Independent degeneration of photoreceptors and retinal pigment epithelium in conditional knockout mouse models of choroideremia

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

“…Both REP-1 and REP-2 have similar functions and are ubiquitously expressed; REP-2 can compensate for the loss of REP-1 in most tissues, but not in the eye. The absence of REP-1 is linked with choroidal, RPE and photoreceptor degeneration in CHM, an X-linked retinal dystrophy with an estimated prevalence of 1-2 per 100,000 individuals (MacDonald et al 2003;Tolmachova et al 2006). CHM appears to be an attractive target for gene therapy.…”

Gene Therapy for Choroideremia Using an Adeno-Associated Viral (AAV) Vector

“…In mice, despite the presence of the Chml gene, the genetic deletion of Chm causes embryonic lethality in hemizygous male mice (Chm null /Y), caused by abnormalities in extraembryonic tissues such as the placenta and yolk sac (Shi et al 2004). Interestingly, carrier female mice (Chm null/þ ) are viable and do show progressive retinal degeneration (van den Hurk et al 1997;Tolmachova et al 2006). Thus, the Chm null/þ female mouse seems to best model the phenotype of affected hemizygous male patients.…”

“…Krock et al www.perspectivesinmedicine.org (2007) used the chm zebrafish model to create genetically mosaic mutant/wild-type eyes (by transplanting cells in blastula stage embryos) and found that REP1 appears to be critical for the pigment epithelium but not photoreceptors. In the mouse, a conditional knockout allele (Chm Flox ) has been made that allows for the selective ablation of the Chm gene in a particular cell/tissue type (Tolmachova et al 2006). When Chm was selectively ablated in either the neurosensory retina or the RPE, it was found that different subsets of Rabs were underprenylated, implying that both layers have an intrinsic prenylation defect (Tolmachova et al 2006).…”

“…In the mouse, a conditional knockout allele (Chm Flox ) has been made that allows for the selective ablation of the Chm gene in a particular cell/tissue type (Tolmachova et al 2006). When Chm was selectively ablated in either the neurosensory retina or the RPE, it was found that different subsets of Rabs were underprenylated, implying that both layers have an intrinsic prenylation defect (Tolmachova et al 2006). In further work, Chm was selectively ablated in photoreceptor cells or the RPE, resulting in independent degeneration of both layers (Tolmachova et al 2010).…”

“…Through its action on Rab GTPases, REP1 plays a role in the fundamental cellular processes of intracellular vesicle trafficking and recycling. Despite about two decades of work to understand the role of REP1 deficiency in the pathogenesis of the disease (e.g., Seabra et al 1992Seabra et al , 1993Seabra et al , 1995Larijani et al 2003;Pylypenko et al 2003;Tolmachova et al 2006Tolmachova et al , 2010, no established treatments currently exist to stop or even slow the progression of retinal degeneration in choroideremia.…”