New design guidelines simplify development of targeted therapies for muscular dystrophy and other diseases

January 30, 2013
Patients with DMD lack the protein dystrophin, which causes muscles to deteriorate and break down, leading to progressive difficulty with walking and general mobility. Credit: Huntstock/Thinkstock

The dystrophin protein offers critical support to muscle fibers. Mutations affecting dystrophin's expression cause the muscle-wasting disease muscular dystrophy. In Duchenne muscular dystrophy (DMD), these mutations take the form of small sequence changes that make much of the dystrophin gene (DMD) untranslatable, yielding nonfunctional protein or no protein at all.

Therapies based on a strategy known as 'exon skipping' could undo the damage from these mutations. Development of such treatments is set to accelerate, thanks to research by a team led by Keng Boon Wee of the A*STAR Institute of and Zacharias Pramono of the National Skin Centre in Singapore.

Proteins are translated from messenger of genes; however, only certain RNA regions—known as exons—actually encode protein, and these are enzymatically spliced together prior to translation. Several clinical studies have demonstrated that small '' (AON) molecules that bind mutated DMD exons can induce elimination of those defective exons during splicing, yielding shorter but largely functional versions of dystrophin. "We are cautiously optimistic that AON-induced exon skipping could be the first effective therapy for DMD patients," says Wee.

Unfortunately, DMD arises from many different mutations, and targeted AON design remains a time-consuming, trial-and-error process. To address this challenge, Wee and Pramono sought to define the characteristics of AONs that efficiently promote exon-skipping. They used to zoom in on exonic sequences that coordinate splicing. They also identified regions of suitable length within dystrophin RNA transcripts that span these sequences and would be accessible to AONs in living cells.

The researchers thus derived a set of guidelines enabling them to effectively design AONs that targeted nine different exons affected in DMD patients. For each exon, at least one AON proved capable of boosting dystrophin expression to clinically relevant thresholds in cultured muscle cells (see image). "Our proposed set of factors resulted in a reasonable success rate of designing efficient AONs—61% versus 38% using semi-empirical methods," says Wee. Clinical studies have already demonstrated the promise of efficient exon skipping in treating DMD patients.

Wee notes that other diseases arising from abnormal RNA processing could also benefit from this approach. However, his team is also exploring this method as a general strategy to abort production of disease-causing proteins in cancer and other conditions. "In contrast to small-molecule inhibitor drugs that can target only about 10% of the human genome, this approach could downregulate most human genes," Wee says.

Explore further: 'Skipping' drug marks step forward for muscular dystrophy

More information: Pramono, Z. A. D., Wee, K. B., Wang, J. L., Chen, Y. J., Xiong, Q. B. et al. A prospective study in the rational design of efficient antisense oligonucleotides for exon skipping in the DMD gene. Human Gene Therapy 23, 781–790 (2012). online.liebertpub.com/doi/abs/10.1089/hum.2011.205

Related Stories

'Skipping' drug marks step forward for muscular dystrophy

July 25, 2011
An experimental drug designed to fit a DNA patch in a flawed gene has cleared an important hurdle in tests on boys struck by a tragic muscle-wasting disease, a British study on Monday says.

Scientists find drug that may help fight duchenne muscular dystrophy

December 12, 2012
Drugs are currently being tested that show promise in treating patients with Duchenne muscular dystrophy (DMD), an inherited disease that affects about one in 3,600 boys and results in muscle degeneration and, eventually, ...

New compound holds promise for treating Duchenne MD, other inherited diseases

June 27, 2012
Scientists at UCLA have identified a new compound that could treat certain types of genetic disorders in muscles. It is a big first step in what they hope will lead to human clinical trials for Duchenne muscular dystrophy.

A quantum leap in gene therapy of Duchenne muscular dystrophy

January 15, 2013
Usually, results from a new study help scientists inch their way toward an answer whether they are battling a health problem or are on the verge of a technological breakthrough. Once in a while, those results give them a ...

Recommended for you

Scientists provide insight into genetic basis of neuropsychiatric disorders

July 21, 2017
A study by scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) is providing insight into the genetic basis of neuropsychiatric disorders. In this research, the first mouse model of a mutation ...

Scientists identify new way cells turn off genes

July 19, 2017
Cells have more than one trick up their sleeve for controlling certain genes that regulate fetal growth and development.

South Asian genomes could be boon for disease research, scientists say

July 18, 2017
The Indian subcontinent's massive population is nearing 1.5 billion according to recent accounts. But that population is far from monolithic; it's made up of nearly 5,000 well-defined sub-groups, making the region one of ...

Mutant yeast reveals details of the aberrant genomic machinery of children's high-grade gliomas

July 18, 2017
St. Jude Children's Research Hospital biologists have used engineered yeast cells to discover how a mutation that is frequently found in pediatric brain tumor high-grade glioma triggers a cascade of genomic malfunctions.

Late-breaking mutations may play an important role in autism

July 17, 2017
A study of nearly 6,000 families, combining three genetic sequencing technologies, finds that mutations that occur after conception play an important role in autism. A team led by investigators at Boston Children's Hospital ...

Newly identified genetic marker may help detect high-risk flu patients

July 17, 2017
Researchers have discovered an inherited genetic variation that may help identify patients at elevated risk for severe, potentially fatal influenza infections. The scientists have also linked the gene variant to a mechanism ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.