In the latest edition of the New England Journal of Medicine, Dr. Hoffman posits that the results of a small clinical trial involving a new treatment for Duchenne muscular dystrophy provides a proof-of-principle for personalized molecular medicine. Practical implementation of the ‘exon-skipping’ approach described in the co-published report of vanDeutekom et al. will require advances in systemic administration of large amounts of customized DNA-like drugs, and proof that long-term delivery is not toxic. However, these advances are likely to come in short order, with the oversight and regulations of the FDA critical for appropriate labeling and marketing of such personalized molecular target drugs.

Though this particular treatment remains in its early stages, within the foreseeable future the now-standard Phase I, II, and III pathway to drug approvals may need to be re-evaluated.

How can DNA-like drugs specific to a single patient’s mutation go through the existing approval process” Are the current standards of rodent and monkey toxicity studies relevant and appropriate for DNA-like drugs, when the animals do not have the same DNA target (or off-target) sequences as humans” These and other questions are certain to pose exciting challenges to both the approval and marketing processes of drugs.

The study featured in the latest edition of The New England Journal of Medicine, involves application of a nucleic acid drug called PRO051. It shows some success at restoring the expression of the specific protein–dystrophin, that is linked to healthy muscle tissue. This approach was shown to reactivate dystrophin protein production in small areas of muscle tissue at the injection site of muscular dystrophy patients.

“Dozens of specific sequences will be required for effectively treating the majority of patients with Duchenne muscular dystrophy,” writes Dr. Hoffman. “But in order to realize the promise of personalized molecular medicine in muscular dystrophies and, ultimately, other disorders, it will be important to re-evaluate current measures of toxicity, efficacy, and marketing that ensure both safety for the patient, as well as rapid development and distribution of life-saving drugs.”

Dr. Hoffman envisions that some parts of the approval process may be developed for DNA-like molecular medicine as a ‘class’ of drugs, rather than individual testing of hundreds of different sequences.

“The patients and their families are crossing their fingers that the drug’s overall chemistry can be shown to be safe,” he says.

About Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) affects about 1 in 3,500 boys of all races and ethnicities born in the U.S. and around the world. DMD has the greatest annual per-person cost for outpatient rehabilitation treatment of all neuromuscular disorders. The combination of the disease’s prevalence, seriousness, unpredictable occurrence, cross-cultural presentation and combined emotional and financial expense make DMD a significant public health concern.

About Eric P. Hoffman, PhD

Dr. Hoffman is a world-renowned human geneticist, who is the Director of the Research Center for Genetic Medicine, a James Clark Professor of Pediatrics at Children’s National Medical Center and George Washington University in Washington DC. The Center has integrated state-of-the-art basic genetics research (genome, transcriptome, and proteome), with an international clinical trial network, and ethics research. He has one of the largest and most diverse portfolios of research and foundation funding world-wide, with nearly $9 million per year in support on topics ranging from muscular dystrophy, medical rehabilitation studies, type 2 diabetes, and asthma. He leads a team of about 100 researchers dedicated to the study of translational research and therapeutics in pediatric medicine. He has over 300 publications, some of which are among the most cited.

Children’s National Medical Center, located in Washington, DC, is a proven leader in the development of innovative new treatments for childhood illness and injury. Consistently ranked among the top pediatric hospitals in America, Children’s has been serving the nation’s children for more than 135 years. Children’s National is proudly ranked among the best pediatric hospitals in America by US News & World Report and the Leapfrog Group. For more information, visit http://www.dcchildrens.com. Children’s Research Institute, the academic arm of Children’s National Medical Center, encompasses the translational, clinical and community research efforts of the institution. Visit our web site at http://www.dcchildrens.com.

Reporting in the Nov. 28th issue of the Journal of Neuroscience, the researchers said treatments of recombinant heat shock protein 70 (Hsp70) increased total lifespan by 10 percent significantly more than Riluzole®, the only ALS treatment approved by the U.S. Food and Drug Administration. They cautioned that while the research suggests a new treatment approach for ALS, it is not ready for studies in patients.

“This is another piece in the puzzle of what causes ALS and how to best treat it,” said David Gifondorwa, lead author and a Ph.D. candidate at Wake Forest. “It’s possible that one day a treatment based on this finding could be part of a ‘cocktail’ for attacking the disease from different fronts.”

ALS is a disease that causes death of motor neurons, the nerve cells that control muscles. There are two sets of motor neurons affected in ALS: upper motor neurons that are located in the brain and brainstem, and lower motor neurons that are located in the spinal cord but send out nerve fibers, or “transmission lines,” to connect with muscles.

The study focused on the lower motor neurons. Previous research by Wake Forest and others had shown that before the motor neuron dies, it first detaches, or denervates, from the muscle.

“There is a growing amount of research that suggests denervation is what happens first,” said Carol Milligan, Ph.D., senior researcher. “Our hope is that the results of our study will help steer thinking into focusing on what happens at the junction of nerve and muscle. It is possible that if we can develop treatments to maintain the contact of nerves and muscle, we can maintain the health of the motor neurons longer.”

The current study involved mice that are genetically engineered to develop ALS. They have the same genetic defect found in about 2 to 3 percent of human ALS cases. The mice were treated with either a placebo, Riluzole, or Hsp70, a protein made by the cells of both animals and humans. Heat shock proteins are produced by cells as part of the stress response to protect themselves from injury. In several animal models of ALS, motor neurons do not mount a typical stress response.

The researchers tested whether injecting the mice with Hsp70 would help protect the motor neurons. The mice in the study got injections of Hsp70 three times a week beginning 50 days after birth. The injections were effective at increasing lifespan, delaying symptom onset, preserving motor function and prolonging motor neuron survival. Lifespan increased by 10 days in the Hsp70 treated mice, compared to one day in the Riluzole group. Ten days represents about 10 percent increase in the lifespan of this animal model of ALS. In humans, Riluzole increases lifespan by about 60 days.

The treatment was not detected in the central nervous system, leading the researchers to believe that it acts not in the spinal cord, but where the neurons attach to muscle. Treatment with Hsp70 resulted in an increased number of innervated muscles, compared to the other groups.

“The protein seems to work at the neuromuscular junction,” said Gifondorwa. “Because current ALS treatments work at the spinal cord, our finding suggests the possibility of a cocktail that works to prevent damage in both locations may prove more beneficial.”

Wake Forest is currently studying new ALS treatments, as well as working to better understand what goes wrong to cause the disease. The Wake Forest ALS Center, under the directorship of James Caress, M.D., will soon be part of the clinical trial of Arimoclomol, a drug that works to enhance the stress response of nerve cells. And, a team of nine researchers from five departments that includes Milligan and Caress is developing a series of projects with the goal of understanding more about the early events in the development of ALS.

In mice, the researchers will study changes that occur in the muscles, nerves and spinal cord with denervation. They will also work to determine which nerves and muscles are affected first. In humans with ALS, they hope to look at early muscle changes using advanced imaging technology.

Co-researchers on the current study were Mac Robinson, Ph.D., Crystal Hayes, M.S., Anna Taylor, Ph.D., David Prevette, B.S., Ronald Oppenheim, Ph.D., and James Caress, M.D.

Wake Forest University Baptist Medical Center is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university’s School of Medicine. U.S. News & World Report ranks Wake Forest University School of Medicine 18th in primary care and 44th in research among the nation’s medical schools. It ranks 35th in research funding by the National Institutes of Health. Almost 150 members of the medical school faculty are listed in Best Doctors in America.

Rochester scientists were able to design a synthetic RNA-based molecule that, when injected into mice with myotonic dystrophy, restored a critical cellular mechanism, or pathway, that controls electrical activity in muscles. In people with the disease, this function is essentially disabled and muscle cells cannot relax properly. The researchers found that once this pathway was re-established, normal muscle function returned.

“The significance of this work is the proof of concept that a fundamental aspect of this genetic disease can be reversed even after it is very well established,” said Charles Thornton, M.D., co-director of the URMC Neuromuscular Disease Center and senior author of the study. “It encourages us to believe that other parts of the disease could be reversible as well.”

Myotonic dystrophy — the most common form of muscular dystrophy in adults — is characterized by progressive muscle wasting and weakness, particularly in the lower legs, hands, neck, and face. People with myotonic dystrophy have prolonged muscle tensing (myotonia) and are not able to relax certain muscles after use. The condition is particularly severe in the hand muscles and can cause a person’s grip to lock, making it difficult to perform rapid, repeated movements. Consequently, myotonia significantly interferes with a person’s ability to work and function. Myotonia is also one of the earliest signs of myotonic dystrophy and is the symptom by which physicians typically recognize the disease.

Five years ago, Thornton and his colleagues in Rochester helped to unravel the genetic flaw that causes the disease by showing that messenger RNA (mRNA) — responsible for transmitting genetic information out of the nucleus and into the main part of the cell where instructions from the molecular blueprint get carried out — is responsible for the symptoms of the disease. In individuals with myotonic dystrophy, a faulty genetic “stutter” results in the over-production of a certain type of mRNA that, in turn, interferes with other important cellular functions including muscle control.

The regulation of muscle activity and relaxation is basically electrical and is governed by the movement of small charged particles into and out of muscle cells in a very controlled manner. This electrical flow goes through very specific pathways, including one called the chloride channel. In individuals with myotonic dystrophy, the chloride channel is essentially disabled, causing electrical signals in muscles stay “on” for too long, resulting in unstable muscle control — like when someone grasps another’s hand and can’t let go.

The Rochester team, working with the biotechnology company Gene Tools, created a synthetic RNA-based compound that restores the proper genetic instructions for building the chloride channel. When this compound, called a morpholino, was injected into the muscle cells of a set of mice with myotonic dystrophy, the chloride channel was restored and the myotonia all but disappeared and did not return for several weeks.

“This material is incredibly stable in the cells once we get it inside the muscle,” said URMC neurologist Thurman Wheeler, M.D., lead author of the study. “And the effects are surprisingly prolonged, which makes it potentially more attractive as a treatment.”

The Rochester team cautions that more work needs to be done before this new approach can be tested in people. First and foremost, a better method for delivering the compound throughout the body needs to be developed. However, researchers are encouraged by the results and believe that it could ultimately be a step toward a breakthrough treatment for the disease.

“This work should provide hope and encouragement to people with myotonic dystrophy and their families,” said Thornton. “This is a progressive and debilitating condition, but there are early indications that effective treatments are possible. To see a problem like myotonia disappear after it has been present for a long time is certainly a hopeful sign. As we move forward, we should not be content to keep this condition from getting worse. We should set our set our sights on making it better”