Molecular anthropology meets genetic medicine to treat blindness in the North African Jewish population: human gene therapy initiated in Israel.
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.
Banin
Eyal
E
Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. banine@cc.huji.ac.il
Bandah-Rozenfeld
Dikla
D
Obolensky
Alexey
A
Cideciyan
Artur V
AV
Aleman
Tomas S
TS
Marks-Ohana
Devora
D
Sela
Malka
M
Boye
Sanford
S
Sumaroka
Alexander
A
Roman
Alejandro J
AJ
Schwartz
Sharon B
SB
Hauswirth
William W
WW
Jacobson
Samuel G
SG
Hemo
Itzhak
I
Sharon
Dror
D
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
D002352:Carrier Proteins; D005136:Eye Proteins; D022821:RNA Splice Sites; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase