Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial.
BACKGROUND
Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber's congenital amaurosis.


METHODS
We assessed the retinal and visual function in 12 patients (aged 8-44 years) with RPE65-associated Leber's congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1.5 x 10(10) vector genomes), medium (4.8 x 10(10) vector genomes), or high dose (1.5 x 10(11) vector genomes) for up to 2 years.


RESULTS
AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov, number NCT00516477.


CONCLUSIONS
The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain.


BACKGROUND
Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.
Maguire
Albert M
AM
F M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
High
Katherine A
KA
Auricchio
Alberto
A
Wright
J Fraser
JF
Pierce
Eric A
EA
Testa
Francesco
F
Mingozzi
Federico
F
Bennicelli
Jeannette L
JL
Ying
Gui-shuang
GS
Rossi
Settimio
S
Fulton
Ann
A
Marshall
Kathleen A
KA
Banfi
Sandro
S
Chung
Daniel C
DC
Morgan
Jessica I W
JI
Hauck
Bernd
B
Zelenaia
Olga
O
Zhu
Xiaosong
X
Raffini
Leslie
L
Coppieters
Frauke
F
De Baere
Elfride
E
Shindler
Kenneth S
KS
Volpe
Nicholas J
NJ
Surace
Enrico M
EM
Acerra
Carmela
C
Lyubarsky
Arkady
A
Redmond
T Michael
TM
Stone
Edwin
E
Sun
Junwei
J
McDonnell
Jennifer Wellman
JW
Leroy
Bart P
BP
Simonelli
Francesca
F
Bennett
Jean
J
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001766:Blindness / Q000151:congenital / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D003623:Dark Adaptation; D000229:Dependovirus / Q000235:genetics; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D007267:Injections; D008297:Male; D009154:Mutation / Q000235:genetics; D009760:Nystagmus, Physiologic; D029242:Optic Atrophy, Hereditary, Leber / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*; D012449:Safety; D016896:Treatment Outcome; D014792:Visual Acuity; D055815:Young Adult; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
D002352:Carrier Proteins; D005136:Eye Proteins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase