Featured Research

from universities, journals, and other organizations

Next generation gene therapy

Date:
July 29, 2011
Source:
University of Pennsylvania School of Medicine
Summary:
Inspired by earlier successes using gene therapy to correct an inherited type of blindness, investigators are poised to extend their approach to other types of blinding disorders. In a new study, researchers compared the safety and efficiency of delivery in an animal model of two different types of vectors. This preclinical work will guide dose-level formulation and type of vector to deliver genes to treat blindness caused by the loss of photoreceptors.

Inspired by earlier successes using gene therapy to correct an inherited type of blindness, investigators from the Perelman School of Medicine at the University of Pennsylvania, are poised to extend their approach to other types of blinding disorders.

In a previous human trial conducted at the Children's Hospital of Philadelphia and Penn, researchers packaged a normal version of a gene missing in Leber's congenital amaurosis (LCA) inside a genetically engineered vector, called an adeno-associated virus (AAV). The vector delivered the gene to cells in the retina, where the gene produces an enzyme that restores light receptors.

"The results from three Phase I clinical trials for LCA showed the potential for gene therapy based on adeno-associated viruses delivering corrective genes to the retina," notes co-senior author Jean Bennett, MD, PhD, the F.M. Kirby professor of Ophthalmology. "To broaden treating inherited eye diseases, we will need a larger vector toolkit, and what we have seen of AAV8 gives us hope for creating gene therapies for diseases that attack the retina's photoreceptors. This preclinical study provides the guidance we need to formulate dose level and type of vector to deliver corrective genes to treat blindness caused by the loss of photoreceptors."

In the present study, published in Science Translational Medicine this week, the Penn team compared the safety and efficiency of delivery in an animal model of two different types of AAVs -- AAV2, which was used in the human trials for LCA, and AAV8, a second-generation AAV technology initially discovered in the lab of co-senior author James M. Wilson, MD, PhD, professor of Pathology and Laboratory Medicine.

The researchers used both vectors to deliver a green fluorescent protein (GFP) transgene to the retinal pigment epithelial (RPE) cells and photoreceptor cells of nonhuman primates. Photoreceptor cells are the problem area for other retinal diseases such as retinitis pigmentosa (RP) and others, for which there is no treatment. Photoreceptors are specialized nerve cells that convert light into a biological electrical signal and are designated as rods and cones.

"We showed that we can use AAV8 to deliver genes to the photoreceptor of the primate eye at lower doses, both safely and efficiently," says first author Luk H. Vandenberghe, PhD, Senior Investigator, Gene Therapy Program, and currently at Penn's F.M. Kirby Center for Molecular Ophthalmology.

Both AAV2 and AAV8 delivered the gene safely and efficiently to the monkey retinas, but AAV8 was markedly better at targeting photoreceptor cells.

The STM study describes the dose relationship between AAV2 and AAV8 vectors and their target cells and the immune response in the nonhuman primate retina. From this the researchers found dosage thresholds to safely and efficiently target cells in the outer retina such as RPE cells and rod and cone photoreceptors. While AAV2 and AAV8 efficiently delivered the gene to RPE cells at moderate to low doses, expression of the GFP gene in rod and cone photoreceptors was reached only at higher dosages. Substantial delivery to rods was obtained with moderate doses of AAV8, doses similar to those currently used in experimental clinical protocols.

The vectors at intermediate doses did not cause problematic immune responses and post-surgical injection complications. The delivered gene also stayed in the retina at very high levels throughout the study duration of four months. Additionally, the GFP gene was preferentially transduced to one type of retinal ganglion cells, which surprised the researchers. In general retinal ganglion cells transmit visual information from the retina to several regions of the brain. This knowledge could be used in the future to further delineate the neuronal connections between the retina and the brain.

In earlier animal studies, AAV8 also delivered genes safely and efficiently to the mouse retina. However, the mouse retina differs significantly from the primate retina, most notably in structure, which affects the surgical approach to delivering corrective genes to different parts of the eye. (For example, mice do not have a macula -- the eye structure used for visual discrimination, which is affected in macular degeneration -- and primates do.) The present study in nonhuman primates is the next step to better translate treatment strategies for people.

"To address patients with other retinal diseases, we need a renaissance of technology--new and better vectors to safely and effectively deliver corrective genes to a range of diseases," says Wilson. "My lab has recently isolated new families of simian-based adenoviruses and adeno-associated viruses. Recombinant versions of these viruses are turning out to be useful as improved gene transfer vehicles to a variety of targets."

The other co-authors, all from Penn, are Peter Bell, Albert M. Maguire, Cassia Cearley, Ru Xiao, Roberto Calcedo Lili Wang, Michael J. Castle, Alexandra C. Maguire, Rebecca Grant, and John H. Wolfe. Maguire, Bennett, and Wolfe also have affiliations with The Children's Hospital of Philadelphia.

The study was supported by grants from GlaxoSmithKline Pharmaceuticals Inc.; Foundation Fighting Blindness, Research to Prevent Blindness; the Paul and Evanina Mackall Foundation Trust; the F. M. Kirby Foundation; the National Institute of Neurological Disorders and Stroke; the National Center for Research Resources; and the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania.


Story Source:

The above story is based on materials provided by University of Pennsylvania School of Medicine. Note: Materials may be edited for content and length.


Journal Reference:

  1. L. H. Vandenberghe, P. Bell, A. M. Maguire, C. N. Cearley, R. Xiao, R. Calcedo, L. Wang, M. J. Castle, A. C. Maguire, R. Grant, J. H. Wolfe, J. M. Wilson, J. Bennett. Dosage Thresholds for AAV2 and AAV8 Photoreceptor Gene Therapy in Monkey. Science Translational Medicine, 2011; 3 (88): 88ra54 DOI: 10.1126/scitranslmed.3002103

Cite This Page:

University of Pennsylvania School of Medicine. "Next generation gene therapy." ScienceDaily. ScienceDaily, 29 July 2011. <www.sciencedaily.com/releases/2011/06/110622145858.htm>.
University of Pennsylvania School of Medicine. (2011, July 29). Next generation gene therapy. ScienceDaily. Retrieved October 20, 2014 from www.sciencedaily.com/releases/2011/06/110622145858.htm
University of Pennsylvania School of Medicine. "Next generation gene therapy." ScienceDaily. www.sciencedaily.com/releases/2011/06/110622145858.htm (accessed October 20, 2014).

Share This



More Health & Medicine News

Monday, October 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Microneedle Patch Promises Painless Pricks

Microneedle Patch Promises Painless Pricks

Reuters - Innovations Video Online (Oct. 18, 2014) Researchers at The National University of Singapore have invented a new microneedle patch that could offer a faster and less painful delivery of drugs such as insulin and painkillers. Video provided by Reuters
Powered by NewsLook.com
Raw: Nurse Nina Pham Arrives in Maryland

Raw: Nurse Nina Pham Arrives in Maryland

AP (Oct. 17, 2014) The first nurse to be diagnosed with Ebola at a Dallas hospital walked down the stairs of an executive jet into an ambulance at an airport in Frederick, Maryland, on Thursday. Pham will be treated at the National Institutes of Health. (Oct. 16) Video provided by AP
Powered by NewsLook.com
Raw: Cruise Ship Returns to US Over Ebola Fears

Raw: Cruise Ship Returns to US Over Ebola Fears

AP (Oct. 17, 2014) A Caribbean cruise ship carrying a Dallas health care worker who is being monitored for signs of the Ebola virus is heading back to Texas, US, after being refused permission to dock in Cozumel, Mexico. (Oct. 17) Video provided by AP
Powered by NewsLook.com
Spanish Govt: Four Suspected Ebola Cases in Spain Test Negative

Spanish Govt: Four Suspected Ebola Cases in Spain Test Negative

AFP (Oct. 17, 2014) All four suspected Ebola cases admitted to hospitals in Spain on Thursday have tested negative for the deadly virus in a first round of tests, the government said Friday. Duration: 00:55 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins