Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration.
The safety and efficacy of gene therapy for inherited retinal diseases is being tested in humans affected with Leber's congenital amaurosis (LCA), an autosomal recessive blinding disease. Three independent studies have provided evidence that the subretinal administration of adeno-associated viral (AAV) vectors encoding RPE65 in patients affected with LCA2 due to mutations in the RPE65 gene, is safe and, in some cases, results in efficacy. We evaluated the long-term safety and efficacy (global effects on retinal/visual function) resulting from subretinal administration of AAV2-hRPE65v2. Both the safety and the efficacy noted at early timepoints persist through at least 1.5 years after injection in the three LCA2 patients enrolled in the low dose cohort of our trial. A transient rise in neutralizing antibodies to AAV capsid was observed but there was no humoral response to RPE65 protein. The persistence of functional amelioration suggests that AAV-mediated gene transfer to the human retina does not elicit immunological responses which cause significant loss of transduced cells. The persistence of physiologic effect supports the possibility that gene therapy may influence LCA2 disease progression. The safety of the intervention and the stability of the improvement in visual and retinal function in these subjects support the use of AAV-mediated gene augmentation therapy for treatment of inherited retinal diseases.
Simonelli
Francesca
F
Department of Ophthalmology, Second University of Naples, Naples, Italy. franctes@tin.it
Maguire
Albert M
AM
Testa
Francesco
F
Pierce
Eric A
EA
Mingozzi
Federico
F
Bennicelli
Jeannette L
JL
Rossi
Settimio
S
Marshall
Kathleen
K
Banfi
Sandro
S
Surace
Enrico M
EM
Sun
Junwei
J
Redmond
T Michael
TM
Zhu
Xiaosong
X
Shindler
Kenneth S
KS
Ying
Gui-Shuang
GS
Ziviello
Carmela
C
Acerra
Carmela
C
Wright
J Fraser
JF
McDonnell
Jennifer Wellman
JW
High
Katherine A
KA
Bennett
Jean
J
Auricchio
Alberto
A
D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D000229:Dependovirus / Q000235:genetics; D018450:Disease Progression; D005136:Eye Proteins / Q000235:genetics*; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics* / Q000628:therapy*; D008957:Models, Genetic; D012160:Retina / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes; D016896:Treatment Outcome; D014785:Vision, Ocular; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
D002352:Carrier Proteins; D005136:Eye Proteins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase