title: Molecular anthropology meets genetic medicine to treat blindness in the North African Jewish population: human gene therapy initiated in Israel.
abstract: The history of the North African Jewish community is ancient and complicated with a number of immigration waves and persecutions dramatically affecting its population size. A decade-long process in Israel of clinical-molecular screening of North African Jews with incurable autosomal recessive blindness led to the identification of a homozygous splicing mutation (c.95-2A > T; IVS2-2A > T) in RPE65, the gene encoding the isomerase that catalyzes a key step in the retinoid-visual cycle, in patients from 10 unrelated families. A total of 33 patients (four now deceased) had the severe childhood blindness known as Leber congenital amaurosis (LCA), making it the most common cause of retinal degeneration in this population. Haplotype analysis in seven of the patients revealed a shared homozygous region, indicating a population-specific founder mutation. The age of the RPE65 founder mutation was estimated to have emerged 100-230 (mean, 153) generations ago, suggesting it originated before the establishment of the Jewish community in North Africa. Individuals with this RPE65 mutation were characterized with retinal studies to determine if they were candidates for gene replacement, the recent and only therapy to date for this otherwise incurable blindness. The step from molecular anthropological studies to application of genetic medicine was then taken, and a representative of this patient subgroup was treated with subretinal rAAV2-RPE65 gene therapy. An increase in vision was present in the treated area as early as 15 days after the intervention. This process of genetically analyzing affected isolated populations as a screen for gene-based therapy suggests a new paradigm for disease diagnosis and treatment.
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. banine@cc.huji.ac.il
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.forename: Dikla
authors.initials: D
authors.lastname: Bandah-Rozenfeld
authors.forename: Alexey
authors.initials: A
authors.lastname: Obolensky
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.forename: Devora
authors.initials: D
authors.lastname: Marks-Ohana
authors.forename: Malka
authors.initials: M
authors.lastname: Sela
authors.forename: Sanford
authors.initials: S
authors.lastname: Boye
authors.forename: Alexander
authors.initials: A
authors.lastname: Sumaroka
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Roman
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Schwartz
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Itzhak
authors.initials: I
authors.lastname: Hemo
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
mesh_terms: D000293:Adolescent; D000328:Adult; D000352:Africa, Northern / Q000208:ethnology; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D000229:Dependovirus / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D005838:Genotype; D006801:Humans; D007557:Israel; D057130:Leber Congenital Amaurosis / Q000235:genetics* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010775:Photic Stimulation; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites; D012160:Retina / Q000473:pathology; D014787:Vision Tests; D055815:Young Adult; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; D022821:RNA Splice Sites; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase