EIAV-based retinal gene therapy in the shaker1 mouse model for usher syndrome type 1B: Development of UshStat

Marisa L Zallocchi, Katie Binley, Yatish Lad, Scott Ellis, Peter Widdowson, Sharifah Iqball, Vicky Scripps, Michelle Kelleher, Julie Loader, James Miskin, You Wei Peng, Wei Min Wang, Linda Cheung, Duane Delimont, Kyriacos A. Mitrophanous, Dominic E Cosgrove

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

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 a-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 a-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.

Original languageEnglish (US)
Article numbere94272
JournalPloS one
Volume9
Issue number4
DOIs
StatePublished - Apr 4 2014

Fingerprint

Equine infectious anemia virus
Gene therapy
gene therapy
photoreceptors
Genetic Therapy
Transducin
Retinal Pigments
animal models
Genes
Macaca
Restoration
myosin
Vertebrate Photoreceptor Cells
Retinal Pigment Epithelium
Blindness
Safety
Light
blindness
mice
light intensity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

EIAV-based retinal gene therapy in the shaker1 mouse model for usher syndrome type 1B : Development of UshStat. / Zallocchi, Marisa L; Binley, Katie; Lad, Yatish; Ellis, Scott; Widdowson, Peter; Iqball, Sharifah; Scripps, Vicky; Kelleher, Michelle; Loader, Julie; Miskin, James; Peng, You Wei; Wang, Wei Min; Cheung, Linda; Delimont, Duane; Mitrophanous, Kyriacos A.; Cosgrove, Dominic E.

In: PloS one, Vol. 9, No. 4, e94272, 04.04.2014.

Research output: Contribution to journalArticle

Zallocchi, ML, Binley, K, Lad, Y, Ellis, S, Widdowson, P, Iqball, S, Scripps, V, Kelleher, M, Loader, J, Miskin, J, Peng, YW, Wang, WM, Cheung, L, Delimont, D, Mitrophanous, KA & Cosgrove, DE 2014, 'EIAV-based retinal gene therapy in the shaker1 mouse model for usher syndrome type 1B: Development of UshStat', PloS one, vol. 9, no. 4, e94272. https://doi.org/10.1371/journal.pone.0094272
Zallocchi, Marisa L ; Binley, Katie ; Lad, Yatish ; Ellis, Scott ; Widdowson, Peter ; Iqball, Sharifah ; Scripps, Vicky ; Kelleher, Michelle ; Loader, Julie ; Miskin, James ; Peng, You Wei ; Wang, Wei Min ; Cheung, Linda ; Delimont, Duane ; Mitrophanous, Kyriacos A. ; Cosgrove, Dominic E. / EIAV-based retinal gene therapy in the shaker1 mouse model for usher syndrome type 1B : Development of UshStat. In: PloS one. 2014 ; Vol. 9, No. 4.
@article{aff6e052aabd4ffea7450bd36a7b5296,
title = "EIAV-based retinal gene therapy in the shaker1 mouse model for usher syndrome type 1B: Development of UshStat",
abstract = "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 a-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 a-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.",
author = "Zallocchi, {Marisa L} and Katie Binley and Yatish Lad and Scott Ellis and Peter Widdowson and Sharifah Iqball and Vicky Scripps and Michelle Kelleher and Julie Loader and James Miskin and Peng, {You Wei} and Wang, {Wei Min} and Linda Cheung and Duane Delimont and Mitrophanous, {Kyriacos A.} and Cosgrove, {Dominic E}",
year = "2014",
month = "4",
day = "4",
doi = "10.1371/journal.pone.0094272",
language = "English (US)",
volume = "9",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "4",

}

TY - JOUR

T1 - EIAV-based retinal gene therapy in the shaker1 mouse model for usher syndrome type 1B

T2 - Development of UshStat

AU - Zallocchi, Marisa L

AU - Binley, Katie

AU - Lad, Yatish

AU - Ellis, Scott

AU - Widdowson, Peter

AU - Iqball, Sharifah

AU - Scripps, Vicky

AU - Kelleher, Michelle

AU - Loader, Julie

AU - Miskin, James

AU - Peng, You Wei

AU - Wang, Wei Min

AU - Cheung, Linda

AU - Delimont, Duane

AU - Mitrophanous, Kyriacos A.

AU - Cosgrove, Dominic E

PY - 2014/4/4

Y1 - 2014/4/4

N2 - 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 a-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 a-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.

AB - 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 a-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 a-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.

UR - http://www.scopus.com/inward/record.url?scp=84899069485&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899069485&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0094272

DO - 10.1371/journal.pone.0094272

M3 - Article

C2 - 24705452

AN - SCOPUS:84899069485

VL - 9

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 4

M1 - e94272

ER -