Gene Therapies Emerging for Multiple Retinal Degenerative Diseases
Report from the annual ARVO (Association for Research in Vision and Ophthalmology) meeting
May 2, 2011 - Two large sessions at the 2011 Association for Research in Vision & Ophthalmology Meeting have highlighted the wide range of gene therapies now in development for retinal degenerative disorders.
Many different substances made within the retina and its photoreceptors are necessary if they are to function correctly. Gene defects that result in deficiencies of these substances can lead to heritable retinal degenerative disorders including retinitis pigmentosa, Stargardt disease, and many others. Gene defects may result in a total absence of important substances (specific proteins), because they are not made at all; or the manufacture of proteins that don’t function properly, because they are misshapen in some way and consequently cannot contribute to the process of vision.
Most of the gene therapies that are being developed now seek to place new, undamaged genes into the cells of a person’s retina. When this is done successfully, the retina can make the “missing ingredients” and use them to work the way it is supposed to. Currently the most common strategy for gene therapies is to use a harmless, non-infectious virus, to trick cells of the retina or pigmented epithelium (RPE) into taking in a new undamaged gene and putting it into operation. Other tricks to accomplish this are also being studied. For example, several groups made presentations about the use of tiny nanoparticles to carry healthy replacement genes into the cell.
The results of many preclinical and animal studies of gene therapies for a various conditions have been presented at this year’s ARVO meeting. Promising results in cellular or animal models were reported for:
- Replacement of the RS1 gene, the gene associated with most cases of x-linked retinoschisis (See Canadian scientists play leading role in the development of gene therapies)
- Replacement of several genes, including Gucy2d, AIPL1, and CEP290, in which mutations cause Leber Congenital Amaurosis
- A gene therapy for mutations in the ND4 gene, which are responsible for many cases of Leber Hereditary Optic Neuropathy
- • A potential gene therapy for mutations in the CHM gene, which are associated with most cases of choroideremia, now in its early stages
- • A gene therapy for blue cone monochromacy – a type of complete colour blindness, in which a person is unable to distinguish different hues
In addition, the conference featured more extensive reports on preclinical findings for several gene therapies that have begun or are about to begin human trials particularly those developed by Oxford Biomedica, including Retinostat (for wet AMD), UshStat (for Usher syndrome type 1B) and StarGen (a gene therapy for defects in ABCR, the gene associated with most cases of Stargardt disease)
Although the vast major of gene therapy studies reported at ARVO show signs of promise, at least one set of findings sounded a cautionary note. Dr. Gustavo Aguirre of the University of Pennsylvania and his colleagues reported on their attempts to insert healthy copies of the RPGR gene in animals with this type of X-linked retinitis pigmentosa. In their study, cancerous lesions developed in the eye, and the layers of the retina were disrupted. This illustrates the powerful negative effects that gene therapies can have, if too much of a particular gene is expressed in the eye, and emphasizes why clinical trials always begin with tests of safety.
On a more positive note, an international team of investigators from Michigan State University and the Institute of Ophthalmology in London reported on a study of gene therapy for older dogs with mutations in the RPE-65 gene. This mutation occurs naturally in Briard dogs. Studies of gene therapies in these dogs led to the first successful gene therapy for LCA, however the studies were typically done in young dogs less than 2 years of age. This team tested gene therapy in older dogs and showed positive outcomes in several dogs 2-5 years of age. This suggests that RPE-65 gene therapy may also be useful for older people with this form of LCA who have had significant vision loss for some time.
ARVO Sessions
228. Genes: Therapies and Silencing. Monday May 2, 2011. Multiple presenters.
117: Nanomedicine, Nanopharmaceuticals, Tissue Bioengineering, Regenerative Medicine and Nanodiagnostics. Sunday May 1, 2011. Multiple presenters.