EIAV-based retinal gene therapy in the shaker1 mouse model for usher syndrome type 1B: development of UshStat.
Usher syndrome type 1B is a combined deaf-blindness condition caused by mutations in the MYO7A gene. Loss of functional myosin VIIa in the retinal pigment epithelia (RPE) and/or photoreceptors leads to blindness. We evaluated the impact of subretinally delivered UshStat, a recombinant EIAV-based lentiviral vector expressing human MYO7A, on photoreceptor function in the shaker1 mouse model for Usher type 1B that lacks a functional Myo7A gene. Subretinal injections of EIAV-CMV-GFP, EIAV-RK-GFP (photoreceptor specific), EIAV-CMV-MYO7A (UshStat) or EIAV-CMV-Null (control) vectors were performed in shaker1 mice. GFP and myosin VIIa expression was evaluated histologically. Photoreceptor function in EIAV-CMV-MYO7A treated eyes was determined by evaluating α-transducin translocation in photoreceptors in response to low light intensity levels, and protection from light induced photoreceptor degeneration was measured. The safety and tolerability of subretinally delivered UshStat was evaluated in macaques. Expression of GFP and myosin VIIa was confirmed in the RPE and photoreceptors in shaker1 mice following subretinal delivery of the EIAV-CMV-GFP/MYO7A vectors. The EIAV-CMV-MYO7A vector protected the shaker1 mouse photoreceptors from acute and chronic intensity light damage, indicated by a significant reduction in photoreceptor cell loss, and restoration of the α-transducin translocation threshold in the photoreceptors. Safety studies in the macaques demonstrated that subretinal delivery of UshStat is safe and well-tolerated. Subretinal delivery of EIAV-CMV-MYO7A (UshStat) rescues photoreceptor phenotypes in the shaker1 mouse. In addition, subretinally delivered UshStat is safe and well-tolerated in macaque safety studies These data support the clinical development of UshStat to treat Usher type 1B syndrome.
Boys Town National Research Hospital, Omaha, Nebraska, United States of America.
Marisa
M
Zallocchi
Oxford BioMedica (UK) Ltd, Oxford Science Park, Oxford, United Kingdom.
Katie
K
Binley
Oxford BioMedica (UK) Ltd, Oxford Science Park, Oxford, United Kingdom.
Yatish
Y
Lad
Oxford BioMedica (UK) Ltd, Oxford Science Park, Oxford, United Kingdom.
Scott
S
Ellis
Oxford BioMedica (UK) Ltd, Oxford Science Park, Oxford, United Kingdom.
Peter
P
Widdowson
Oxford BioMedica (UK) Ltd, Oxford Science Park, Oxford, United Kingdom.
Sharifah
S
Iqball
Oxford BioMedica (UK) Ltd, Oxford Science Park, Oxford, United Kingdom.
Vicky
V
Scripps
Oxford BioMedica (UK) Ltd, Oxford Science Park, Oxford, United Kingdom.
Michelle
M
Kelleher
Oxford BioMedica (UK) Ltd, Oxford Science Park, Oxford, United Kingdom.
Julie
J
Loader
Oxford BioMedica (UK) Ltd, Oxford Science Park, Oxford, United Kingdom.
James
J
Miskin
Boys Town National Research Hospital, Omaha, Nebraska, United States of America.
You-Wei
YW
Peng
Boys Town National Research Hospital, Omaha, Nebraska, United States of America.
Wei-Min
WM
Wang
Boys Town National Research Hospital, Omaha, Nebraska, United States of America.
Linda
L
Cheung
Boys Town National Research Hospital, Omaha, Nebraska, United States of America.
Duane
D
Delimont
Oxford BioMedica (UK) Ltd, Oxford Science Park, Oxford, United Kingdom.
Kyriacos A
KA
Mitrophanous
Boys Town National Research Hospital, Omaha, Nebraska, United States of America; University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
Dominic
D
Cosgrove
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D023061:Gene Order; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D004860:Infectious Anemia Virus, Equine / Q000235:genetics*; D008251:Macaca; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics; D010641:Phenotype; D010786:Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D012160:Retina / Q000378:metabolism / Q000473:pathology; D015293:Transducin / Q000378:metabolism; D052245:Usher Syndromes / Q000235:genetics* / Q000628:therapy*
C000631455:MYO7A protein, human; C000631456:Myo7a protein, mouse; D000081412:Myosin VIIa; D009218:Myosins; D015293:Transducin