The retinal pigment epithelium
(RPE) plays a critical role in vision, maintaining the structural integrity, function, and survival of photoreceptor cells (Sparrow et al
). On its apical side, the RPE extends numerous microvilli around the light-sensitive photoreceptor outer segments and into the interphotoreceptor matrix. Microvilli considerably increase the surface area of the RPE apical membrane, and establish a critical interface for many RPE functions including phagocytosis of shed outer segments, visual chromophore transport and regeneration, production of trophic and antiangiogenic factors, directional transport of oxygen and nutrients from the choroid to sustain the high metabolic rate of photoreceptors, and removal of water and aqueous waste products from the subretinal space (Strauss, 2005
; Bonilha et al.
). Mutations in genes expressed in RPE cells can result in retinal degeneration and loss of vision (Sparrow et al.
). Some of these include RPE
65 and LRAT
(Leber congenital amaurosis, LCA), MERTK
(early-onset retinitis pigmentosa, RP), BEST1
(Best disease), TIMP3
(Sorsby fundus dystrophy), EFEMP1
(malattia leventinese), RDH5
(fundus albipunctatus), and RLBP1
(retinitis punctata albescens).
A relative newcomer to this group is autosomal recessively inherited RP caused by mutations in the human MFRP
(membrane-type frizzled related protein) gene, located on chromosome 11q23 (Ayala-Ramirez et al.
; Crespí et al.
; Zenteno et al.
; Mukhopadhyay et al.
). The MFRP
gene encodes a type II transmembrane protein of 584 amino acid residues, which consists of an N-terminal cytoplasmic region, a transmembrane domain, and an extracellular region with a C-terminal cysteine-rich domain similar to that observed in Wnt-binding frizzled proteins (Katoh, 2001
; Kameya et al.
is expressed as one element of a dicistronic transcript (Kameya et al.
; Hayward et al.
; Mandal et al.
), which also encodes the complement C1q tumor necrosis factor-related protein-5 (C1QTNF5/CTRP5). CTRP5
also has a human disease association; specifically, a Ser163Arg mutation causes an autosomal dominant late-onset retina-wide degeneration, which can feature neovascular macular degeneration (Milam et al
; Jacobson et al
; Hayward et al
). The functional relationship between the two proteins remains under investigation (Fogerty and Besharse, 2011
With clinical trials of gene therapy ongoing for another autosomal recessive RPE disease leading to retinal degeneration, RPE65
-LCA (reviewed in Cideciyan, 2010
), we inquired whether MFRP
-RP was a potential candidate for this form of treatment. A patient with MFRP
-RP was examined in detail by noninvasive studies and the results were compared with those of patients with other molecularly proven MFRP
-RP in the literature. Like RPE65
-LCA, there is an animal model of the MFRP
-RP disease for proof-of-concept studies. The rd6
mouse has a naturally occurring autosomal recessive retinal degeneration associated with a 4-bp deletion in a splice donor site in the Mfrp
gene (Hawes et al.
; Kameya et al.
). This results in the skipping of exon 4 and deletion of 58 amino acids from the Mfrp protein (Kameya et al.
). The present study uses subretinal delivery of a self-complementary tyrosine-capsid mutant adeno-associated virus serotype 8 (AAV8) (Y733F) vector carrying the mouse Mfrp
gene to determine whether photoreceptor degeneration can be prevented in rd6
mice, thereby paving the way for further proof-of-concept, dosing, and safety studies in gene therapy en route to a clinical trial in patients with MFRP