A novel day blindness in sheep: Epidemiological, behavioural, electrophysiological and histopathological studies

Shamir, Merav H.; Ofri, Ron; Bor, A.; Brenner, Ori; Reicher, Shay; Obolensky, Alexey; Averbukh, Edward; Banin, Eyal; Gootwine, E.

doi:10.1016/j.tvjl.2009.05.029

Cited by 35 publications

(42 citation statements)

References 14 publications

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“…As shown previously 19 and in the present study, CNGA3-mutant sheep fail their behavioral maze tests. However, ERG recordings demonstrate that their cone function is attenuated, but not absent 19,41 .…”

Section: Discussionsupporting

confidence: 91%

“…However, ERG recordings demonstrate that their cone function is attenuated, but not absent 19,41 . This is in contrast to ERG recordings in most human ACHM patients in which cone function is usually undetectable [51][52][53][54] to be further investigated.…”

Section: Discussionmentioning

confidence: 94%

“…In 2010, we reported appearance of congenital day blindness in the Improved Awassi sheep breed in Israel 19 . This autosomal-recessive hereditary disease was determined to be caused by a C→T substitution leading to a premature stop codon at residue 236 (c.706C>T, p.R236*) of the ovine CNGA3 gene 20 , thus providing a naturally occurring large animal model for human CNGA3-related ACHM.…”

Section: Introductionmentioning

confidence: 99%

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Gene Augmentation Therapy Restores Retinal Function and Visual Behavior in a Sheep Model of CNGA3 Achromatopsia

et al. 2015

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Achromatopsia is a hereditary form of day blindness caused by cone photoreceptor dysfunction. Affected patients suffer from congenital color blindness, photosensitivity, and low visual acuity. Mutations in the CNGA3 gene are a major cause of achromatopsia, and a sheep model of this disease was recently characterized by our group. Here, we report that unilateral subretinal delivery of an adeno-associated virus serotype 5 (AAV5) vector carrying either the mouse or the human intact CNGA3 gene under the control of the red/green opsin promoter results in long-term recovery of visual function in CNGA3-mutant sheep. Treated animals demonstrated shorter maze passage times and a reduced number of collisions with obstacles compared with their pretreatment status, with values close to those of unaffected sheep. This effect was abolished when the treated eye was patched. Electroretinography (ERG) showed marked improvement in cone function. Retinal expression of the transfected human and mouse CNGA3 genes at the mRNA level was shown by polymerase chain reaction (PCR), and cone-specific expression of CNGA3 protein was demonstrated by immunohistochemisrty. The rescue effect has so far been maintained for over 3 years in the first-treated animals, with no obvious ocular or systemic side effects. The results support future application of subretinal AAV5-mediated gene-augmentation therapy in CNGA3 achromatopsia patients.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Gene Augmentation Therapy Restores Retinal Function and Visual Behavior in a Sheep Model of CNGA3 Achromatopsia

et al. 2015

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“…Being a closed flock, where replacements are only recruited from within, increased inbreeding is expected, which may lead to the manifestation of undesired recessive traits and to diminution in performances. Such a situation has been recently shown with the identification, within the Improved Awassi of the Ein Harod flock, of segregation of a novel recessive mutation that causes day blindness (Shamir et al 2010). Using the candidate gene approach, it was found that the Awassi's day blindness is due to a mutation in the CNGA3 gene that codes for the cone photoreceptor cyclic nucleotide-gated channel subunit α ).…”

Section: Milk (G/day)mentioning

confidence: 94%

Mini review: breeding Awassi and Assaf sheep for diverse management conditions

Gootwine

2011

Trop Anim Health Prod

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The Local Awassi, a triple-purpose breed for meat, milk, and carpet-wool production, is a low-prolific, hardy breed that is well adapted to the unfavorable conditions of the Middle East, where it is managed under traditionally extensive to semi-extensive conditions. Breeding work with the Awassi has included within-breed selection, crossbreeding, and gene introgression. Those efforts resulted in a variety of Awassi-derived genotypes that successfully occupy semi-intensive as well as intensive production systems. Thus, within-breed selection resulted in development of the "Improved Awassi"-a dairy-type Awassi strain which, under intensive management, produces over 500 l milk/ewe annually; crossbreeding with the East Friesian breed led to the development of the Assaf dairy breed, which exceeds the Improved Awassi in prolificacy and in year-round breeding activity, and introgression of the B allele of the FecB locus into the Awassi and Assaf breeds resulted in the formation of the prolific Afec Awassi and Afec Assaf strains, with prolificacies of 1.9 and 2.5 lambs born per ewe lambing, respectively. Advanced molecular genetics tools have enabled a better understanding of how the Awassi breed was formed during domestication and have uncovered differences in its genetic structure compared to other breeds. Implementing large-scale selection schemes that implement emerging new information on the sheep genome, overcoming threats of inbreeding depression, and further breeding for high uterine capacity are the new breeding goals for the Awassi, Assaf, and their derivatives.

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“…25 Briefly, animals were directed to pass through a 9 m maze with two barrier obstacles. A group of sheep positioned at the end of the maze attracted the test animal to pass through the maze as quickly as possible.…”

Section: Visually Guided Behavior Testingmentioning

confidence: 99%

Safety and Efficacy Evaluation of rAAV2tYF-PR1.7-hCNGA3 Vector Delivered by Subretinal Injection in CNGA3 Mutant Achromatopsia Sheep

Gootwine

Ofri

Banin

et al. 2017

Human Gene Therapy Clinical Development

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{These authors contributed equally to this work.Applied Genetic Technologies Corporation (AGTC) is developing a recombinant adeno-associated virus (rAAV) vector expressing the human CNGA3 gene designated AGTC-402 (rAAV2tYF-PR1.7-hCNGA3) for the treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. The results are herein reported of a study evaluating safety and efficacy of AGTC-402 in CNGA3-deficient sheep. Thirteen day-blind sheep divided into three groups of four or five animals each received a subretinal injection of an AAV vector expressing a CNGA3 gene in a volume of 500 lL in the right eye. Two groups (n = 9) received either a lower or higher dose of the AGTC-402 vector, and one efficacy control group (n = 4) received a vector similar in design to one previously shown to rescue cone photoreceptor responses in the day-blind sheep model (rAAV5-PR2.1-hCNGA3). The left eye of each animal received a subretinal injection of 500 lL of vehicle (n = 4) or was untreated (n = 9). Subretinal injections were generally well tolerated and not associated with systemic toxicity. Most animals had mild to moderate conjunctival hyperemia, chemosis, and subconjunctival hemorrhage immediately after surgery that generally resolved by postoperative day 7. Two animals treated with the higher dose of AGTC-402 and three of the efficacy control group animals had microscopic findings of outer retinal atrophy with or without inflammatory cells in the retina and choroid that were procedural and/or test-article related. All vector-treated eyes showed improved cone-mediated electroretinography responses with no change in rod-mediated electroretinography responses. Behavioral maze testing under photopic conditions showed significantly improved navigation times and reduced numbers of obstacle collisions in all vector-treated eyes compared to their contralateral control eyes or predose results in the treated eyes. These results support the use of AGTC-402 in clinical studies in patients with achromatopsia caused by CNGA3 mutations, with careful evaluation for possible inflammatory and/ or toxic effects.

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A novel day blindness in sheep: Epidemiological, behavioural, electrophysiological and histopathological studies

Cited by 35 publications

References 14 publications

Gene Augmentation Therapy Restores Retinal Function and Visual Behavior in a Sheep Model of CNGA3 Achromatopsia

Gene Augmentation Therapy Restores Retinal Function and Visual Behavior in a Sheep Model of CNGA3 Achromatopsia

Mini review: breeding Awassi and Assaf sheep for diverse management conditions

Safety and Efficacy Evaluation of rAAV2tYF-PR1.7-hCNGA3 Vector Delivered by Subretinal Injection in CNGA3 Mutant Achromatopsia Sheep

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