BACKGROUND: Choroideremia (CHM) is a slowly progressive X-linked retinal degeneration that results in a loss of photoreceptors, retinal pigment epithelium and choroid. CHM, the gene implicated in choroideremia, encodes Rab escort protein-1 (REP-1), which is involved in the post-translational activation via prenylation of Rab proteins. METHODS: We evaluated AAV8.CBA.hCHM, a recombinant adeno-associated virus serotype 8 (rAAV8) vector, which targets retinal cells efficiently, for both therapeutic effect and safety in vitro and in vivo in a murine model. In vitro studies included western blot analyses and prenylation assays. In vivo studies included ophthalmoscopy, pupillometry, histology and immunofluorescence analysis. RESULTS: Infection with AAV8.CBA.hCHM induced the expression of REP-1 protein in a dose-responsive fashion. Transduction with AAV8.CBA.hCHM reverses the biochemical and pathogenetic defects in CHM both in vitro and in vivo and showed no safety concerns in the in vivo investigations performed in the present study. CONCLUSIONS: AAV8 is a promising vector for human clinical gene therapy trials for choroideremia.
BACKGROUND:Choroideremia (CHM) is a slowly progressive X-linked retinal degeneration that results in a loss of photoreceptors, retinal pigment epithelium and choroid. CHM, the gene implicated in choroideremia, encodes Rab escort protein-1 (REP-1), which is involved in the post-translational activation via prenylation of Rab proteins. METHODS: We evaluated AAV8.CBA.hCHM, a recombinant adeno-associated virus serotype 8 (rAAV8) vector, which targets retinal cells efficiently, for both therapeutic effect and safety in vitro and in vivo in a murine model. In vitro studies included western blot analyses and prenylation assays. In vivo studies included ophthalmoscopy, pupillometry, histology and immunofluorescence analysis. RESULTS: Infection with AAV8.CBA.hCHM induced the expression of REP-1 protein in a dose-responsive fashion. Transduction with AAV8.CBA.hCHM reverses the biochemical and pathogenetic defects in CHM both in vitro and in vivo and showed no safety concerns in the in vivo investigations performed in the present study. CONCLUSIONS: AAV8 is a promising vector for human clinical gene therapy trials for choroideremia.
Authors: Luke A Wiley; Erin R Burnight; Emily E Kaalberg; Chunhua Jiao; Megan J Riker; Jennifer A Halder; Meagan A Luse; Ian C Han; Stephen R Russell; Elliott H Sohn; Edwin M Stone; Budd A Tucker; Robert F Mullins Journal: Hum Gene Ther Date: 2018-02-23 Impact factor: 5.695
Authors: Pavitra S Ramachandran; Vivian Lee; Zhangyong Wei; Ji Yun Song; Giulia Casal; Therese Cronin; Keirnan Willett; Rachel Huckfeldt; Jessica I W Morgan; Tomas S Aleman; Albert M Maguire; Jean Bennett Journal: Hum Gene Ther Date: 2016-10-17 Impact factor: 5.695
Authors: Ioannis S Dimopoulos; Stephanie Chan; Robert E MacLaren; Ian M MacDonald Journal: Expert Opin Orphan Drugs Date: 2015-07-01 Impact factor: 0.694