New gene transfer strategy shows promise for limb girdle and other muscular dystrophies
The challenge of treating patients with genetic disorders in which a single mutated gene is simply too large to be replaced using traditional gene therapy techniques may soon be a thing of the past. A Nationwide Children's Hospital study describes a new gene therapy approach capable of delivering full-length versions of large genes and improving skeletal muscle function. The strategy may hold new hope for treating dysferlinopathies and other muscular dystrophies.
A group of untreatable muscle disorders known as dysferlinopathies are caused by mutations in the dysferlin gene. Patients with these disorders, including limb girdle muscular dystrophy type 2B, are typically diagnosed in their early twenties. Approximately one-third will become wheelchair dependent by their mid-30s.
Gene therapy using adeno-associated virus (AAV) to deliver genes to cells has been pursued as an option for some patients with muscular dystrophy. However, AAV's packaging limitations have served as obstacles in using gene therapy to deliver large genes like dysferlin. Scientists in the past have attempted to work around AAV's packaging limitations by inserting a small version of large genes into the viral vector to induce gene expression. Some have also used more than one viral vector at a time to deliver a large gene. However, micro and mini versions of large genes don't always have the power of full-length gene expression and an increased viral load can lead to negative side effects.
"We have had success in the clinic using AAV gene therapy with limb girdle muscular dystrophy type 2D, which is caused by mutations in the alpha-sarcoglycan gene," said Louise Rodino-Klapac, PhD, principal investigator in the Center for Gene Therapy at The Research Institute of Nationwide Children's Hospital. "However, the dysferlin gene is very large, about six times larger than the alpha-sarcoglycan gene and can't fit into a traditional AAV vector."
A 2008 study identified AAV5, an AAV serotype that could package large transcripts. "This made us wonder whether it could be used for gene replacement requiring inserts as large as the dysferlin gene," said Dr. Rodino-Klapac.
In their 2012 study appearing in PLoS ONE, Dr. Rodino-Klapac's team used AAV5 to package a full-length, intact dysferlin gene and directly deliver it to the diaphragm of dysferlin-deficient mice. They also injected the leg muscles of dysferlin-deficient mice using both intramuscular and vascular approaches to further evaluate whether the gene delivery could improve skeletal muscle function.
They found that both the intravascular and intramuscular delivery approaches led to full-length, intact dysferlin gene expression in the leg and diaphragm muscle cells of the mice. More importantly, they saw that the newly-restored dysferlin repaired membrane deficits previously seen in the dysferlin-deficient mice.
"Our findings demonstrate highly favorable results with full restoration of dysferlin without compromise in function," said Dr. Rodino-Klapac. "With regard to neuromuscular diseases, these studies provide new perspective for conditions caused by mutations of large genes. Duchenne muscular dystrophy is the most common severe childhood muscular dystrophy and would seem to benefit from expression of the larger transcripts than mini- and micro-dystrophins that only partially restore physiologic function in mouse models of the disease."
Dr. Rodino-Klapac and her team are currently defining a path for a dysferlin clinical gene therapy trial. "We have shown that AAV5-dysferlin delivery is a very promising therapeutic approach that could restore functional deficits in dysferlinopathy patients," she says.
More information: Grose WE, Clark KR, Griffin D, Malik V, Shontz KM, Montgomery CL, Lewis S, Brown RH Jr, Janssen PM, Mendell JR, Rodino-Klapac LR. Homologous Recombination Mediates Functional Recovery of Dysferlin Deficiency following AAV5 Gene Transfer. PLoS One. 2012;7(6):e39233. Epub 2012 Jun 15.
Journal reference: PLoS ONE
Provided by Nationwide Children's Hospital
- Faulty cell membrane repair causes heart disease Jul 03, 2007 | not rated yet | 0
- Clearer day for gene therapy: New vector carries big genes linked to inherited blindness Apr 16, 2008 | not rated yet | 0
- Clinical trial for muscular dystrophy demonstrates safety of customized gene therapy Nov 30, 2011 | not rated yet | 0
- Identification of the gene responsible for a new form of adult muscular dystrophy Jan 21, 2010 | not rated yet | 0
- Gene therapy for muscular dystrophy shows promise beyond safety Apr 15, 2009 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Classical and Quantum Mechanics via Lie algebras
Apr 15, 2011 I'd like to open a discussion thread for version 2 of the draft of my book ''Classical and Quantum Mechanics via Lie algebras'', available online at http://lanl.arxiv.org/abs/0810.1019 , and for the...
- More from Physics Forums - Independent Research
More news stories
Northwestern University scientists have shown a gene involved in neurodegenerative disease also plays a critical role in the proper function of the circadian clock.
Genetics May 16, 2013 | 3 / 5 (1) | 0 |
Informed consent is the backbone of patient care. Genetic testing has long required patient consent and patients have had a "right not to know" the results. However, as 21st century medicine now begins to use the tools of ...
Genetics May 16, 2013 | 5 / 5 (1) | 3 |
Ethicists provide framework supporting new recommendations on reporting incidental findings in gene sequencing
In a paper published in Science Express, a group of experts led by bioethicists in the Center for Medical Ethics and Health Policy at Baylor College of Medicine provide a framework for the new American College of Medical Geneti ...
Genetics May 16, 2013 | not rated yet | 0
The use of genome-wide analysis (GWA), where the entirety of an individual's DNA is examined to look for the genomic mutations or variants which can cause health problems is a massively useful technology for diagnosing disease. ...
Genetics May 16, 2013 | not rated yet | 0
DNA databases might help identify victims of crime and human trafficking, but how do we safeguard the personal privacy of innocent victims and family members? A new report online May 15 in the Cell Press journal Trends in ...
Genetics May 15, 2013 | not rated yet | 0
The hunt for an HIV vaccine has gobbled up $8 billion in the past decade, and the failure of the most recent efficacy trial has delivered yet another setback to 26 years of efforts.
1 hour ago | not rated yet | 0
Regular consumption of coffee is associated with a reduced risk of primary sclerosing cholangitis (PSC), an autoimmune liver disease, Mayo Clinic research shows. The findings were being presented at the Digestive Disease ...
9 hours ago | not rated yet | 0 |
Patients with treatment-resistant major depression saw dramatic improvement in their illness after treatment with ketamine, an anesthetic, according to the largest ketamine clinical trial to-date led by researchers from the ...
9 hours ago | 4.7 / 5 (3) | 0 |
Research presented at Digestive Disease Week (DDW) explores new methods for managing digestive health through diet and lifestyle.
9 hours ago | not rated yet | 1
An increasing number of U.S. children are experiencing gastrointestinal issues that require interventions to resolve, according to research presented at Digestive Disease Week (DDW).
May 18, 2013 | not rated yet | 0 |
The use of a smartphone application significantly improves patients' preparation for a colonoscopy, according to new research presented today at Digestive Disease Week (DDW). The preparation process, which begins days in ...
8 hours ago | not rated yet | 0