RT Journal Article
A1 Sothilingam, Vithiyanjali
A1 Muehlfriedel, Regine Lotte
A1 Tanimoto, Naoyuki
A1 Koch, Fred
A1 Schön, Christian
A1 Garcia Garrido, Marina
A1 Beck, Susanne C
A1 Biel, Martin
A1 Michalakis, Stylianos
A1 Seeliger, Mathias W
T1 Therapeutic cross-species efficacy of vectors for human gene therapy in achromatopsia type 2 (ACHM2)
JF Investigative Ophthalmology & Visual Science
JO Invest. Ophthalmol. Vis. Sci.
YR 2014
VO 55
IS 13
SP 3335
OP 3335
SN 1552-5783
AB  Achromatopsia type 2 (ACHM2) is caused by loss-of-function mutations in CNGA3 that lead to a total lack of cone photoreceptor function. The vast success of gene therapy in the respective disease model (Michalakis et al. 2010) has been the basis for the translation to human patients which is currently underway. In this process, a novel vector has been developed that contains the human CNGA3 gene whose expression is controlled by the human cone arrestin promotor. Here, we assessed the therapeutic efficacy of this vector intended for clinical use in the murine model. Gene replacement therapy in Cnga3-/- mice was done via injections of a AAV8 vector carrying the human CNGA3 gene driven by the human cone arrestin promotor into the subretinal space of 2 week-old knockout mice. The treatment success was monitored in vivo for short- (PI 8W) and long term- (PI 6M) efficacy using Ganzfeld electroretinography (ERG). Animals subsequently underwent immunohistomorphological analysis. The novel vector construct containing a human cone arrestin promotor and the human CNGA3 gene resulted, like its murine counterpart, in stable and efficient restoration of cone photoreceptor function in Cnga3-deficient mice after treatment. In this work, we provide proof-of-principle for the cross-species efficacy of the AAV8 vector developed for use in human patients. Our data show a stable, long-term rescue effect of this vector in mice. Based on these findings, the murine disease model will play an important role in the quality control during the further vector development process for the human ACHM2 clinical trials. 
RD 4/22/2021