Gene augmentation in FAM161A ciliopathy: Toward functional vision rescue.

Molecular therapy : the journal of the American Society of Gene Therapy(2023)

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Retinitis pigmentosa (RP; also known as rod-cone dystrophy) is the most common inherited retinal disease, affecting approximately 1:4,000–1:5,000 people in the general population. However, RP has a much higher prevalence among the Israeli population—approximately 1:2,000. 1 Sharon D. Banin E. Nonsyndromic retinitis pigmentosa is highly prevalent in the Jerusalem region with a high frequency of founder mutations. Mol. Vis. 2015; 21: 783-792 PubMed Google Scholar ,2 Sharon D. Ben-Yosef T. Goldenberg-Cohen N. Pras E. Gradstein L. Soudry S. Mezer E. Zur D. Abbasi A.H. Zeitz C. et al. A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC). Hum. Mutat. 2020; 41: 140-149 Crossref PubMed Scopus (0) Google Scholar RP is a genetically highly heterogeneous disease that can be inherited in all Mendelian modes and is associated, at present, with mutations in more than 80 genes and loci (https://web.sph.uth.edu/RetNet/), such as FAM161A. In 2010, two independent groups identified the FAM161A gene as a cause of RP. 3 Bandah-Rozenfeld D. Mizrahi-Meissonnier L. Farhy C. Obolensky A. Chowers I. Pe'er J. Merin S. Ben-Yosef T. Ashery-Padan R. Banin E. Sharon D. Homozygosity mapping reveals null mutations in FAM161A as a cause of autosomal-recessive retinitis pigmentosa. Am. J. Hum. Genet. 2010; 87: 382-391 Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar ,4 Langmann T. Di Gioia S.A. Rau I. Stöhr H. Maksimovic N.S. Corbo J.C. Renner A.B. Zrenner E. Kumaramanickavel G. Karlstetter M. et al. Nonsense mutations in FAM161A cause RP28-associated recessive retinitis pigmentosa. Am. J. Hum. Genet. 2010; 87: 376-381 Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar FAM161A encodes a ciliary protein localized to the base of the photoreceptor connecting cilium and is expressed in the photoreceptor inner segments, the retinal inner and outer plexiform layers, and the ganglion cell layer. 5 Zach F. Grassmann F. Langmann T. Sorusch N. Wolfrum U. Stöhr H. The retinitis pigmentosa 28 protein FAM161A is a novel ciliary protein involved in intermolecular protein interaction and microtubule association. Hum. Mol. Genet. 2012; 21: 4573-4586 Crossref PubMed Scopus (39) Google Scholar ,6 Zach F. Stöhr H. FAM161A, a novel centrosomal-ciliary protein implicated in autosomal recessive retinitis pigmentosa. Adv. Exp. Med. Biol. 2014; 801: 185-190 Crossref PubMed Scopus (12) Google Scholar ,7 Di Gioia S.A. Letteboer S.J.F. Kostic C. Bandah-Rozenfeld D. Hetterschijt L. Sharon D. Arsenijevic Y. Roepman R. Rivolta C. FAM161A, associated with retinitis pigmentosa, is a component of the cilia-basal body complex and interacts with proteins involved in ciliopathies. Hum. Mol. Genet. 2012; 21: 5174-5184 Crossref PubMed Scopus (38) Google Scholar Pathogenic variants in FAM161A are also the most common cause of RP in the Israeli-Jewish population, accounting for approximately 20% of autosomal recessive RP in an identified cohort. 8 Beryozkin A. Khateb S. Idrobo-Robalino C.A. Khan M.I. Cremers F.P.M. Obolensky A. Hanany M. Mezer E. Chowers I. Newman H. et al. Unique combination of clinical features in a large cohort of 100 patients with retinitis pigmentosa caused by FAM161A mutations. Sci. Rep. 2020; 1015156 Crossref PubMed Scopus (11) Google Scholar Clinically, FAM161A-associated RP presents with a slow disease course, severe visual handicap in the fifth decade, and legal blindness in the sixth to seventh decades of life. 4 Langmann T. Di Gioia S.A. Rau I. Stöhr H. Maksimovic N.S. Corbo J.C. Renner A.B. Zrenner E. Kumaramanickavel G. Karlstetter M. et al. Nonsense mutations in FAM161A cause RP28-associated recessive retinitis pigmentosa. Am. J. Hum. Genet. 2010; 87: 376-381 Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Beryozkin et al. 8 Beryozkin A. Khateb S. Idrobo-Robalino C.A. Khan M.I. Cremers F.P.M. Obolensky A. Hanany M. Mezer E. Chowers I. Newman H. et al. Unique combination of clinical features in a large cohort of 100 patients with retinitis pigmentosa caused by FAM161A mutations. Sci. Rep. 2020; 1015156 Crossref PubMed Scopus (11) Google Scholar performed an in-depth characterization of the spectrum of FAM161A-associated phenotypes and typical clinical features, which demonstrated moderate to high myopia in the majority of FAM161A patients, constricted visual fields with relatively well-preserved visual acuity at early ages, and very poor best-corrected visual acuity after the age of 50, in addition to the most frequent initial symptom—night blindness (appearing in childhood or during adolescence). Considering the relatively long preservation of photoreceptors in the central macula, often until the fourth or fifth decade of life, these data are relevant for future therapeutic interventions, including gene augmentation therapy. Gene augmentation therapy attenuates retinal degeneration in a knockout mouse model of Fam161a retinitis pigmentosaMatsevich et al.Molecular TherapyAugust 13, 2023In BriefMatsevich and colleagues show significant attenuation of retinal degeneration in the Fam161a knockout mouse model of retinitis pigmentosa (RP) following subretinal injections of an AAV8 vector carrying the longer isoform of Fam161a. This may serve as an important step toward future application of gene augmentation therapy in FAM161A-RP patients. Full-Text PDF
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