Navigation Links
Genetic therapy reverses nervous system damage in animal model of inherited human disease

By injecting a therapeutic gene directly into the brain, researchers have treated a naturally occurring genetic disease in cats. This is the first genetic disease affecting the central nervous system to be successfully treated in an animal larger than mice and rats. If this approach can be successfully applied to humans, say the researchers, it might one day treat an entire class of diseases called lysosomal storage disorders which cause severe, sometimes fatal, disabilities in about one in 5,000 births. The members of the research team from the University of Pennsylvania School of Veterinary Medicine, the Children's Hospital of Philadelphia and the U.S. Naval Academy published their findings in this month's issue of the Annals of Neurology

The animals involved in the study are born with a genetic disorder directly analogous to alpha-mannosidosis or AMD, an inherited disease in humans that causes severe mental retardation and skeletal abnormalities. Cats with AMD do not live more than six months. Children born with the worst form of the disease rarely survive into their teens.

"Through gene therapy, we replace a 'broken' gene responsible for alpha-mannosidase with the correct, functioning copy, to dramatic results," said John H. Wolfe, a professor of pathology and medical genetics at the Penn School of Veterinary Medicine and a neurology researcher at Children's Hospital. "The treated cats were markedly improved compared to diseased cats, with better balance and muscle control and fewer tremors."

Although the disease itself is rare, AMD is one of about 50 lysosomal storage diseases, a class of diseases that accounts for a significant portion of the instances of mental retardation in children. Other examples include Tay-Sachs disease, Hunter disease and Pompe disease. In a lysosomal storage disease, cellular debris accumulates within storage areas of cells called lysosomes. In the case of AMD, children are born with a faulty version of the gene for an enzyme called lysosomal alpha-mannosidase or LAMAN.

"Shortly after birth, brain tissue is still physically maturing, which means that there is a particularly important window of opportunity for gene therapy in infants," Wolfe said. "In our study, we could see that gene therapy used during this particular time led to a restoration of damaged neurons, even though the lesions that represent the disease were already extensive."

According to Charles H. Vite, the lead author of the paper and an assistant professor of veterinary neurology at Penn, the treated cats not only demonstrated dramatic clinical improvement, but MRI also revealed that white matter tracks, myelin, in the brain had been largely restored.

"As we move toward the clinical use of this therapy in humans, we must develop and utilize non-invasive methods to monitor the regression of the disease following treatment," Vite said. "The ability to monitor the improvement in brain myelination in alpha-mannosidosis using imaging allows the clinician to see improvement in brain pathology without the need for brain biopsy."

"Lysosomal storage diseases are particularly good candidates for gene therapy because, as we show with LAMAN, active enzymes from genetically corrected cells will be secreted into brain tissue and taken up by neighboring cells, Wolfe said. "In this case we see that storage lesions throughout the brain had been greatly reduced, even though gene transfer was limited to areas surrounding where injections had been made."

The large animal study also demonstrated that only a limited number of injections are necessary to introduce the working LAMAN gene, one of the first steps that will prepare this particular gene therapy for practical use in humans. The gene is transported via a neutralized virus that "infects" cells with the functioning gene. Since the blood-brain barrier would block the virus carrying the gene if it were circulating in the bloodstream, the researchers injected the virus directly into the brain.

"The brain of the cat is much closer in size to the human infant brain compared to mice. Thus we think that it may be possible to achieve similar results in humans with as few as 20 to 30 injections in each of the two hemispheres of the brain," Wolfe said. "We believe, however, we can further limit the number of injections by the use of strong promoters that could increase the amount of enzyme that comes from corrected cells."

Although encouraged by their findings, the researchers note that any clinical trials in humans might be years in the future.

###

Video comparing a cat with AMD to one that had been given gene therapy is available at www.mrw.interscience.wiley.com/suppmat/0364-5134/suppmat/2005/57/v57.3.355.html.


'"/>

Source:University of Pennsylvania


Related biology news :

1. Novel Asthma Study Shows Multiple Genetic Input Required; Single-gene Solution Shot Down
2. Genetically modified natural killer immune cells attack, kill leukemia cells
3. Ants Genetic Engineering Leads To Species Interdependency
4. Genetic Variation Visualization - From EMBL
5. Genetically modified rice in China benefits farmers health, study finds
6. Infants With Rare Genetic Disease Saved by Cord Blood Stem Cells
7. Genetically Modified Natural Killer Immune Cells Attack, Kill Leukemia Cells
8. Genetic defects give the immune system the green light to attack the pancreas
9. Maine Researchers Find Exceptions to Old Rules of Genetic Inheritance
10. Infants with Rare Genetic Disease Saved By Cord Blood Stem Cells
11. Researchers Find New Technique To Identify Fetal Genetic Material From Amniotic Fluid
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:12/5/2016)...  The Office of Justice Programs, National Institute ... Enhance or Replace Medico Legal Autopsies?" on NIJ.gov.  ... replacing forensic autopsies with postmortem X-ray computed tomography, ... response to recommendations made by The National Academy ... as a potential component of medicolegal death investigations. ...
(Date:11/30/2016)... 30, 2016 Not many of us realize that we spend ? of ... we need to do it well. Inadequate sleep levels have been found to lead ... diabetes, and even cancer. Maybe now is the best time to rethink ... them to manage their sleep quality? Continue Reading ... ...
(Date:11/29/2016)... 29, 2016   Neurotechnology , a ... recognition technologies, today released FingerCell 3.0, a ... solutions that run on low-power, low-memory microcontrollers. ... less than 128KB of memory, enabling it ... have limited on-board resources, such as: mobile ...
Breaking Biology News(10 mins):
(Date:12/8/2016)... 2016 Eutilex Co. Ltd. today announced that ... Series A financing. This financing round included participation from ... SNU Bio Angel. This new funding brings the total ... $27.7M) since its founding in 2015. ... and commercialization of its immuno-oncology programs, expand its R&D ...
(Date:12/7/2016)... ... December 07, 2016 , ... A new ... the setting of previously treated, advanced pancreatic cancer, liquid biopsies are not yet ... population and timing of blood sampling may improve the value of a blood-based ...
(Date:12/7/2016)... CALGARY , Dec. 7, 2016 /PRNewswire/ - Zenith Capital Corp. ... update that will be presented at the Company,s Annual and ... Meeting of Shareholders will take place on Thursday, December 15, ... Ross Glenn Hall (Room EC1040), 4825 Mount Royal Gate ... am (MST). A notice of meeting and management information circular, ...
(Date:12/7/2016)... 7, 2016  Vyriad Inc. announced today the appointment ... Board of Directors. "We are delighted to ... business and develop our oncolytic viruses as the next ... Stephen Russell , MD, PhD, CEO of Vyriad. "Al ... vision and passion for making a difference for cancer ...
Breaking Biology Technology: