Gene Therapy With a Difference

Jeff Swensen for The New York Times

Genetic Treatment Aims for a Workaround: Experimental drugs use a technique called exon skipping to try to counteract genetic errors that cause muscular dystrophy.

Published: September 23, 2013

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Terri Ellsworth is convinced that her 12-year-old son Billy, who has Duchenne muscular dystrophy, is being helped by an experimental drug that counteracts the genetic mutation causing his disease.

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His ability to walk has not deteriorated in the two years he has been on the drug, whereas many boys with the disease would be in wheelchairs by his age. Billy opened a Gatorade bottle by himself recently, beaming from ear to ear. He even took off down an uneven dirt path without falling.

“He never would have done that, ever,” said Ms. Ellsworth, 55, a kitchen and bath designer from Coraopolis, Pa., outside Pittsburgh. “Without this drug, he would not be walking today.”

Such anecdotal reports, and data from small clinical trials, have raised hopes that a new genetic technique called exon skipping may slow the progression of Duchenne muscular dystrophy, finally yielding a treatment for which parents have prayed for decades. Scientists say the technique or related ones might also point the way to treatments for other inherited diseases, including Huntington’s.

The idea behind exon skipping is an ingenious one: a disease can be cured, or at least ameliorated, not by replacing a defective gene, as is done in gene therapy, but by correcting it.

“We’re sort of manipulating what the gene is ultimately making,” said Adrian R. Krainer, a professor of molecular genetics at the Cold Spring Harbor Laboratory.

Hopes for the new technique suffered a big blow on Friday when the results of the first large randomized clinical trial of a drug designed to induce exon skipping were announced. The drug, called drisapersen, was no better than placebo in preserving muscle function of boys with Duchenne muscular dystrophy.

The announcement was devastating to some parents of boys with muscular dystrophy and has raised questions about whether exon skipping will ever work. Could parents like Ms. Ellsworth be seeing only what they wish to see?

But some scientists and parents of children with muscular dystrophy said it was too early to write off the technique.

“We are fully confident in the exon-skipping technology as a viable platform to develop a treatment for Duchenne, and Duchenne families should not give up hope,” Debra Miller, chief executive of CureDuchenne, an advocacy group that sponsored research on the technique, said in a statement.

Drisapersen is being developed by GlaxoSmithKline and Prosensa, a small Dutch company whose stock lost 70 percent of its value after the announcement.

Billy Ellsworth is taking a different exon-skipping drug, eteplirsen, developed by Sarepta Therapeutics. The two drugs are different chemically, and it is possible that eteplirsen may prove more effective.

Protein Malfunction

Duchenne, which affects as many as 15,000 Americans, mainly boys, is the most severe common form of muscular dystrophy, the focus of those Jerry Lewis telethons. There is no good treatment, though steroids help. Boys with Duchenne are typically in wheelchairs by their early teenage years and die from cardiac or respiratory failure in their 20s.

People with Duchenne have a genetic mutation that prevents their bodies from producing dystrophin, a protein that is a sort of coiled spring and acts as a shock absorber for muscles.

Genes contain the recipes for the body’s proteins. They exist in the chromosomes in discrete segments called exons that are spliced together in RNA to form templates for proteins. Mutations resulting in missing exons can lead to the wrong proteins being produced, or none at all.

The chemical units in RNA, typically represented by the letters A, C, G and U, are read three letters at a time, with each three-letter combination specifying a particular amino acid, the building blocks of proteins. Sometimes, a three-letter combination starts in one exon and continues into the next.

Consider this stretch of oversimplified hypothetical exons: CA-UUUU-CAA-GAAG-CC. The protein recipe would be read CAU-UUU-CAA-GAA-GCC. But if the second exon, UUUU, were missing because of a mutation, the sequence would be read CAC-AAG-AAG. The wrong amino acids would be specified and the correct protein would not be made.

A clever, perhaps counterintuitive solution to this problem: create a drug that causes an additional exon to be deleted, or skipped, in a way that restores the proper reading. In this example, if the drug caused the initial exon, CA, to be deleted, the remaining sequence would be read CAA-GAA-GCC. The first two amino acids specified by the original sequence are missing, but the amino acids after that are the correct ones.

Video by DuchenneNederland

Exon skipping for Duchenne muscular dystrophy explained in dance.

In muscular dystrophy, this exon-skipping technique results in a dystrophin protein missing a piece in the middle. But scientists are hoping that the protein is at least partly functional.

“It’s a shock absorber,” Hans Schikan, the chief executive of Prosensa, said. “If you miss a ring in a shock absorber, it still works.”