CEP290- and NPHP5-associated Leber congenital amaurosis


Leber congenital amaurosis (LCA) is a severe autosomal recessive childhood blindness caused by vision loss occurring at the rod and cone photoreceptors of the retina. Mutations in at least 20 genes are known to cause non-syndromic or syndromic forms of LCA. The molecular pathophysiology varies but at least one third of all LCA is thought to represent ciliopathies where the primary defect acts at the connecting cilium located between inner and outer segments of rod and cone photoreceptors.

Cideciyan Lab has contributed substantially to the description of the specific human phenotype resulting from mutations in two ciliopathy genes CEP290 (also known as NPHP6) and NPHP5 (also known as IQCB1). In patients, there is a precipitous loss of rod photoreceptors across the retina within the first decade of life. Cone photoreceptors are retained in a central island over decades and provide a window of opportunity for treatment to improve their function (85,114,116,132,155,201). Murine, canine and in vitro models show similarities to human patients and allow better understanding of the underlying pathophysiology (116,138,166,181). Gene augmentation therapy in the canine model is shown to improve retinal function and regrow cone outer segments (217).

The most common CEP290 mutation in North America and Europe is an intronic single nucleotide change that creates a strong splice donor site and inserts cryptic pseudoexon and a premature stop codon p.Cys998X. Previous in vitro research supported the hypothesis that an antisense oligonucleotide (AON, also called ASO) can bind to a sequence of CEP290 pre-mRNA and modulate RNA splicing by blocking access to the active cryptic splicing site. Our Lab helped design a series of specific outcome measures to use in patients taking part in clinical trials (175,180,199,201,207).

In 2017, an international multi-center Phase I/II clinical trial started to evaluate the consequences intravitreal injections of the Sepofarsen (QR-110), an AON specifically developed for the common intronic mutation. Our group was one of the three centers. Findings of large improvements in vision in one patient led to performance of interim analyses across all patients taking part in the trial. The results in 10 patients showed substantial and significant improvements in visual acuity and the ability to detect flashes of light (197). Most recently we showed unexpected durability of the vision improvements to at least 15 months after a single intravitreal injection of sepofarsen in an eleventh patient taking part in the Phase I/II trial (219), consequences of treating patients with LP vision (227), and full trial results (229).

17 Publications On CEP290- and NPHP5-LCA

229. Russell SR, Drack AV, CIDECIYAN AV, Jacobson SG, Leroy BP, Van Cauwenbergh C, Ho AC, Dumitrescu AV, Han IC, Martin M, Pfeifer WL, Sohn EH, Walshire J, Garafalo AV, Krishnan AK, Powers CA, Sumaroka A, Roman AJ, Vanhonsebrouck E, Jones E, Nerinckx F, De Zaeytijd J, Collin RWJ, Hoyng C, Adamson P, Cheetham ME, Schwartz MR, den Hollander W, Asmus F, Platenburg G, Rodman D, Girach A. Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: A Phase 1b/2 trial. Nature Medicine, 28:1014-1021, 2022. [PubMed] [DOI] 

227. CIDECIYAN AV, Jacobson SG, Ho AC, Krishnan AK, Roman AJ, Garafalo AV, Wu V, Swider M, Sumaroka A, Van Cauwenbergh C, Russell SR, Drack AV, Leroy BP, Schwartz MR, Girach A. Restoration of cone sensitivity to individuals with congenital photoreceptor blindness within the phase 1/2 sepofarsen trial. Ophthalmology Science, 2:100133, 2022. [PubMed] [DOI]

219. CIDECIYAN AV, Jacobson SG, Ho AC, Garafalo AV, Roman AJ, Sumaroka A, Krishnan AK, Swider M, Schwartz MR, Girach A. Durable vision improvement after a single treatment with antisense oligonucleotide sepofarsen: a case report. Nature Medicine, 27:785-789, 2021. [PubMed] [DOI] [Clinicaltrials.gov] [Penn Press Release]

217. Aguirre GD, CIDECIYAN AV, Dufour VL, Garcia AR, Sudharsan R, Swider M, Nikonov R, Iwabe S, Boye SL, Hauswirth WW, Jacobson SG, Beltran WA. Gene therapy reforms photoreceptor structure and restores vision in NPHP5-associated Leber congenital amaurosis. Molecular Therapy, 29:2456-2468, 2021. [PubMed] [DOI]

207. Krishnan AK, Jacobson SG, Roman AJ, Iyer BS, Garafalo AV, Héon E, CIDECIYAN AV. Transient pupillary light reflex in CEP290- or NPHP5-associated Leber congenital amaurosis: Latency as a potential outcome measure of cone function. Vision Research, 168:53-63, 2020. [PubMed] [PMC PDF]

201. Sumaroka A, Garafalo AV, Semenov EP, Sheplock R, Krishnan AK, Roman AJ, Jacobson SG, CIDECIYAN AV. Treatment potential for macular cone vision in Leber congenital amaurosis due to CEP290 or NPHP5 mutations: Predictions from artificial intelligence. Investigative Ophthalmology & Visual Science, 60:2551-2562, 2019. [PubMed]

199. CIDECIYAN AV, Jacobson SG. Leber congenital amaurosis (LCA): Potential for improvement of vision. Investigative Ophthalmology & Visual Science, 60:1680-1695, 2019. [PubMed] [Introduction to Proctor Lecture by Elise Heon and Gus Aguirre]

197. CIDECIYAN AV, Jacobson SG, Drack AV, Ho AC, Charng J, Garafalo AV, Roman AJ, Sumaroka A, Han IC, Hochstedler MD, Pfeifer WL, Sohn EH, Taiel M, Schwartz MR, Biasutto P, de Wit W, Cheetham ME, Adamson P, Rodman DM, Platenburg G, Tome MD, Balikova I, Nerinckx F, De Zaeytijd J, Van Cauwenbergh C, Leroy BP, Russell SR. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nature Medicine, 25:225-228, 2019. [PubMed] [Nat Med: News and Views] [Clinicaltrials.gov] [UPenn Press Release] [ProQR Press Release] 

181. Shimada H, Lu Q, Insinna-Kettenhofen C, Nagashima K, English MA, Semler EM, Mahgerefteh J, CIDECIYAN AV, Li T, Brooks BP, Gunay-Aygun M, Jacobson SG, Cogliati T, Westlake CJ, Swaroop A. In vitro modeling using ciliopathy-patient-derived cells reveals distinct cilia dysfunctions caused by CEP290 mutations. Cell Reports 20, 384-396, 2017. [PubMed]

180. Charng J, Jacobson SG, Heon E, Roman AJ, McGuigan DB, Sheplock R, Kosyk MS, Swider M, CIDECIYAN AV. Pupillary light reflexes in severe photoreceptor blindness isolate the melanopic component of intrinsically photosensitive retinal ganglion cells. Investigative Ophthalmology & Visual Science 58:3215-3224, 2017. [PubMed]

175. Jacobson SG, CIDECIYAN AV, Sumaroka A, Roman AJ, Charng J, Lu M, Choi W, Sheplock R, Swider M, Kosyk MS, Schwartz SB, Stone EM, Fishman GA. Outcome measures for clinical trials of Leber congenital amaurosis caused by the intronic mutation in the CEP290 gene. Investigative Ophthalmology & Visual Science 58:2609-2622, 2017. [PubMed]

166. Downs LM, Scott EM, CIDECIYAN AV, Iwabe S, Dufour V, Gardiner KL, Genini S, Marinho LF, Sumaroka A, Kosyk MS, Swider M, Aguirre GK, Jacobson SG, Beltran WA, Aguirre GD. Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused by NPHP5 mutation.  Human Molecular Genetics 25:4211-4226, 2016. [PubMed]

155. Jacobson SG, CIDECIYAN AV, Huang WC, Sumaroka A, Nam HJ, Sheplock R, Schwartz SB. Leber congenital amaurosis: Genotypes and retinal structure phenotypes. Advances in Experimental Medicine and Biology 854:169-75, 2016. [PubMed]

138. Boye SE, Huang WC, Roman AJ, Sumaroka A, Boye SL, Ryals RC, Olivares MB, Ruan Q, Tucker BA, Stone EM, Swaroop A, CIDECIYAN AV, Hauswirth WW, Jacobson SG. Natural history of cone disease in the murine model of Leber congenital amaurosis due to CEP290 mutation: Determining the timing and expectation of therapy. PLoS One 9:e92928, 2014. [PubMed]

132. Jacobson SG, Sumaroka A, Luo X, CIDECIYAN AV. Retinal optogenetic therapies: clinical criteria for candidacy. Clinical Genetics 84:175–182, 2013. [PubMed]

116. CIDECIYAN AV, Rachel RA, Aleman TS, Swider M, Schwartz SB, Sumaroka A, Roman AJ, Stone AM, Jacobson SG, Swaroop A. Cone photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathy. Human Molecular Genetics, 20:1411-1423, 2011. [PubMed]

114. Stone EM, CIDECIYAN AV, Aleman TS, Scheetz TE, Sumaroka A, Ehlinger MA, Schwartz SB, Fishman GA, Traboulsi EI, Lam BL, Fulton AB, Mullins RF, Sheffield VC, Jacobson SG. Variations in NPHP5 in patients with nonsyndromic Leber congenital amaurosis (LCA) and Senior-Loken syndrome. Archives of Ophthalmology, 129:81-87, 2011. [PubMed]

85. CIDECIYAN AV, Aleman TS, Jacobson SG, Khanna H, Sumaroka A, Aguirre GK, Schwartz SB, Windsor EAM, He S, Chang B, Stone EM, Swaroop A. Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: implications for therapy of Leber congenital amaurosis. Human Mutation, 28:1074-1083, 2007. [PubMed]

Last updated August 4, 2021