Text Size Normal Text Sizing Button Medium Text Sizing Button Large Text Sizing Button Text Contrast Normal Contrast Button Reverse Contrast Button Switch to Spanish Language Press Room Contact Us Sitemap Sign In Register
Link to Homepage About BrightFocus
BrightFocus
Donate Now Get Involved  
Alzheimer's Disease Research Macular Degeneration Research National Glaucoma Research


Stay Informed: Medical and Research Updates
Connect With Us! Visit the Children's Corner for Macular Degeneration
 

 

Researchers Take First Step Toward a Gene Therapy for Macular Dystrophy

October 17, 2013
Source:PLOS ONE

Untitled Document

A photomicrograph collage shows a vector delivering a healthy copy of a BEST1 gene to a vision-impaired dog.Courtesy of the University of PennsylvaniaVitelliform macular dystrophy, also known as Best disease, is one of a group of vision-robbing conditions called bestrophinopathies that affect children and young adults. Caused by inherited mutations in the BEST1 gene, these diseases cause severe declines in central vision as patients age.

With a new study, University of Pennsylvania researchers report “encouraging” findings that mark the first clear step in developing a gene therapy that could prevent vision loss or even restore vision in individuals suffering from these conditions.

The research, conducted in dogs, which can naturally develop a disease similar to Best disease, was led by Karina E. Guziewicz and Gustavo D. Aguirre of Penn’s School of Veterinary Medicine. Penn Vet collaborators included Barbara Zangerl, Andras M. Komaromy, Simone Iwabe and William A. Beltran. The Penn team worked with University of Florida investigators Vincent A. Chiodo, Sanford L. Boye and William W. Hauswirth. They reported their findings in the journal PLOS ONE.

“Step one in designing a gene therapy for these conditions is to make sure that we can target the cells that are affected,” Aguirre said. “That’s what our study has done.”

Aguirre’s lab has previously designed successful therapeutics for other forms of blindness that strike both dogs and humans, including retinitis pigmentosa, Leber congenital amaurosis and achromatopsia.

The “dog version” of Best disease is called canine multifocal retinopathy (CMR), and shares many of the hallmarks of the human condition. Knowing that Best disease and CMR, like these other vision problems, is a heritable condition attributable to mutations in a single gene, the Penn Vet researchers sought to deliver a healthy copy of the BEST1 gene to a portion of retina to substitute for the malfunctioning copy.

As in previous work in Aguirre’s lab, the scientists performed this delivery using a vector—a harmless virus genetically modified to carry specific genetic material. The cargo included either the human or canine version of BEST1.

The researchers injected the vector beneath 18 retinas in 12 dogs, all of which either had normal copies of BEST1 or had one normal copy and one mutated copy. To make sure the injected gene was going to the correct location in the retina, they tagged the vector with green fluorescent protein, which would “light up” where the healthy gene was introduced. They tested two different vectors, called rAAV2/1 and rAAV2/2, both of which are under consideration for use in human clinical trials for other types of vision-related gene therapy.

Injecting the vector under the retina, the researchers then tracked expression of the protein up to six months. They found that expression peaked four to six weeks after injection, and remained stable for six months—a sign that the therapy would be lasting.

The researchers were surprised, however, to see that dogs that received injections from vector rAAV2/1 had some “funny green cells,” according to Aguirre. When they investigated further, they found what appeared to be damage to cone cells, which give color vision and central visual acuity, as a result of the treatment.

“It was a serendipitous finding, because when we looked at the retina in sections it looked perfectly normal,” Aguirre said. “But when we looked at these green cells we found that all the cones were dead. If this therapy were given to the entire retina, it could have significant implications for vision impairment, the ability to see colors and function in bright light.”

The result raises questions about the potential usefulness of rAAV2/1 in future therapies.

“One of the goals of our study was to compare the two vectors,” Guziewicz said. “We now see that the rAAV2/2 vector is the clear candidate for gene therapy, and can let other researchers know that rAAV2/1 needs further evaluation if it is going to be considered.”

Both the human and canine versions of BEST1 behaved the same way, offering encouragement that such an approach could translate to humans.

Though Best disease is relatively uncommon, affecting approximately one in 10,000 people, the approaches being refined to treat it by Aguirre and Guziewicz team could be extended to still other macular diseases.

“Some of the hallmarks of disease are shared,” said Guziewicz “If this works, we could apply our platform to benefit other types of macular degeneration that affects the retinal pigment epithelial cells.”

“Our preliminary work leaves us feeling very optimistic,” Aguirre said.

Adapted from the University of Pennsylvania

 

View all news updates for macular degeneration


Disclaimer: The information provided in this section is a public service of the BrightFocus Foundation, and should not in any way substitute for the advice of a qualified healthcare professional, and is not intended to constitute medical advice. Although we take efforts to keep the medical information on our website updated, we cannot guarantee that the information on our website reflects the most up-to-date research. Please consult your physician for personalized medical advice; all medications and supplements should only be taken under medical supervision. BrightFocus Foundation does not endorse any medical product or therapy.

Some of the content in this section is adapted from other sources, which are clearly identified within each individual item of information.

Twitter YouTube Facebook Shop for a Cause Pinterest Google+ Connect With Us