Ocular and systemic safety of a recombinant AAV8 vector for X-linked retinoschisis gene therapy: GLP studies in rabbits and Rs1-KO mice.
X-linked retinoschisis (XLRS) is a retinal disease caused by mutations in the gene encoding the protein retinoschisin (RS1) and is one of the most common causes of macular degeneration in young men. Our therapeutic approach for XLRS is based on the administration of AAV8-scRS/IRBPhRS, an adeno-associated viral vector coding the human RS1 protein, via the intravitreal (IVT) route. Two Good Laboratory Practice studies, a 9-month study in New Zealand White rabbits (n = 124) injected with AAV8-scRS/IRBPhRS at doses of 2E9, 2E10, 2E11, and 1.5E12 vector genomes/eye (vg/eye), and a 6-month study in Rs1-KO mice (n = 162) dosed with 2E9 and 2E10 vg/eye of the same vector were conducted to assess ocular and systemic safety. A self-resolving, dose-dependent vitreal inflammation was the main ocular finding, and except for a single rabbit dosed with 1.5E12 vg/eye, which showed a retinal detachment, no other ocular adverse event was reported. Systemic toxicity was not identified in either species. Biodistribution analysis in Rs1-KO mice detected spread of vector genome in extraocular tissues, but no evidence of organ or tissues damage was found. These studies indicate that IVT administration of AAV8-scRS/IRBPhRS is safe and well tolerated and support its advancement into a phase 1/2a clinical trial for XLRS.
National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA; Department of Biotechnology and Applied Clinical Science, University of L'Aquila, L'Aquila, Italy.
Dario
D
Marangoni
National Institute on Deafness and Other Communication Disorders, National Institutes of Health , Bethesda, Maryland, USA.
Ronald A
RA
Bush
National Institute on Deafness and Other Communication Disorders, National Institutes of Health , Bethesda, Maryland, USA.
Yong
Y
Zeng
National Eye Institute, National Institutes of Health , Bethesda, Maryland, USA.
Lisa L
LL
Wei
National Institute on Deafness and Other Communication Disorders, National Institutes of Health , Bethesda, Maryland, USA.
Lucia
L
Ziccardi
National Institute on Deafness and Other Communication Disorders, National Institutes of Health , Bethesda, Maryland, USA.
Camasamudram
C
Vijayasarathy
MPI Research , Mattawan, Michigan, USA.
Joshua T
JT
Bartoe
MPI Research , Mattawan, Michigan, USA.
Kiran
K
Palyada
National Institute on Deafness and Other Communication Disorders, National Institutes of Health , Bethesda, Maryland, USA.
Maria
M
Santos
National Eye Institute, National Institutes of Health , Bethesda, Maryland, USA.
Suja
S
Hiriyanna
National Eye Institute, National Institutes of Health , Bethesda, Maryland, USA.
Zhijian
Z
Wu
National Eye Institute, National Institutes of Health , Bethesda, Maryland, USA.
Peter
P
Colosi
National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA; National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
Paul A
PA
Sieving