Through the Pipeline, as Fast as Possible

MDA's research program in 2010

Article Highlights:
  • MDA's research "pipeline" funds both basic scientific research and translational research (focused on therapy development), with the goal of moving promising discoveries into viable treatments as quickly as possible.
  • MDA partners with biopharmaceutical companies and the National Institutes of Health in pursuing its research goals.
  • In evaluating grant applications, MDA always asks, "How will this lead us in a foreseeable fashion to improve the diagnosis and treatment of a neuromuscular disease?"
by Margaret Wahl on December 31, 2009 - 1:10am

QUEST Vol. 17, No. 1

As MDA's research program heads into 2010, new directions, strategies and partnerships are under way.

All have the ultimate goal of moving research through the “pipeline” from basic science discoveries in university laboratories, to biotechnology development, and ultimately into viable therapies that can be prescribed in the clinic.

Below are examples of how this “pipeline” research approach is playing out for several diseases in MDA’s program.

Then and now

The history of MDA's research grants program, which began in 1950, can be very roughly divided into four periods, with the understanding that there's a great deal of overlap among them.

From approximately 1950 to 1965, the bulk of MDA's funding went toward discovering the basic mechanisms underlying nerve and muscle function, many of which had barely been elucidated.

From the mid 60s until about 1980, MDA’s research emphasis was on defining and classifying the various neuromuscular diseases. This was followed by an intense period that peaked during the 1990s of identifying genes underlying these diseases. (Gene identifications continue to this day.)

In the 21st century, MDA's research program has focused on applying the knowledge gained over the last half-century, with the goal of obtaining a full understanding of the biology of the diseases in its program, and developing therapies based on the underlying biological pathways that have been identified.

Into the pipeline

Imagine biomedical research as a pipeline. Raw materials enter at one end in the form of basic scientific research, are processed and analyzed in the pipeline, and then are released at the far end as potential therapies.

“Basic scientific research” refers to investigations into the fundamental way things work at the cellular or molecular level, without any immediate relevance to disease treatment.

Rodney Howell, M.D.
Rodney Howell, M.D.

MDA continues to fund basic research that feeds the pipeline, but it has increasingly partnered with and relied upon the National Institutes of Health (NIH) for this raw material.

"A few years ago, MDA really didn't interact with the NIH at all," says Rod Howell, a medical geneticist and professor of pediatrics at the University of Miami. Howell is a senior adviser to NIH's National Institute of Child Health and Human Development, and chairman of MDA's Board of Directors.

"With the passage of the MD-CARE Act, and with the periodic meetings that occur with its oversight, that interaction increased, and the relationship between MDA and NIH has become considerably more effective," says Howell, who was part of MDA's Medical Advisory Committee in the 1980s and chaired its Scientific Advisory Committee until recently.

(The Muscular Dystrophy Community Assistance, Research and Education Act was passed by the U.S. Congress in December 2001. It directed NIH to establish a series of “centers of excellence” in MD research, the first three of which were co-funded by NIH and MDA.)

Howell noted that NIH’s principal research program is charged with accepting scientific proposals for basic research without necessarily being concerned about developing that research into disease treatments. That’s where MDA steps in.

"The key difference that I see between MDA and NIH is that MDA reviews grant applications just as rigorously, but always with the question, ‘how will this observation lead us in a foreseeable fashion to improve the diagnosis and treatment of a neuromuscular disease?’ Not tomorrow morning, necessarily, but you want the grant applicant to explain right now how a discovery may improve our ability to do those things."

Howell says the relationship between MDA's funding program and NIH's is complementary. He cites the recent $18.6 million in stimulus grants received by more than 50 current and former MDA research grantees as a good example of this principle. (See "MDA Scientists Win Federal Stimulus Grants for Neuromuscular Disease Research.")

Examples of drug development

Meanwhile, at the other end of the pipeline, MDA's translational (lab to clinic) research program has begun working much more closely with the drug development industry.

Drug development for the strategy called "exon skipping" is a good example of how MDA helps move basic research through the pipeline, in coordination with other institutions and industry.

As soon as it became clear that an exon skipping strategy potentially could boost production of the missing muscle protein dystrophin in Duchenne muscular dystrophy (DMD), MDA began funding laboratory research with an eye toward treatment development.

The process started about a decade ago, with MDA giving funding to Stephen Wilton at the University of Western Australia and Judith van Deutekom at Leiden University Medical Center in the Netherlands. 

Next, the U.S. biotechnology company AVI BioPharma developed an exon skipping compound for Duchenne dystrophy based on Wilton's work that’s now being tested in patients.

At about the same time, Judith van Deutekom's exon skipping work was picked up by the Dutch biotechnology company Prosensa, where van Deutekom is now discovery director. After the compound showed promise in early-stage clinical trials, it drew the attention of the “big guns” - the multinational pharmaceutical company GlaxoSmithKline, which recently committed to further development and commercialization of this strategy.

MDA’s research program followed a similar course with another potential therapy for DMD (and perhaps other genetic diseases) known as "stop codon read-through." This strategy, which instructs cells to "read through" molecular stop signs that prematurely end the synthesis of needed proteins, began with MDA funding to academic labs.

As the research matured, MDA funded PTC Therapeutics, a New Jersey biotech company, which has since taken its drug Ataluren into phase 2 clinical trials in DMD-affected boys who are still walking and in those who are not walking.

Many irons in the fire

In yet another example of the pipeline approach, late in 2009, MDA began funding the small biotechnology companies Catabasis Pharmaceuticals of Cambridge, Mass., and Validus BioPharma of Rockville, Md., to take different approaches to develop anti-inflammatory compounds that act similarly to corticosteroid medications (like prednisone) but with fewer side effects.

The initial experiments will be directed at quelling inflammation in DMD, but other disease applications are possible. The investigations these companies are undertaking are based on years of MDA-supported laboratory research to understand the pathways involved in the inflammatory response.

A similar pattern was followed in the development of a potential therapy for Friedreich's ataxia. A few years ago, MDA funded Joel Gottesfeld at The Scripps Research Institute in La Jolla, Calif., to work on a strategy to enhance production of the needed muscle protein frataxin by FA-affected cells, despite the presence of genetic mutations.

The Waltham, Mass., biotechnology company Repligen, which began receiving MDA support in 2007 and received a new grant in 2009, has now begun to develop a specific experimental drug to increase frataxin production.

Decades of laboratory research and millions of MDA dollars are behind yet another highly promising strategy - gene transfer therapy for Duchenne and limb-girdle muscular dystrophies.

Starting with academic research in the 1990s, MDA moved to supporting the North Carolina biotechnology company Asklepios BioPharmaceutical as clinical trials became a reality.

The MDA-supported trial of alpha-sarcoglycan gene transfer for type 2D limb-girdle MD is moving forward, and an additional trial to transfer the dystrophin gene in Duchenne MD is on the drawing board. (Results of a phase 1 trial are still under review, and discussions of the best approach to take going forward are under way.) At some point, this process will likely require the involvement of a large pharmaceutical company.

It’s complicated

Howell emphasizes that basic research and "translational"  research (geared toward therapy development) always have to move forward together.

In the early 1990s, he recalls, it was thought "once we know what the gene is [that underlies a disease], we'll simply give the genetic information, the person will make the protein, and all will be well." Unfortunately, he says, "It's much more complicated than we thought.”

For instance, he notes, research still hasn’t solved the immune response problems that appear in some gene recipients. That, he imagines, will take a great deal of research by basic scientists.

Howell recalls the history of therapeutic development for Pompe disease (acid maltase deficiency), a disease that was fatal in infants until recently, but which now can be treated, in some cases, by the laboratory-developed enzyme Myozyme.

Myozyme is yet another example of MDA-supported basic research that attracted the attention of the biotechnology industry and ultimately of the large biopharmaceutical Genzyme, which brought Myozyme to market.

It took a lot of basic research before this drug could become a reality.

"Well over 25 years ago, I was closely following the clinical studies of Pompe disease," Howell recalls. "We knew what the enzyme defect was. We thought, ‘if you know what the enzyme defect is, you just give the enzyme, and that should correct the problem, right?’ Researchers infused the enzyme and it didn't work, although we didn't know the reason at the time. That was before we knew about side chains containing mannose receptors — part of the biology of how the enzyme targets the cells — and specific locations inside the cell, such as the lysosome, and how to get the enzyme to the exact right spot." 

During the 1990s, MDA grantee Yuan-Tsong Chen and colleagues at Duke University, and other researchers, had to work out the basic molecular biology before the field could move forward.

Moving in tandem

Basic scientific discovery and translational research are not individual "silos" existing independently of each other, Howell says. "We’re still describing and defining some of our diseases," he says, and the focus of research periodically shifts between basic and applied science.

MDA doesn't necessarily have to be the sole research funder during this long and expensive process. MDA and NIH have co-funded many basic science projects that the Association believes have long-term therapeutic potential. And at the other end of the pipeline, MDA partners with biotechnology and pharmaceutical companies to bring that potential to fruition.

Howell notes, "I think we owe it to the patients and the people that give to MDA that if we fund a basic research grant to find out how something works, we'll then be ready to think about what sorts of drugs will affect it."

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