Manzar Ashtari PhD, Presenter: Nothing to Disclose

Laura Cyckowski BA, Abstract Co-Author: Nothing to Disclose

Daniel Chung, Abstract Co-Author: Nothing to Disclose

Kathleen Marshall, Abstract Co-Author: Nothing to Disclose

Albert Maguire, Abstract Co-Author: Nothing to Disclose

Jean Bennett, Abstract Co-Author: Scientific Advisory Board, sanofi-aventis Group Scientific Advisory Board, Avalanche Technology Consultant, GlaxoSmithKline plc

To identify areas of viable and functional retina in a group of LCA2 patients undergoing retinal gene therapy using fMRI.

Leber’s Congenital Amaurosis type 2 (LCA2), involving the gene encoding retinal pigment epithelium specific protein 65kDa (RPE65), is a rare degenerative disease that has recently been treated with gene therapy of the retina. Success of this treatment relies heavily on identifying retinal loci that harbor viable cells. Eight LCA2 subjects (9-35 Yrs) underwent fMRI before and 1-3 months after unilateral gene therapy. Although LCA patients are not functional in ambient light, depending on their disease stage, they may respond to very bright light. Thus, two types of stimuli, low (1.5 cd/m2) and high light intensities (3000 cd/m2) were used to map the retina. Along with routine clinical tests, fMRI was obtained and analyzed correcting for multiple comparison.

fMRI results, before gene therapy, for low (ambient) light stimuli did not invoke activity in the primary visual cortex (V1, V2 areas) and was mostly distributed on the lateral and basal surface of the occipital lobes. High intensity light stimuli, on the other hand, induced V1/V2 activations. These results were most significantly observed in younger participants with less advanced disease. Clinical and fMRI data together were used to predict the area of retina with viable retinal cells. The vector was delivered in and around the identified site. fMRI results, 1-3 months after surgery, showed significant activations in the primary visual cortex in response to low light stimuli (no activation before therapy).

While clinical measures used for pre-surgical evaluation of LCA2 patients are excellent, they don’t provide a direct measure of retinal cells viable and capable of stimulating activity in the visual cortex. We have demonstrated that fMRI, especially using high intensity light, can provide this valuable data to the surgical team and predict retinal locations likely to be revived by gene therapy and result in visual activity. This information, along with other clinical measures, has been found useful for planning gene treatment strategies to enhance the effectiveness of this powerful technique.

fMRI may play a critical role in pre-surgical mapping of patients with LCA2 disease undergoing gene therapy by identifying the areas of retina that harbor viable/functional cells.

Ashtari, M, Cyckowski, L, Chung, D, Marshall, K, Maguire, A, Bennett, J, Presurgical Planning For Retinal Gene Therapy Using Functional MRI.  Radiological Society of North America 2012 Scientific Assembly and Annual Meeting, November 25 - November 30, 2012 ,Chicago IL. http://archive.rsna.org/2012/12043555.html