Long-term retinal cone rescue using a capsid mutant AAV8 vector in a mouse model of CNGA3-achromatopsia

Dai, Xufeng; He, Ying; Zhang, Hua; Zhang, Yangyang; Liu, Yan; Wang, Muran; Chen, Hao; Pang, Jijing

doi:10.1371/journal.pone.0188032

Cited by 15 publications

(9 citation statements)

References 52 publications

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“…The therapeutic effect was also observed when treatment was initiated at a more advanced stage of the disease at 1 or 3 months of age and was stable for at least 12 months after treatment [ 79 ]. Similar therapeutic effects with subretinal Cnga3 gene supplementation were reported from another study that used the naturally occurring cpfl5 mouse model of CNGA3 -ACHM [ 62 , 80 ]. The studies described so far used subretinal delivery of rAAV vectors for Cnga3 gene supplementation.…”

Section: Gene Supplementation Therapy: Preclinical Studiessupporting

confidence: 72%

Achromatopsia: Genetics and Gene Therapy

et al. 2021

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Achromatopsia (ACHM), also known as rod monochromatism or total color blindness, is an autosomal recessively inherited retinal disorder that affects the cones of the retina, the type of photoreceptors responsible for high-acuity daylight vision. ACHM is caused by pathogenic variants in one of six cone photoreceptor-expressed genes. These mutations result in a functional loss and a slow progressive degeneration of cone photoreceptors. The loss of cone photoreceptor function manifests at birth or early in childhood and results in decreased visual acuity, lack of color discrimination, abnormal intolerance to light (photophobia), and rapid involuntary eye movement (nystagmus). Up to 90% of patients with ACHM carry mutations in CNGA3 or CNGB3, which are the genes encoding the alpha and beta subunits of the cone cyclic nucleotide-gated (CNG) channel, respectively. No authorized therapy for ACHM exists, but research activities have intensified over the past decade and have led to several preclinical gene therapy studies that have shown functional and morphological improvements in animal models of ACHM. These encouraging preclinical data helped advance multiple gene therapy programs for CNGA3-and CNGB3-linked ACHM into the clinical phase. Here, we provide an overview of the genetic and molecular basis of ACHM, summarize the gene therapy-related research activities, and provide an outlook for their clinical application. Key PointsAchromatopsia (ACHM) is caused by mutations in one of six autosomal recessive genes and affects all aspects of daylight vision.No therapy for ACHM has yet been approved, but several preclinical studies provided proof of concept for adeno-associated virus gene therapy.Five clinical gene therapy trials are currently underway for CNGA3-and CNGB3-related ACHM.

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Section: Gene Supplementation Therapy: Preclinical Studiessupporting

confidence: 72%

Achromatopsia: Genetics and Gene Therapy

et al. 2021

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“…At the oldest time point, nob9 retinas display some residual cones with S-opsins abnormally migrated to inner photoreceptor segments. Mislocalization of cone opsins was seen not only in nob9 retinas but also in some photoreceptor deficiency models such as Cnga3-mutant cpfl5 (Dai et al, 2017) and Rpe65-mutant rd12 mice (Li et al, 2011). No UV ERG responses could be detected in nob9 retinas indicating that the residual S-cones are also functionally abnormal.…”

Section: Discussionmentioning

confidence: 99%

Photoreceptor degeneration in a new Cacna1f mutant mouse model

Dai

Pang

Wang

et al. 2019

Experimental Eye Research

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The Cacna1f gene encodes the α1F subunit of an L-type voltage-gated calcium channel, Cav1.4. In photoreceptor synaptic terminals, Cav1.4 channels mediate glutamate release and postsynaptic responses associated with visual signal transmission. We have discovered a new Cacna1f mutation in nob9 mice, which display more severe phenotypes than do nob2 mice. To characterize the nob9 phenotype at different ages, we examined the murine fundus, applied retinal optical coherence tomography, measured flash electroretinograms (ERGs) in vivo, and analyzed the retinal histology in vitro. After identifying the X-linked recessive inheritance trait, we sequenced Cacna1f as the candidate gene. Mutations in this gene were detected by polymerase chain reaction (PCR) and confirmed by restriction fragment length polymorphism. Morphologically, an early-onset of retinal disorder was detected, and the degeneration of the outer plexiform layers progressed rapidly. Moreover, the mutant mice showed drastically reduced scotopic ERGs with increasing age. In 14month-old nob9 retinas, immunostaining of cone opsins demonstrated a reduction in the number *

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“…Many groups have reported the results of gene therapy strategies in animal models of achromatopsia. Gene replacement can improve the function of cone cells in achromatopsia mouse models with CNGB3- (43), CNGA3- (44–46), and GNAT2-associated disease (47). Treatment of dogs with achromatopsia secondary to CNGB3 mutation have shown durable rescue of cone function after viral-mediated gene replacement for at least 33 months (48).…”

Section: Discussionmentioning

confidence: 99%

A nonhuman primate model of inherited retinal disease

Moshiri

Chen

Kim

et al. 2019

Journal of Clinical Investigation

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Inherited retinal degenerations are a common cause of untreatable blindness worldwide, with retinitis pigmentosa and cone dystrophy affecting approximately 1 in 3500 and 1 in 10,000 individuals, respectively. A major limitation to the development of effective therapies is the lack of availability of animal models that fully replicate the human condition. Particularly for cone disorders, rodent, canine, and feline models with no true macula have substantive limitations. By contrast, the cone-rich macula of a nonhuman primate (NHP) closely mirrors that of the human retina. Consequently, well-defined NHP models of heritable retinal diseases, particularly cone disorders that are predictive of human conditions, are necessary to more efficiently advance new therapies for patients. We have identified 4 related NHPs at the California National Primate Research Center with visual impairment and findings from clinical ophthalmic examination, advanced retinal imaging, and electrophysiology consistent with achromatopsia. Genetic sequencing confirmed a homozygous R565Q missense mutation in the catalytic domain of PDE6C, a cone-specific phototransduction enzyme associated with achromatopsia in humans. Biochemical studies demonstrate that the mutant mRNA is translated into a stable protein that displays normal cellular localization but is unable to hydrolyze cyclic GMP (cGMP). This NHP model of a cone disorder will not only serve as a therapeutic testing ground for achromatopsia gene replacement, but also for optimization of gene editing in the macula and of cone cell replacement in general.

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Long-term retinal cone rescue using a capsid mutant AAV8 vector in a mouse model of CNGA3-achromatopsia

Cited by 15 publications

References 52 publications

Achromatopsia: Genetics and Gene Therapy

Achromatopsia: Genetics and Gene Therapy

Photoreceptor degeneration in a new Cacna1f mutant mouse model

A nonhuman primate model of inherited retinal disease

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