Professor of Molecular Biology with Northwestern's department of molecular biosciences, Center for Genetic Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, says the team's results also offer hopeful signs about the safety of the technique.

"A major concern with previous methods involved inadvertent or off-target cleaving, raising issues about the potential impact in regenerative medicine applications," he said. "Beyond overcoming the safety obstacles, the system's ease of use will make what was once considered a difficult project into a routine laboratory technique, catalyzing future research."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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Efficient genome engineering in human pluripotent stem cells using Cas9 from Neisseria meningitidis

Also contributing to the study, which was supported by funding from sources including the National Institutes of Health, the Wynn Foundation and the Morgridge Institute for Research, were Nicholas Propson, Sara Howden and Li-Fang Chu from the Morgridge Institute for Research.

Zhonggang Hou, Yan Zhang, Nicholas E. Propson, Sara E. Howden, Li-Fang Chu, Erik J. Sontheimer, and James A. Thomson. PNAS 2013 ; published ahead of print August 12, 2013, doi:10.1073/pnas.1313587110

University of Wisconsin-Madison

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Potential use of Excellagen to repair prenatally diagnosed birth defects using mesenchymal stem cells

Main Category: Stem Cell Research
Article Date: 14 Aug 2013 - 2:00 PDT Current ratings for:
Potential use of Excellagen to repair prenatally diagnosed birth defects using mesenchymal stem cells

Cardium Therapeutics has reported on a research collaboration with researchers at Boston Children's Hospital, to assess the medical utility of Excellagen® as a delivery scaffold to seed autologous mesenchymal fetal stem cells for ex-vivo engineering of tissue grafts for transplantation into infants to repair prenatally diagnosed birth defects.

Autologous mesenchymal fetal stem cells are derived prenatally from infants with a medical defect requiring life-saving tissue repairs. These stem cells are sourced from amniotic fluid, the placenta or umbilical cord blood. The stem cells are then seeded into a scaffold to promote the growth of an engineered tissue graft. These grafts will potentially be used to surgically repair, either in the fetus or immediately following birth, certain prenatally diagnosed birth defects that could include congenital diaphragmatic hernia, tracheal and chest wall defects, bladder extrophy and various cardiac anomalies. Preliminary pre-clinical research has confirmed that Excellagen collagen homogenate maintains mesenchymal fetal stem cell viability. Additional proof of concept studies are currently underway.

"Boston Children's team has made remarkable progress in the field of tissue regeneration and surgical repair of prenatally diagnosed congenital defects. We believe that Excellagen has an opportunity serve as a delivery platform in the field of stem cell therapy and we look forward to continuing to work with the Boston Children's team to help make their innovative therapeutic vision a new standard of care, and potentially advance stem cell therapies toward commercialization," stated Christopher J. Reinhard, Chairman and Chief Executive Officer of Cardium. "Excellagen was specifically designed to support advanced biologics and this new application further highlights its potential versatility as an important delivery agent for a variety of innovative therapeutic applications."

Cardium's FDA-cleared Excellagen is an aseptically-manufactured, quaternary fibrillar Type I bovine collagen homogenate that is configured into a staggered array of three-dimensional, triple helical, telopeptide-deleted, tropocollagen molecules. This linear array forms a flowable, biocompatible and bioactive structural matrix that can promote chemotaxis, cellular adhesion, migration and proliferation to stimulate tissue formation. The Excellagen homogenate represents a new product delivery platform that allows for the potential development of a portfolio of advanced tissue regeneration therapeutic opportunities that could include anti-infectives, antibiotics, peptides, proteins, small molecules, DNA, stem cells, differentiated cells and conditioned cell media.

Excellagen is a syringe-based, professional-use, pharmaceutically-formulated 2.6% fibrillar Type I bovine collagen homogenate that functions as an acellular biological modulator to activate the wound healing process and significantly accelerate the growth of granulation tissue. Excellagen's FDA clearance provides for very broad labeling including partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (donor sites/graft, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds (abrasions, lacerations, second-degree burns and skin tears) and draining wounds. Excellagen is intended for professional use following standard debridement procedures in the presence of blood cells and platelets, which are involved with the release of endogenous growth factors. Excellagen's unique fibrillar Type I bovine collagen homogenate formulation is topically applied through easy-to-control, pre-filled, sterile, single-use syringes and is designed for application at only one-week intervals.

There have been important, positive findings reported by physicians using Excellagen as part of Cardium's physician sampling, patient outreach and market "seeding" programs. In several case studies, physicians reported a rapid onset of the growth of granulation tissue in a wide array of wounds, including non-healing diabetic foot ulcers (consistent with the results of Cardium's Matrix clinical study), as well as pressure ulcers, venous ulcers and Mohs surgical wounds. In certain cases, rapid granulation tissue growth and wound closure have been achieved with Excellagen following unsuccessful treatment with other advanced wound care approaches. From a dermatology perspective, a previously unexplored vertical market, remarkable healing responses have been observed following Mohs surgery for patients diagnosed with squamous and basal cell carcinomas, including deep surgical wounds extending to the periosteum (a membrane that lines the outer surface of bones). Additionally, because of the easy-use and platelet activating capacity, physicians have been employing Excellagen in severe non-healing wounds at near-amputation status, in combination with autologous platelet-rich plasma therapy and collagen sheet products. These case studies and positive physician feedback provide additional support of Excellagen's potential utility as an important new tool to help promote the wound healing process. Excellagen case studies are available at http://www.excellagen.com/surgical-wounds.html.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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Study offers promising new direction for organ regeneration and tissue repair

Main Category: Biology / Biochemistry
Also Included In: Rehabilitation / Physical Therapy
Article Date: 02 Aug 2013 - 1:00 PDT Current ratings for:
Study offers promising new direction for organ regeneration and tissue repair

Because most human tissues do not regenerate spontaneously, advances in tissue repair and organ regeneration could benefit many patients with a wide variety of medical conditions.

Now a research team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and Dana-Farber/Boston Children's Cancer and Blood Disorders Center has identified an entirely new approach to enhance normal tissue growth, a finding that could have widespread therapeutic applications.

Their findings were published on-line in the Proceedings of the National Academy of Sciences (PNAS).

Tissue regeneration is a process that is not fully understood, but previous research has demonstrated that endothelial cells lining the insides of small blood vessels play a key role in tissue growth. It is also known that these endothelial cells generate chemical messengers called epoxyeicosatrienoic acids (EETs), which stimulate blood vessel formation in response to tissue injury.

In this new research, first author Dipak Panigrahy, MD, an investigator in BIDMC's Center for Vascular Biology Research, and his colleagues wanted to find out how EETs might participate in organ and tissue regeneration. To answer this question, they created seven different mouse models. The models focused on liver, kidney and lung regeneration; wound healing; corneal vascularization; and retinal vascularization.

"We used genetic and pharmacologic tools to manipulate EET levels in the animals to show that EETs play a critical role in accelerating tissue growth, providing the first in vivo demonstration that pharmacological modulation of EETs can affect organ regeneration," explains Panigrahy, an Instructor in Pathology at Harvard Medical School. Administering synthetic EETs spurred tissue growth in the research models; conversely, lowering EET levels - by either manipulating genes or administering drugs - delayed tissue regeneration.

The team also demonstrated that proteins called soluble epoxide hydrolase (sEH) inhibitors, known to elevate EET levels, promoted liver and lung regeneration. (sEH is the main metabolizing enzyme of EETs.)

"Our results offer a mechanistic rationale for evaluating sEH inhibitors as novel therapeutics for a number of human diseases such as hepatic insufficiency after liver damage and diseases characterized by immature lung development, such as bronchopulmonary dysplasia," says Panigrahy, adding that the use of topical sEH inhibitors on the skin might also be useful for the acceleration of wound healing.

The researchers suspected that EETs were stimulating tissue regeneration by way of blood vessel formation, specifically by producing vascular endothelial growth factor (VEGF) to promote vessel growth. As predicted, when the investigators depleted VEGF in the mice, EETs' effects on organ regeneration disappeared.

"Discovering EETs' role could be of critical importance to help control the repair of liver, lungs and kidneys," says senior author Mark Kieran, MD, PhD, of the Division of Pediatric Oncology at Dana-Farber/Boston Children's Cancer and Blood Disorders Center. "Since diseases of these organs are a major cause of morbidity and mortality in the North American population, the opportunity to modulate the regeneration of healthy tissue could have significant therapeutic implications for many patients." These findings may also apply to conditions or physical defects that lead to the loss of specialized cells in other organ systems, such as the nervous system and the immune system.

The investigators stress that it will be important to determine whether EETs affect other factors, besides VEGF, in influencing tissue repair. Additionally, they add, the beneficial effects of EETs will have to be carefully weighed against their finding that direct administration of EETs can stimulate cancer growth in animal models. Several clinical trials that are currently testing the potential of sEH inhibitors for purposes other than organ regeneration or wound repair could offer valuable insights into the safety of elevating EET levels in patients.

"Although our work suggests synthetic EETs would promote wound healing after surgery, more clinical trials are needed to assess the potential benefits and possible risks of these novel lipids," adds co-corresponding author Darryl Zeldin, MD, Scientific Director for the National Institute of Environmental Health Sciences, part of the National Institutes of Health.

In addition to laying the groundwork for future research, the investigators point out that this study highlights the benefits of experts from varying disciplines and organizations working together, noting that coauthors work in departments ranging from oncology to ophthalmology and from pharmacotherapy to transplantation. They included investigators from Boston Children's Hospital; the Institute for Systems Biology; the University of California, Davis; the National Institute of Environmental Health Science at the National Institutes of Health; the University of North Carolina at Chapel Hill; the Lahey Clinic Medical Center; the University of Texas Southwestern Medical Center; the Fred Hutchinson Cancer Research Center; and Schepens Eye Research Institute/Massachusetts Eye and Ear.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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Epoxyeicosanoids promote organ and tissue regeneration, PNAS published online before print July 29, 2013, doi: 10.1073/pnas.1311565110

In addition to Panigrahy, Kieran and Zeldin, coauthors include Bruce D. Hammock (co-corresponding author); Brian T. Kalish, Sui Huang, Diane R. Bielenberg, Hau D. Lee, Jun Yang, Matthew L. Edin, Craig R. Lee, Ofra Benny, Dayna K. Mudge, Catherine E. Butterfield, Akiko Mammoto, Tadanori Mammoto, Bora Inceoglu, Roger L. Jenkins, Mary A. Simpson, Tomoshige Akino, Fred B. Lih, Kenneth B. Tomer, Donald E. Ingber, John R. Falck, Vijaya L. Manthati, Arja Kaipainen, Patricia A. D'Amore, and Mark Puder.

This work was supported by grants from the National Cancer Institute (RO1CA148633-01A4); the Stop and Shop Pediatric Brain Tumor Fund; the C. J. Buckley Pediatric Brain Tumor Fund; the Children's Hospital Boston Surgical Foundation and the Vascular Biology Program; the Robert A. Welch Foundation (GL625910); the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 025034 and Z01 050167); the National Institutes of Health (R01 GM088199; GM31278; R01 ES002710; R01 ES013933, and CA045548; and the NIEHS Superfund Basic Research Program (NIH Grant P42 ES004699). The work was also supported through the Joshua Ryan Rappaport Fellowship and Howard Hughes Medical Institute Research Fellowship.

Beth Israel Deaconess Medical Center

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Stem cell discovery: Astrocytes could repair stroke brain damage

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Academic Journal
Main Category: Stroke
Also Included In: Neurology / Neuroscience;  Stem Cell Research
Article Date: 29 Jul 2013 - 0:00 PDT Current ratings for:
Stem cell discovery: Astrocytes could repair stroke brain damage

Stem cell researchers have discovered that astrocytes may prove useful against stroke and other brain disorders.

Astrocytes - neural cells that form the blood-brain barrier and so control what can and cannot enter the brain from the blood supply - have previously been overlooked in this area of stroke research.

A collaborative study published in Nature Communications suggests that astrocytes can do far more than simply support nerve cells (neurons).

Wenbin Deng, senior author of the study and associate professor of biochemistry and molecular medicine at UC Davis in California, told Medical News Today:

"This exciting research uncovers the brain-protective powers of stem cell-derived astrocytes.

Astrocytes may help to limit the spread of damage after an ischemic brain stroke in patients, and may also help to regenerate and repair damaged brain cells.

Both of these actions may lead to better functional recovery in patients."

Dr. Wenbin Deng added that astrocyte-centered therapy "could also be used for many other nervous system disorders." He said the following could be included in a list of potential targets for therapy:

Stem cell research has focused until now on developing stroke treatments using therapeutic neurons to stimulate electrical impulses in the brain, and restore tissue that has been damaged by oxygen deprivation. Dr. Wenbin Deng said astrocytes had often been considered just "housekeeping" cells that merely support nerve cells.

An astrocyte - more useful than previously thought. Courtesy Dr. Peng Jiang

"But they're actually much more sophisticated," Dr. Wenbin Deng explained. "They are critical to several brain functions and are believed to protect neurons from injury and death. They are not excitable cells like neurons and are easier to harness. We wanted to explore their potential in treating neurological disorders, beginning with stroke."

The UC Davis team faced an immediate challenge, however - there was little existing understanding on which specific types of astrocyte might have therapeutic potential in brain disorders. Also, the principal reason astrocytes had not been investigated in this context was the difficulty in producing them to the purity levels needed for stem cell therapies.

The UC Davis team decided to use a transcription factor protein called Olig2 to differentiate human embryonic stem cells into astrocytes. This approach generated a previously undiscovered type of astrocyte called Olig2PC-Astros - it was almost 100% pure.

"In this study, we report a surprising twist of fate," Dr. Wenbin Deng told MNT. He added:

"Our novel findings are that highly purified Olig2+ progenitors can give rise to astrocytes and that these astrocytes derived from highly purified Olig2+ progenitors are different from the astrocytes described in any previous work."

In short, the team's quest for a sufficiently pure astrocyte had, by serendipity, also led them to isolate a previously unknown astrocyte with particularly therapeutic properties.

Researchers used three groups of rats with ischemic brain injuries to compare the effects of Olig2PC-Astros, another type of astrocyte called NPC-Astros, and no treatment. The animals were placed in a water maze to assess their learning and memory.

Two weeks after transplantation, the rats receiving Olig2PC-Astros navigated the maze significantly quicker than the other groups. This group also exhibited higher levels of brain-derived neurotrophic factor (BDNF), a protein associated with nerve growth and resilience.

Cell cultures were also used to measure what protection the astrocytes could provide to neurons against the oxidative stress that contributes to brain injury following stroke.

When exposed to hydrogen peroxide, both types of astrocytes provided some protection but the Olig2PC-Astros showed greater antioxidant effects. Further investigation indicated higher levels of the protein Nrf2, which increases antioxidant activity in mouse neurons.

Additionally, the Olig2PC-Astros cells remained in brain areas where they were transplanted, did not differentiate into neurons or other cell types and formed no tumors.

Jan Nolta, director of the UC Davis Institute for Regenerative Cures, commented: "Dr. Deng's team has shown that this new method for deriving astrocytes from embryonic stem cells creates a cell population that is more pure and functionally superior to the standard method for astrocyte derivation."

Jan Nolta added:

"The functional improvement seen in the brain injury models is impressive, as are the higher levels of BDNF.

I will be excited to see this work extended to other brain disease models such as Huntington's disease and others, where it is known that BDNF has a positive effect."

Written by Nick Valentine

Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today Visit our stroke section for the latest news on this subject. "hESC-derived Olig2+ progenitors generate a subtype of astroglia with protective effects against ischaemic brain injury," Nature Communications, 23 July 2013. Full text Please use one of the following formats to cite this article in your essay, paper or report:

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