February 2006 | VOL. 2 | www.McGowan.pitt.edu

Duchenne muscular dystrophy (DMD) is a genetic disease marked by continual disintegration of muscle tissue. There’s no cure for the disease, which affects one in every 3,500 boys born, and there is no effective treatment. Most afflicted with the disease die before the age of 30.

Dr. Xiao Xiao is leading a study in gene therapy that has matured to the point that the first gene therapy trial for Duchenne muscular dystrophy in the United States will begin this year.

Dr. Xiao and his colleagues have been exploring the efficacy of a once-ignored virus, adeno-associated virus (AAV), as a delivery system for gene therapy.  Xiao notes that AAV is ideal for this application because it doesn’t cause disease, explaining why it was given little attention until the 1980s. AAV does, however, have a couple of things going for it as a treatment vector—it can infect all kinds of cells and does not provoke an overt immune response.

A defect in the dystrophin gene—which spurs the production of the dystrophin protein, a major player in a protein chain that keeps muscle cells intact—causes DMD. Xiao and his colleagues decided to insert a healthy dystrophin gene into AAV and inject the virus into the muscle tissue of a DMD-afflicted mouse.

Using a modified dystrophin gene, the research team has developed a therapy that has proved effective, reversing DMD in mice and is showing promise in dogs. Proving efficacy in people is the next step, one which Dr. Xiao expects to take sometime in the first half of this year in a new clinical trial.

Adapted from PITTMED, February 2006, page 9, MORE

 

The Institute is sponsoring a new podcast on regenerative medicine.  The format consists of interviews with key researchers and clinicians in the field addressing topics of interest and germane to regenerative medicine, and the podcast also provides highlights upcoming events.  To date three shows have been posted and the response has been very enthusiastic with hundreds of downloads for each of the shows.

You can visit the podcast web site at www.regenerativemedicinetoday.com.  If you have an iPod (or similar device) you know how to subscribe to the RSS feed, but for most of us who have not become iPodders, you can listen to the interviews on your PC.

 

Over 200 faculty, students, staff and industry representatives are registered to participate in the 2006 McGowan Institute Retreat on March 6 and 7, 2006 at the Nemacolin Resort.  The focus of the retreat this year is enhancing our networking and collaboration with industry, by sharing our capabilities with prospective industrial partners and learning about the needs of industry relative to bringing regenerative medicine technologies to clinical use. 

For the 2006 Retreat, the Program Committee has identified key industrial leaders in different industrial sectors related to regenerative medicine who will work with faculty on needs identification and identification of potential barriers to collaboration

The participation and contributions of the industrial leaders along with McGowan Faculty and Trainees will provide for insightful discussions and opportunities for promising outcomes for each organization that participates.

The highlights of the 2006 retreat program include:

• Keynote address by key faculty and the following leaders in the industry:
  • Gail Naughton, Ph.D., Dean of College of Business Administration, San Diego State University, and Advanced Tissue Sciences Co-Founder and Vice Chair;
  • Bill Van Antwerp, Chief Scientific Officer, Medtronic
  • Dick Tarr, Executive Director, Memphis Musculoskeletal Research Institute Former Vice President of Worldwide Research and Emerging Technologies for DePuy Orthopaedics
• Introduction of the new and improved pathways to collaborate with and license University of Pittsburgh technologies;
• One-on-one “mini-sessions” between key industry personnel and faculty;
• Definition of industrial needs and development of means for enhanced collaboration;
• Poster session to introduce the focus and interests of Institute faculty (posters from the industrial participants are welcomed but not required);
• Special postdoctoral and graduate student networking sessions.

For the full program, please click here. We look forward to you joining us at Nemacolin in March for a very productive meeting.

 

Under the leadership of Drs. Douglas Kondziolka and Peter J. Jannetta, the School of Medicine is participating in a multicenter study that may help stroke survivors gain greater use of their arms and hands by electrically stimulating the brain during physical rehabilitation. Previous pilot studies have shown that such a combination is safe and enhances motor function more than rehabilitation alone. The electrical stimulation is provided by the temporary surgical placement of an electrode on the covering of the brain.

Stroke is a leading cause of serious, long-term disability in the United States. According to the American Stroke Association, approximately 4.8 million people are affected by stroke in the U.S., with approximately 700,000 additional strokes occurring annually. The 2004 cost of stroke is estimated to have been $53.6 billion.

Nationwide, the study will enroll 174 subjects. It will include participants age 21 years or older who have had an ischemic stroke at least four months prior to screening and suffered resulting weakness in one hand and/or arm. Participants will be randomized to either stimulation with rehabilitation or rehabilitation alone.

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Dr. Badylak has received second year support on a project that is funded by the Juvenile Diabetes Research Foundation. The objective of the project is to create functional, insulin secreting beta cells for use in patients with Type 1 diabetes.  By way of background, the Badylak lab has developed biologic scaffolds derived from the extracellular matrix (ECM) from a variety of tissues and organs. These various ECMs appear to promote the selective differentiation of cells by creating a microenvironment that sends instructive signals. For example, pancreatic ECM has the potential to promote the differentiation of pancreatic cell types such as insulin secreting islet cells. All preliminary evidence and ongoing studies will determine whether or not this represents a feasible approach to the treatment of Type 1 diabetes in human patients.  

The focus of the current study is to isolate ECM biologic scaffolds from numerous organs including the liver and pancreas and determine the ability to promote the differentiation of cells toward insulin secreting cells both in vitro (cell culture) and in vivo.

The study is expected to show that islet cells not only maintain their viability when cultured on appropriate ECM biologic scaffolds, but also proliferate and maintain levels of insulin production that exceed those of cells that are cultured on traditional media. Realizing that outcome would provide a valuable tool for the treatment of Type 1 diabetes. It would offer several potential modes of therapy including the use of biologic scaffolds alone, the use of biologic scaffolds seeded with progenitor cells, and/or the use biologic scaffolds seeded with differentiated islet cells in patients affected by Type 1 diabetes.

 

Author(s)	Hideki Oshima, Thomas R. Payne, Kenneth L. Urish, Tetsuro Sakai, Yiqun Ling, Burhan Gharaibeh, Kimimasa Tobita, Bradley B. Keller, James H. Cummins, and Johnny Huard
Title	Differential Myocardial Infarct Repair with Muscle Stem Cells Compared to Myoblasts
Summary	Myoblast transplantation for cardiac repair has generated beneficial results in both animals and humans; however, poor viability and poor engraftment of myoblasts after implantation in vivo limit their regeneration capacity. We and others have identified and isolated a subpopulation of skeletal muscle-derived stem cells (MDSCs) that regenerate skeletal muscle more effectively than myoblasts. Here we report that in comparison with a myoblast population, MDSCs implanted into infracted hearts displayed greater and more persistent engraftment, induced more neoangiogenesis through graft expression of vascular endothelial growth factor, prevented cardiac remodeling, and elicited significant improvements in cardiac function. MDSCs also exhibited a greater ability to resist oxidative stress-induced apoptosis compared to myoblasts, which may partially explain the improved engraftment of MDSCs. These findings indicate that MDSCs constitute an alternative to other myogenic cells for use in cardiac repair applications.
Source	MOLECULAR THERAPY Vol. 12, No. 6, December 2005 Page 1141; published by The American Society of Gene Therapy

 

Author(s)	Jörg Gerlach, M.D., Ph.D
Title	3D Culture of mES Cells in Four-Compartment Bioreactors
Description	Embryonic stem (ES) cell research and scale-up for development of possible clinical therapies is limited by the existing 2D dish culture methods. Our proposed studies present a new approach, in which ES cells are expanded under 3D medium perfusion conditions within four-compartment hollow fiber-based bioreactors. The design of the bioreactors allows integral oxygenation and efficient transfer of nutrients and waste products to and from the cells, cultured at high density involving minimal solute gradients within the cell compartment. Additionally, the interwoven fibers provide a scaffold allowing the cells to form 3D structures where the size of cellular aggregates is limited by the spacing between the hollow fibers. We propose that the well-controlled and versatile culture environment provided by our bioreactor is ideal for both large-scale expansion of undifferentiated ES cells and directed differentiation of ES cells using numerous strategies, including controlled exposure of the cells to molecular reagents and compartmentalized co-culture with mature cells. The objective of this 2-year project is to take the first step toward applying our bioreactor technology to ES cell research, by expanding and maintaining undifferentiated mouse embryonic stem (mES) cells in laboratory-scale versions of our bioreactor. We hypothesize that undifferentiated mES cells can be expanded and maintained in the perfused 3D environment provided by our bioreactor, and that within this 3D culture model mES cell pluripotency can be maintained by culturing mES cells and fibroblast feeder cells in two separate bioreactors perfused within one circuit (compartmentalized co-culture). The specific aim of the project is to: 1. Develop a 3D culture model for bioreactor expansion and maintenance of undifferentiated mES cells, incorporating compartmentalized co-culture of mES cells with fibroblast feeder cells and allowing for enzymatic mES cell harvesting. The research plan consists of the following tasks: 1.1 Develop the 3D culture model incorporating direct co-culture of mES cells and feeder cells; 1.2 Develop the culture model incorporating compartmentalized co-culture of mES cells and feeder cells; and 1.3 Develop a protocol for enzymatic mES cell harvesting from intact bioreactors. Completion of the project will provide a solid foundation for future studies on: 1) large-scale, potentially automated bioreactor expansion of ES cells; and 2) bioreactor-based directed differentiation of ES cells under perfused 3D tissue-density conditions.
Source	NIH R21 EB005739
Date	9/06/2005-7/31/2007

 

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