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Leber Congenital Amaurosis Caused by Mutations in RPGRIP1

Tiansen Li

Retinal Cell Biology and Degeneration Section, Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, Bethesda, Maryland 20892 Correspondence: [email protected]

Recessive null mutations in retinitis pigmentosa GTPase regulator interacting 1 (RPGRIP1) are the cause of LCA6 and account for 5% to 6% of the total patient population. RPGRIP1 has an essential role in the photoreceptor connecting cilia, and pho- toreceptors lacking RPGRIP1 are unable to maintain the light sensing outer segments. As a result, patients lose retinal functions at an early age but retain photoreceptors in the central retina well into adulthood thus holding out the prospect for gene augmentation therapies. Laboratory studies in animal models have demonstrated efficacy of gene therapy in slowing disease progression. With further refinement in the design of the replacement gene construct, clinical trials for Lebercongenital amaurosis (LCA) caused by RPGRIP1 mutations could be in the offing in the near future.

eber congenital amaurosis (LCA) is a more In this regard, it is encouraging that LCA6 as- Lsevere form of retinal degeneration than ret- sociated with RPGRIP1 gene mutations have initis pigmentosa, with visual deficit and loss of been reported to present with a more stable vision in early childhood (Heher et al. 1992; and somewhat nonprogressive disease course Fulton et al. 1996; den Hollander et al. 2008). after the initial rapid decline in visual function Clinical findings indicate that both rod and (Hanein et al. 2004). Photoreceptors in the cen- cone photoreceptors are affected early on in tral retina appear to persist for long periods LCA patients. Mutations in 16 different of time after visual function becomes immea- are currently known to cause LCA (Koenekoop surable (Jacobson et al. 2007). Thus LCA6 pa- www.perspectivesinmedicine.org 2004; den Hollander et al. 2008; Wang et al. tients with underlying RPGRIP1 mutations 2009), one of which is the gene encoding reti- have treatment potential for a gene replacement nitis pigmentosa GTPase regulator interacting strategy if targeted to central, but not peripher- protein 1 (RPGRIP1) (Dryja et al. 2001; Gerber al, retina. Continued improvement in retinal et al. 2001; Koenekoop 2005). The rapid disease gene transduction vectors, validation of replace- progression in LCA presents a significant chal- ment gene design incorporating appropriate lenge to gene therapy because retention of suf- regulatory element and protein coding se- ficient photoreceptors in the retina is a prereq- quence, and better understanding of the disease uisite for a satisfactory therapeutic outcome. pathophysiology will set the stage for clinical

Editors: Eric A. Pierce, Richard H. Masland, and Joan W. Miller Additional Perspectives on Retinal Disorders: Genetic Approaches to Diagnosis and Treatment available at www.perspectivesinmedicine.org Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a017384

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T. Li

trials of therapies targeting LCA6 in the near therapy as a means to preserve or restore some future. vision. The human RPGRIP1 gene is located on 14q11 and is expressed as multiple GENETICS AND PROTEIN FUNCTION splice variants (Lu and Ferreira 2005). Its expres- RPGRIP1 was initially identified through pro- sion can be detected embryonically and also in tein interaction screens (Boylan and Wright tissues outside of the retina. A major retinal var- 2000; Roepman et al. 2000; Hong et al. 2001) iant consists of 24 exons and encodes a pro- as a binding partner of retinitis pigmentosa tein of 1287 amino acid residues. This variant GTPase regulator (RPGR), a protein whose de- of RPGRIP1 contains several structurally con- fects underlie the major form of X-linked reti- served motifs. A domain, frequently nitis pigmentosa (RP). Recessive mutations in found in centrosome-associated , is lo- RPGRIP1 cause LCA (Dryja et al. 2001; Gerber cated within its amino-terminal half. RPGRIP1 et al. 2001; Hanein et al. 2004) and have also binds to the RCC1 homology domain of RPGR been found to cause cone–rod dystrophy via its carboxy-terminal portion, hence this (CORD13) (Hameed et al. 2003). About 5%– region is also known as the RPGR interacting 6% of all cases of LCA are caused by mutations domain. A bipartite nuclear localization signal in RPGRIP1 (Dryja et al. 2001; Gerber et al. is also found in the latter domain (Arts et al. 2001; den Hollander et al. 2008). RPGRIP1 al- 2009). In the middle portion of the protein are leles that cause LCA mostly create premature two C2 domains that may bind Ca2þ. RPGRIP1 termination codons and are therefore presumed has no integral membrane-spanning region to be “null”. The less severe form of disease, but C2 domains in the protein could target it cone–rod dystrophy, is linked to missense mu- to cell membranes. Its closest homolog is tations that likely retain partial function and RPGRIP1L, a protein also implicated in certain thus may be considered hypomorphic. LCA6 syndromic forms of retinal degeneration, with patients manifest loss-of-function of both rods an overall identity between the two proteins and cones early in life and develop a severe loss at 34%. of central acuity, which leads to nystagmus. RPGRIP1 expression is enriched in retinal Electroretinography is nonrecordable from photoreceptors where it is stably associated with these patients even at an early age (Dryja et al. the connecting cilia (structurally and function- 2001; Galvin et al. 2005; Walia et al. 2010; Khan ally analogous to the transition zone of primary et al. 2013). Despite the early onset nature, there cilia) and is resistant to extraction with high salt is some evidence that the central retinal laminar and detergent (Hong et al. 2001), suggesting it www.perspectivesinmedicine.org architecture including the photoreceptor cell is one of the core component of ciliary layer could survive until much later (Jacobson of photoreceptors. By immune electron micros- et al. 2007). The retained retinal structure cor- copy, RPGRIP1 is seen between the axonemal responded to the region of visual sensitivity. microtubules and the plasma membrane sur- Other investigators have also observed that rounding the connecting cilia. Recombinant some LCA patients with RPGRIP1 mutations RPGRIP1 expressed in cultured cells spontane- can retain a substantial number of photorecep- ously form extended filamentous structures tors even when visual function has been lost as (Zhao et al. 2003). In vivo, RPGRIP1 has been measured by visual field and electroretinogram shown to be required for anchoring RPGR at the (ERG) (Pawlyk et al. 2010). These observations connecting cilia (Zhao et al. 2003). The con- stand in contrast to LCA caused by AIPL1 mu- necting provides the only link between tations, in which maculopathy or loss of photo- the biosynthetic inner segment and the light receptors in the center is a prominent feature sensing outer segment in a photoreceptor cell. (Dharmaraj et al. 2004; Jacobson et al. 2011). As such, it is the conduit through which large The residual photoreceptors could be suitable as amounts of nascent proteins must be trafficked a therapeutic target, thus raising hope for gene in support of daily outer segment renewal. The

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Leber Congenital Amaurosis Mutations in RPGRIP1

precise function of RPGRIP1 in photoreceptors by immunoblotting but is no longer found at is not fully understood, but loss of RPGRIP1 the connecting cilium. Thus loss of RPGRIP1 leads to loss of RPGR at the connecting cilia, leads to ectopic distribution of RPGR and but not vice versa, suggesting RPGRIP1 tethers therefore should abolish RPGR function as RPGR to the connecting cilia. In addition, well. RPGRIP1 also likely performs additional RPGRIP1 also interacts with NPHP4, another functions at the connecting cilium, because ciliary protein, via a (Roepman et al. mice lacking RPGRIP1 have a much more severe 2005). Gene mutations in NPHP4 have been retinal phenotype than mice lacking RPGR shown to cause syndromic forms of retinal de- alone. It was hypothesized that RPGRIP1 may generation that also involve the kidney and oth- be involved in photoreceptor disc morphogen- er organs, known as ciliopathy. These data high- esis. The relatively fast rate of photoreceptor light a specific role for RPGRIP1 in ciliary degeneration in the knockout mice makes it a structure and function. RPGRIP1 likely serves useful model of LCA both for studying the dis- as a scaffold that anchors RPGR and additional ease mechanism and for testing new therapies. ciliary components at the transition zone, and A second mouse model carrying a recessive may play a role in ciliary trafficking in support RPGRIP1 mutation, designated Rpgrip1nmf247, of outer segment morphogenesis. In cells other was identified in an ethyl nitrosourea (ENU) than photoreceptors, RPGRIP1 is also localized chemical mutagenesis screen at the Jackson lab- to the ciliary/centrosomal compartment. The oratory (Wonet al. 2009). The mutation alters a role of RPGRIP1 in these cells, if any, is not splice site at exon 7 and results in skipping of known. Given the fact that defects in RPGRIP1 exons 7 and 8 in the mRNA and premature ter- cause only retinal degeneration, one may con- mination of the open reading frame. Interest- clude that its function is important or nonre- ingly, this model shows a more severe retinal dundant primarily in photoreceptors. phenotype compared with the RPGRIP1 knock- out mice. In the homozygous Rpgrip1nmf247 mice, disease onset is early and the rate of de- ANIMAL MODELS generation is faster. ERG is nonrecordable from A number of animal models have become an early age. In photoreceptors, connecting cilia available that carry recessive RPGRIP1 muta- emerge from the apical inner segment, but this tions and recapitulate an LCA-like retinal phe- is not followed by the elaboration of any outer notype. The first one was produced by targeted segments. Most photoreceptors will degenerate disruption of the RPGRIP1 gene in mice (Zhao by the age of postnatal day 21. These data were et al. 2003). Normally, the full-length mouse interpreted to indicate that the Rpgrip1nmf247 www.perspectivesinmedicine.org RPGRIP1 protein migrates on SDS-PAGE at mutation ablates an additional short variant 200 kDa, which corresponds to the long of RPGRIP1 that escaped inactivation in the RPGRIP1 variant mentioned earlier, and this knockout model or that a truncated version full-length protein is ablated in the RPGRIP1 of RPGRIP1 is still expressed in the knockout knockout mouse. Mice lacking RPGRIP1 de- model giving rise to a residual RPGRIP1 func- velop a rapid course of retinal degeneration tion. The more severe phenotype and the ac- involving both rods and cones. At the age of companying protein analyses in the study indi- weaning (postnatal day 20), RPGRIP1 knock- cate that the Rpgrip1nmf247 is likely a true null out mice already show substantial mislocaliza- and more closely recapitulates human LCA. tion of photopigment in both rods and cones. A canine model carrying a spontaneous Rudimentary outer segments do form but mutation in RPGRIP1 has also been reported. they are short and highly disorganized. ERG This mutation was originally discovered and amplitudes are a fraction of the controls. Cell designated as cone–rod dystrophy 1 (cord1) loss is relatively fast, such that by 5 mo of age, that occurs naturally in miniature longhaired most photoreceptor cells have degenerated. In dachshunds (Curtis and Barnett 1993). In the RPGRIP1 knockout mice, RPGR is detectable affected dogs, ERG and histological changes

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T. Li

consistent with retinal degeneration are detect- ate antibodies should help resolve this puzzling able after 10 wk of age. There is evidence that question. cones are affected earlier than rods. The cord1 locus was mapped to a region of canine chro- THERAPEUTIC STUDIES IN ANIMAL mosome 15 containing the RPGRIP1 gene. Ge- MODELS nome sequencing identified a 44-nucleotide in- sertion in exon 2 of RPGRIP1 that alters the Replacement gene therapy studies have been reading frame and introduces a premature performed in both murine and canine models. stop codon (Mellersh et al. 2006). In the initial The first study was conducted in the RPGRIP1 study that identified the RPGRIP1 mutation, knockoutmice(Pawlyketal.2005).Inthatstudy, affected and carrier dogs within an extended a mouse RPGRIP1 cDNA was packaged into an inbred pedigree were homozygous and hetero- AAV2vector under the control of a mouse opsin zygous, respectively, for the mutation (Mellersh promoter and delivered subretinally. Mice were et al. 2006). It was therefore concluded that the followed up to 5 mo after treatment by ERG and RPGRIP1 ins44 mutation was responsible for then analyzed by immunocytochemistry and cord1. Subsequent studies, however, found con- histology. Delivery of recombinant RPGRIP1 siderable phenotypic variation and genotype– by AAVled to the RPGRIP1 protein expression phenotype discordance (Miyadera et al. 2009), that correctly localized to the connecting cilia. raising the possibility that the RPGRIP1 ins44 The thickness of the photoreceptor layer was mutation may not be the primary cause of cord1 significantly increased in the treated retina, and (Kuznetsova et al. 2012a). It was suggested that the morphology of the outer segments, almost because RPGRIP1 undergoes multiple splic- completely absent in the untreated eyes, was ing, the exon containing the insertion could partly restored. Partial functional preservation be spliced out while retaining partial protein was also shown by ERG. Remarkably, RPGR function (Kuznetsova et al. 2012b). Indeed, a again localized to the photoreceptor connecting genome-wide association study identified a sec- cilium in treated eyes, indicating restoration of ond locus also on canine chromosome 15 that its function. Thus the efficacy of AAV-mediated strongly influenced the manifestation of disease replacement gene therapy was unambiguously (Miyadera et al. 2012). Homozygosity for both shown in this first study in a mouse model. De- RPGRIP1 ins44 and the risk haplotype at the spite its apparent success, this study has left newly mapped locus was necessary for develop- much room for further improvement. First, ment of retinal degeneration. To complicate RPGRIP1 is known to be required in both rods matters further, some dogs that developed reti- and cones, and the use of an opsin promoter www.perspectivesinmedicine.org nal degeneration were neither homozygous for would limit expression primarily to rods. Sec- RPGRIP1 ins44 nor for the second risk haplo- ond, AAV2vector has a relatively poor tropism type indicating the presence of further indepen- for photoreceptors leading to lower transduc- dent modifier loci (Miyadera et al. 2012). If this tion efficacyand is slow in turning on expression proves correct, it would make retinal degenera- of the recombinant gene. Because the mouse tion in this dog breed a polygenic trait. Given LCA model has a fast course of disease, by the the clearly showed and critical role of RPGRIP1 time replacement gene is fully expressed, which in human and mouse photoreceptors, it would could take .4–6 wk, a substantial fraction of seem certain that an RPGRIP1 null or sub- photoreceptors would have degenerated. Lastly, stantially null allele would also be causal for the important objective of validating a human photoreceptor degeneration in dogs. Thus the RPGRIP1 replacement gene suitable for clinical available evidence points to RPGRIP1 ins44 be- trials was not tackled in this study. ing a moderately hypomorphic allele. It is a sig- To address some of those issues a second nificant contributor to disease but is not a sole therapeutic study was conducted in the determinant. Direct examination of the pro- RPGRIP1 knockout mice that delivered the hu- tein from native retinal tissues using appropri- man instead of the mouse RPGRIP1 replace-

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Leber Congenital Amaurosis Mutations in RPGRIP1

ment gene (Pawlyk et al. 2010). The second RPGRIP1. If this hypothesis is correct, which study incorporated an improved version of seems likely, a better therapeutic outcome could AAV vector, AAV8. AAV8 is far more efficient reasonably be expected in future clinical studies at transducing photoreceptors than AAV2 and in which a human RPGRIP1 gene is delivered leads to a faster onset of transgene expression. to human recipients. Other factors such as pre- This meant that in a rapidly degenerating retina, cise level of transgene expression and time of the replacement gene would be up and func- replacement gene delivery also likely play roles tional before too many photoreceptors had in determining an optical outcome. disappeared thus leading to a more favorable For preclinical development of gene thera- therapeutic outcome. A human rhodopsin ki- pies that target a specific type of retinal degen- nase gene promoter (Khani et al. 2007) was used eration, proof-of-concept studies in large ani- in place of the rhodopsin promoter to drive mal models that share clinical features with in both rods and cones. After their human counterparts would be highly de- subretinal delivery of the replacement gene in sirable. A recent study evaluated gene therapy in the mutant mice, human RPGRIP1 was ex- the canine cord1 model with homozygous pressed specifically in photoreceptors, localized RPGRIP1 ins44 mutation (Lheriteau et al. correctly in the connecting cilia, and important- 2014). Subretinal injection of a canine RPGRIP1 ly restored the normal localization of RPGR. cDNA driven by the same rhodopsin kinase Histological examinations showed improved promoter as that used in the mouse study and photoreceptor survival in the treated eyes. packaged into AAV vectors improved photore- ERG measurements showed better preservation ceptor survival in treated retinas. The study of rod and cone photoreceptor function: The found that photoreceptor function was signifi- mean rates of monthly decline without treat- cantly improved in all treated eyes for up to ment were 37% for the rod a-wave, 22% for 24 mo postinjection. The rescue of cone func- the rod b-wave, and 25% for the cone b-wave. tion appeared to be more stable and long last- With treatment, these rates of decline de- ing. The treatment did not completely halt pho- creased to 8% for the rod a-wave and rod b- toreceptor degeneration, similar to most gene wave and to no detectable decline for the cone therapy studies, as indicated by the continued b-wave. This represents overall a fourfold slow- thinning of the photoreceptor layer over time. It ing of retinal function loss (Pawlyk et al. 2010). should be noted that, to achieve a measurable Thus, this study showed the efficacy of a human therapeutic benefit, the study had to use a ca- replacement gene and validated a gene therapy nine RPGRIP1 cDNA in the replacement gene design that could be adopted for future clini- construct. This was again presumably because www.perspectivesinmedicine.org cal trials in patients. Despite marked improve- of the low degree of conservation between the ment of photoreceptor function and survival human and dog RPGRIP1 primary sequences in the treated eyes compared with the control (at under 70%) such that a human RPGRIP1 eyes, photoreceptor degeneration was slowed would produce a weaker therapeutic effect in but not stopped. Among many possible factors canine photoreceptors to the point of being dif- that may have influenced the extent of rescue, ficult to show. Another issue that is relevant to the low degree of conservation between human assessing the outcome of the study is the find- and mouse genes is likely a major one. The hu- ings by other investigators that the cord1 phe- man and mouse RPGRIP1 protein sequences notype may be inherited as a polygenic trait. are only 60% identical, relatively low for Nevertheless, the demonstration of efficacy of mammalian orthologs. In fact, the conservation gene therapy in this large animal model of is so poor between the two species that an anti- cone–rod dystrophy is clear evidence that the body raised against one species would not cross- RPGRIP1 ins44 allele is a major pathogenic fac- react with the other. This means a human tor and provides promise that the model will RPGRIP1 would not function in mouse photo- be useful for further preclinical development receptors as effectively as the cognate mouse of therapies for human treatment.

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CONCLUDING REMARKS Galvin JA, Fishman GA, Stone EM, Koenekoop RK. 2005. Clinical phenotypes in carriers of Leber congenital am- Studies by many investigators in the past decade aurosis mutations. Ophthalmology 112: 349–356. have built up a wealth of knowledge about Gerber S, Perrault I, Hanein S, Barbet F, Ducroq D, Ghazi I, Martin-Coignard D, Leowski C, Homfray T, Dufier JL, et RPGRIP1, from genetics, protein function, to al. 2001. Complete exon-intron structure of the RPGR- somatic gene therapies in animal models. The interacting protein (RPGRIP1) gene allows the identifi- remaining tasks before a clinical trial can be ini- cation of mutations underlying Leber congenital amau- tiated are to finalize to choice of promoter and rosis. Eur J Hum Genet 9: 561–571. Hameed A, Abid A, Aziz A, Ismail M, Mehdi SQ, Khaliq S. human RPGRIP1 coding sequence, and to carry 2003. Evidence of RPGRIP1 gene mutations associated out efficacy and toxicology validation. Although with recessive cone-rod dystrophy. J Med Genet 40: 616– all evidence points to the long RPGRIP1 tran- 619. script being the functionally important variant, Hanein S, Perrault I, Gerber S, Tanguy G, Barbet F, Ducroq D, Calvas P,Dollfus H, Hamel C, Lopponen T,et al. 2004. the possibility that some shorter variants addi- Leber congenital amaurosis: Comprehensive survey of tionally contribute to photoreceptor function the genetic heterogeneity, refinement of the clinical def- could bear on efforts on optimizing efficacy of inition, and genotype-phenotype correlations as a strat- egy for molecular diagnosis. Hum Mutat 23: 306–317. therapies and should be further examined. The Heher KL, Traboulsi EI, Maumenee IH. 1992. The natural timing issues of gene therapy intervention also history of Leber’s congenital amaurosis. Age-related find- deserve some attention (Cideciyan et al. 2013). ings in 35 patients. Ophthalmology 99: 241–245. 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Leber Congenital Amaurosis Caused by Mutations in RPGRIP1

Tiansen Li

Cold Spring Harb Perspect Med published online November 20, 2014

Subject Collection Retinal Disorders: Genetic Approaches to Diagnosis and Treatment

A Review of Secondary Photoreceptor What Is Next for Retinal Gene Therapy? Degenerations in Systemic Disease Luk H. Vandenberghe Naveen Mysore, Jamie Koenekoop, Shen Li, et al. Genes and Mutations Causing Autosomal The Status of RPE65 Gene Therapy Trials: Safety Dominant Retinitis Pigmentosa and Efficacy Stephen P. Daiger, Sara J. Bowne and Lori S. Eric A. Pierce and Jean Bennett Sullivan RNA-Seq: Improving Our Understanding of Convergence of Human Genetics and Animal Retinal Biology and Disease Studies: Gene Therapy for X-Linked Retinoschisis Michael H. Farkas, Elizabeth D. Au, Maria E. Ronald A. Bush, Lisa L. Wei and Paul A. Sieving Sousa, et al. Differential Gene Expression in Age-Related Gene Therapies for Neovascular Age-Related Macular Degeneration Macular Degeneration Denise J. Morgan and Margaret M. DeAngelis Peter Pechan, Samuel Wadsworth and Abraham Scaria Genetics of Primary Inherited Disorders of the Gene Therapy for the Retinal Degeneration of Optic Nerve: Clinical Applications Usher Syndrome Caused by Mutations in MYO7A Keri F. Allen, Eric D. Gaier and Janey L. Wiggs Vanda S. Lopes and David S. Williams Genetic Modifiers and Oligogenic Inheritance Gene Therapy of ABCA4-Associated Diseases Maria Kousi and Nicholas Katsanis Alberto Auricchio, Ivana Trapani and Rando Allikmets Stem Cells as Tools for Studying the Genetics of Gene Therapy Using Stem Cells Inherited Retinal Degenerations Erin R. Burnight, Luke A. Wiley, Robert F. Mullins, Luke A. Wiley, Erin R. Burnight, Robert F. Mullins, et al. et al. Leber Congenital Amaurosis Caused by Mutations Gene Therapy for Choroideremia Using an in RPGRIP1 Adeno-Associated Viral (AAV) Vector Tiansen Li Alun R. Barnard, Markus Groppe and Robert E. MacLaren

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