Safety and Efficacy of AAV5 Vectors Expressing Human or Canine CNGB3 in <i>CNGB3</i>-Mutant Dogs

Ye, Guo Jie; Komàromy, András M.; Zeiss, Caroline J.; Calcedo, Roberto; Harman, Christine; Koehl, Kristin; Stewart, Gabriel; Iwabe, Simone; Chiodo, Vince A.; Hauswirth, William W.; Aguirre, Gustavo D.; Chulay, Jeffrey D.

doi:10.1089/humc.2017.125

Cited by 21 publications

(10 citation statements)

References 33 publications

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“…Based on these proof-of-concept studies, two independent translational programs for CNGB3-ACHM were initiated. Safety data obtained in mice, dogs, and cynomolgus monkeys were published from one of the programs [90][91][92]. The studies showed acceptable safety with vectorand dose-dependent inflammation and toxicity.…”

Section: Gene Supplementation Therapy: Preclinical Studiesmentioning

confidence: 99%

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 Studiesmentioning

confidence: 99%

Achromatopsia: Genetics and Gene Therapy

et al. 2021

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“…Even though the inflammation resolved using steroids, only one patient of the 1 × 10 10 vg and none of the 1 × 10 9 vg cohorts developed similar adverse events, emphasizing the impact of the vector dose on ocular inflammation [ 120 ]. Several preclinical studies or clinical trials reported similar data, with what appears to be a threshold targeting inflammation at above 1 × 10 11 vg/eye [ 5 , 121 , 122 , 123 , 124 , 125 , 126 , 127 ].…”

Section: Options To Reduce Immunological Riskmentioning

confidence: 70%

Risk Mitigation of Immunogenicity: A Key to Personalized Retinal Gene Therapy

Varin

Morival

Maillard

et al. 2021

IJMS

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Gene therapy (GT) for ocular disorders has advanced the most among adeno-associated virus (AAV)-mediated therapies, with one product already approved in the market. The bank of retinal gene mutations carefully compiled over 30 years, the small retinal surface that does not require high clinical vector stocks, and the relatively immune-privileged environment of the eye explain such success. However, adverse effects due to AAV-delivery, though rare in the retina have led to the interruption of clinical trials. Risk mitigation, as the key to safe and efficient GT, has become the focus of ‘bedside-back-to-bench’ studies. Herein, we overview the inflammatory adverse events described in retinal GT trials and analyze which components of the retinal immunological environment might be the most involved in these immune responses, with a focus on the innate immune system composed of microglial surveillance. We consider the factors that can influence inflammation in the retina after GT such as viral sensors in the retinal tissue and CpG content in promoters or transgene sequences. Finally, we consider options to reduce the immunological risk, including dose, modified capsids or exclusion criteria for clinical trials. A better understanding and mitigation of immune risk factors inducing host immunity in AAV-mediated retinal GT is the key to achieving safe and efficient GT.

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“…Delivery of a human CNGB3 gene via rAAV5 vector to both Cngb3 −/− and the D262N mutant dogs showed that the vector could be targeted to the medium and long wavelength (M/L) cones via a human red cone opsin promoter and the rescue was dependent on the age of the dog and the promotor, not on the mutation type [90].…”

Section: Cngb3mentioning

confidence: 99%

Large Animal Models of Inherited Retinal Degenerations: A Review

Winkler

Occelli

Petersen‐Jones

2020

Cells

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Studies utilizing large animal models of inherited retinal degeneration (IRD) have proven important in not only the development of translational therapeutic approaches, but also in improving our understanding of disease mechanisms. The dog is the predominant species utilized because spontaneous IRD is common in the canine pet population. Cats are also a source of spontaneous IRDs. Other large animal models with spontaneous IRDs include sheep, horses and non-human primates (NHP). The pig has also proven valuable due to the ease in which transgenic animals can be generated and work is ongoing to produce engineered models of other large animal species including NHP. These large animal models offer important advantages over the widely used laboratory rodent models. The globe size and dimensions more closely parallel those of humans and, most importantly, they have a retinal region of high cone density and denser photoreceptor packing for high acuity vision. Laboratory rodents lack such a retinal region and, as macular disease is a critical cause for vision loss in humans, having a comparable retinal region in model species is particularly important. This review will discuss several large animal models which have been used to study disease mechanisms relevant for the equivalent human IRD.

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Safety and Efficacy of AAV5 Vectors Expressing Human or Canine CNGB3 in CNGB3-Mutant Dogs

Cited by 21 publications

References 33 publications

Achromatopsia: Genetics and Gene Therapy

Achromatopsia: Genetics and Gene Therapy

Risk Mitigation of Immunogenicity: A Key to Personalized Retinal Gene Therapy

Large Animal Models of Inherited Retinal Degenerations: A Review

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