Bangalore: In what could be the first leap towards treating genetic disorders, a group of Dutch researchers has proved in principle that personalized molecular therapy can work in muscular dystrophy and other genetic diseases, such as thalassemia.
In the 27 December issue of the New England Journal of Medicine, the researchers led by J.C. van Deutekom report that a small clinical trial on boys suffering from the most common inherited childhood diseases, Duchenne muscular dystrophy or DMD, proved that targeting individual genetic mutations in patients can restore muscle function. Affecting one in 3,500 live male births worldwide, DMD has no proven cure and is a disease where muscles gradually weaken, forcing the patients to be confined to a wheelchair. The incidence in India, according to experts, is about 3,570 every year, based on 25 million child births. (The ‘Duchenne’ in DMD comes from Guillaume Benjamin Amand Duchenne, who discovered this form of muscular dystrophy in the 19th century.)
The methodology used in the trials is without precedent. “This is the first clinical trial targeted against patients’ specific mutations. It’s an important proof of principle, although the patients received no therapeutic benefit from the trial [because it was a tiny dose],” said Eric Hoffman, director of the Research Centre for Genetic Medicine at Children’s National Medical Centre and George Washington University in Washington, D.C. Dr Hoffman was part of the Harvard University team that discovered the dystrophin gene, which codes a protein critical for the health of any muscle, in 1986.
Scientists have been experimenting with a technique called “exon skipping” in test tubes and animals, but this is the first time they tested it on humans. Exons are regions on the DNA that carry the genetic code for proteins. It has long been believed that using naturally occurring chemicals, in this case a modified nucleic acid drug injected into the muscle, the cellular machinery could be made to “skip over” the mutations in the patients’ muscles. Once the mutations, which prevent normal functioning of the muscle, are skipped, the normal production of the critical protein dystrophin resumes, resulting in restoration of muscle function. Dutch researchers proved this theory in humans.
Doctors in India called the findings a breakthrough. “This is indeed the first big step that opens up the field as the technique can be applied to other disorders like thalassemia or spinal muscular dystrophy,” said Ishwar Chander Verma, head, department of medical genetics at Sir Ganga Ram Hospital in New Delhi. “This finding gives us hope that we can probably use the same DNA drug in our studies.”
That could be a good start in a country where there’s been no systematic effort at data collection. “While the rest of the world has been working on muscular dystrophy for the last 30-40 years, we don’t even have a registry, or a national initiative,” said Lakshmi Raman, head of the coordinating committee at Chennai’s Muscular Dystrophy Association of India.
As far as the “exon skipping” breakthrough goes, medical experts agree that now the task at hand is to increase the potency of the drug. It also needs to achieve a body-wide restoration of dystrophin, rather than just the tiny area of muscle studied in this trial.
But the most important step, according to Dr Hoffman, is getting approval of this “drug as a class” (that is, approval of the chemistry, rather thanspecific DNA sequences), which would be a first in the US and other drug regulatory regimes.