After decades of disappointingly slow progress, researchers have taken a substantial step toward a possible treatment for Duchenne muscular dystrophy with the help of a powerful new gene-editing technique.
Duchenne muscular dystrophy is a progressive muscle-wasting disease that affects boys, putting them in wheelchairs by age 10, followed by an early death from heart failure or breathing difficulties. The disease is caused by defects in a gene that encodes a protein called dystrophin, which is essential for proper muscle function.
Because the disease is devastating and incurable, and common for a hereditary illness, it has long been a target for gene therapy, though without success. An alternative treatment, drugs based on chemicals known as antisense oligonucleotides, is in clinical trials.
But gene therapy — the idea of curing a genetic disease by inserting the correct gene into damaged cells — is making a comeback. A new technique, known as Crispr-Cas9, lets researchers cut the DNA of chromosomes at selected sites to remove or insert segments.
Three research groups, working independently of one another, reported in the journal Science on Thursday that they had used the Crispr-Cas9 technique to treat mice with a defective dystrophin gene. Each group loaded the DNA-cutting system onto a virus that infected the mice’s muscle cells, and excised from the gene a defective stretch of DNA known as an exon.
Without the defective exon, the muscle cells made a shortened dystrophin protein that was nonetheless functional, giving all of the mice more strength.
The teams were led by Charles A. Gersbach of Duke University, Eric N. Olson of the University of Texas Southwestern Medical Center and Amy J. Wagers of Harvard University.
“The papers are pretty significant,” said Louis M. Kunkel, a muscular dystrophy expert at Boston Children’s Hospital who discovered the dystrophin gene in 1986.
The dystrophin protein plays a structural role, anchoring each muscle fiber to the membrane that encloses the muscle-fiber bundle. The dystrophin gene, which guides the protein’s production in the cell, sprawls across about 1 percent of the X chromosome and is the largest in the human genome.
That gene has 79 sections, or exons, but can evidently maintain reasonable function even if a few exons in the middle are lost. The protein works as long as its two ends are intact.
This is what happens in a milder disease known as Becker muscular dystrophy, in which mutations cause instructions from a few exons to be skipped during the protein-making process. In Duchenne muscular dystrophy, however, mutations cause muscle cells to make a truncated protein missing one end, and this protein does not work at all.
This difference suggests a possible treatment strategy: removing damaged exons so Duchenne patients’ muscle cells produce an intact, though shorter, dystrophin protein, much like that seen in Becker patients.
A laboratory strain of mice has Duchenne-type muscular dystrophy in which a major part of the dystrophin protein is lost because of a mutation in the 21st exon of the gene. In 2014, Dr. Olson’s team reported that it had been able to edit out the damaged exon, enabling muscle cells to generate a functional protein.
That gene editing was done in the fertilized egg of the mouse, making an inheritable change to the mouse’s genome. There is a moratorium on making such changes to the human genome, and in any case, such an intervention would come too late for muscular dystrophy patients. So Dr. Olson’s next step was to see if he could produce the same result in the muscles of young mice.
In the study published Thursday, Dr. Olson’s team reported that they loaded the gene-editing system into a harmless virus, along with guides that directed it to cut the two ends of the 21st exon. The virus infected muscle cells throughout the mouse’s body, snipping out the exon from the dystrophin gene.
The muscle cells repaired the DNA by joining the pieces of the cut chromosome and generated an effective dystrophin protein.
The two other teams performed almost exactly the same experiment, each pursuing a consequence of its own previous research. Dr. Gersbach’s groupreported earlier in 2015 that, with Crispr-Cas9 editing, they could remove the 45th to 55th exons of the dystrophin gene from Duchenne patient cells grown in laboratory cultures. With the damaged exons removed, the cells started to produce dystrophin proteins.
More than 60 percent of Duchenne patients have mutations in these exons, so this approach could be significant for them.
Dr. Wagers has long been interested in the stem cells that generate new muscle cells. Her team’s experiment differed from the others in that it looked specifically at whether the gene-altering virus could infect thesestem cells, and found that it could.
Treating a patient’s muscle stem cells could produce a more permanent result than changing ordinary muscle cells, which turn over at a brisk rate in muscular dystrophy patients, though not in healthy people.
All three teams have filed for patents. But considerable work lies ahead before clinical trials can start. It is not clear how the human immune system would react to the components of the gene-editing system or to modified dystrophin proteins to which it has not been habituated.
If a gene therapy for muscular dystrophy can be developed, it will compete with the antisense oligonucleotide drugs that are already in clinical trials. These work on the same principle of avoiding damaged exons, but instead of cutting them out of the DNA, they force the exons to be skipped at a later stage of the protein manufacturing process.
The drugs do not target the heart muscles very well, however, and they must be given weekly. A gene therapy treatment should last longer.
“The advantage of the DNA approach is that the cell has no choice but to make the protein you want,” Dr. Wagers said.
Some fear that Duchenne patients may get only one shot at treatment before developing resistance to the virus used to edit the defective exons. But Dr. Gersbach played down this concern.
“The hope for gene editing is that if we do this right, we will only need to do one treatment,” he said. “This method, if proven safe, could be applied to patients in the foreseeable future.”
Dr. Olson also said that progress would be rapid.
“To launch a clinical trial, we need to scale up, improve efficiency and assess safety,” Dr. Olson said. “I think within a few years, those issues can be addressed.”