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Clinical Perspectives on Gene Therapy for Retinal and Eye Diseases
Published in Yashwant Pathak, Gene Delivery, 2022
Devika S. Joshi, Gaurav M. Karve, Shrikant D. Joshi
In rodent models of both CNGA3-ACHM31 and CNGB3-ACHM32, and in canine models of CNGB3-ACHM, AAV-mediated gene replacement therapy can improve cone function. Early phase clinical trials in humans of the above genes will further help to elucidate whether it is effective in humans as well.4
Hibernation and Aging
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Cheng-Wei Wu, Kenneth B. Storey
The regulatory pattern of insulin signaling observed during ground squirrel hibernation, which include the reduction of serum insulin level, decrease in Akt and mTOR activity, and inhibition of protein synthesis through 4E-BP and S6 protein, although currently viewed as a strategy to reduce energy expenditure during hibernation, also mirrors mechanisms that have been shown to significantly increase life span in other species. The involvement of the insulin signaling pathway in longevity and hibernation was also recently shown to be influenced by genetic factors, with the genome sequencing of a long-lived hibernating Brandt's bat M. brandtii. In the early 2000s, scientists captured a male Brandt's bat in the wild that was originally tagged and released in the 1960s, with this particular bat calculated to be approximately 41 years old (Podlutsky et al. 2005). By the longevity quotient standard, this bat lives 9.8-times longer than expected given its body size, a number that was easily the highest for any mammal known to date measured either in the wild or in captivity. Although both hibernating and non-hibernating bats are considered long-lived, bats that hibernate live an average of six years longer than their non-hibernating equals (Wilkinson and South 2002). When the genome of the Brandt's bat was sequenced, unique evolutionary adaptations were found in forms of distinct amino acid substitutions for several genes, these include changes to genes that are involved in the regulation of hibernation, echolocation, vision, and reproduction (Seim et al. 2013). At the transcriptomic level, bats show many similar molecular changes during hibernation when compared to ground squirrels, these include the downregulation of genes involved in protein synthesis, and the upregulation of genes involved in lipid metabolism, oxidative stress, and adaptation to starvation (Seim et al. 2013). A the genetic level, unique nucleotide substitutions in the bat include changes to the SLC45A2 transporter protein that is involved in sound absorption, and CNGB3 protein that regulates sensory transduction of cone receptors. Most interestingly, unique amino acid substitutions were also found for the GHR and IGF-1 receptor (IGF-1R) proteins in the Brandt's bat, at amino acids residues within the highly conserved transmembrane domain of each protein. These unique mutations to the GHR/IGF-1R proteins are only present in the Vespertilionoidea superfamily, and are absent in other mammals like horse, cat, human, and mouse (Seim et al. 2013). As mentioned earlier, mutations to either GHR and IGF-1 proteins can lead to an extended life span in mice, and its potential role in hibernator's longevity is supported by an increase in the expression of several insulin associated genes in the Brandt's bat, at a level that is comparable to the upregulation observe between GHR mutant and wild-type mice. Furthermore, Brandt's bats also show similar expression changes in 11 out of 15 genes differentially expressed between long-lived and wild-type mice (Seim et al. 2013). Taken together, these results suggest an important overlapping role of the insulin signaling pathway in contributing to hibernation as well as promoting a long-lived phenotype.
Gene therapy for inherited retinal diseases: progress and possibilities
Published in Clinical and Experimental Optometry, 2021
Monica L Hu, Thomas L Edwards, Fleur O’Hare, Doron G Hickey, Jiang-Hui Wang, Zhengyang Liu, Lauren N Ayton
Mutations in CNGB3 and CNGA3, which encode subunits of a cone photoreceptor cGMP-gated channel, account for the majority of achromatopsia cases.10 Gene augmentation studies using AAV vectors carrying either of the two genes, and targeting cone photoreceptors, have progressed from showing proof-of-concept in murine,70 ovine71 and canine72 models. An open-label dose-escalation trial conducted in Germany demonstrated the safety and efficacy of an AAV8 vector carrying the CNGA3 gene in nine achromatopsia patients.73 During 12 months of follow-up, there were no substantial safety problems, and all treated eyes showed improvement in cone photoreceptor function, including an increased mean visual acuity of 2.9 letters (p = 0.006) and increased mean contrast sensitivity of 0.33 log (p = 0.003). Other phase 1/2 clinical trials are underway across the USA, UK, and Israel (Table 1).
Ciliary neurotrophic factor (CNTF) delivery to retina: an overview of current research advancements
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Maryam Ghasemi, Effat Alizadeh, Khatereh Saei Arezoumand, Behzad Fallahi Motlagh, Nosratollah Zarghami
As it was mentioned previously, CNTF protein could be injected to the retina by intravitreal injection [108–110], but this is not suitable for its sustained transportation because of dose dependency of CNTF, that impairs vision at high dose in several weeks after injection, whereas in low dose provides protection against the light damage [111]. Mathew et al., showed that intravitreal injection of the CNTF improved ganglion cell survival in non-arteritic anterior ischaemic optic neuropathy (NAION) of rodent model [112]. In adult hamster CNTF or BDNF, and also in a similar way, hepatocyte growth factor (HGF) showed sustained long-term survival of ganglion cell and desired sensitivity to stimulations [113]. Marangoni and colleagues studied the effect of CNTF on retinal function at Achromatopsia model, that is, the CNGB3−/− mouse. They found that CNTF protein caused a transient improve of the cone-mediated function [114]. The CNTF showed a role in the migration of mouse corneal epithelial stem cells via upregulation of matrix metalloproteinases and accelerated the repair of the mouse corneal epithelial wound [115]. The research on the effect of CNTF on stem/progenitor cells is interesting. In a study, CNTF delivery into mouse diabetic corneal epithelial promoted wound healing and activation of corneal epithelial stem/progenitor cells along with triggering regeneration process in corneal nerve fibres [116]. Although there are many studies supporting promising effects of CNTF, a human clinical trial reported no measurable improve for cone function [117].
Achromatopsia: clinical features, molecular genetics, animal models and therapeutic options
Published in Ophthalmic Genetics, 2018
Nashila Hirji, Jonathan Aboshiha, Michalis Georgiou, James Bainbridge, Michel Michaelides
Successful gene supplementation has also been described in models of CNGB3-associated disease, with improvement of cone function and daylight vision for at least 33 months in two canine models (72). Older animals, particularly those over 1 year old, with more advanced disease showed less improvement. To explore this further, gene replacement has also been undertaken after intravitreal ciliary neurotrophic factor (CNTF) treatment. CNTF causes transient dedifferentiation of photoreceptors, a process during which the cells become morphologically immature, with resulting decreased function and gene expression. With adjunctive CNTF treatment, gene supplementation restored cone function in all mutant dogs treated at the ages of 14–42 months (73). Interestingly, restoration of cone function (as evidenced by restoration of cone ERG amplitudes of up to 90% of normal), has been observed in CNGB3 knock-out mice even when treated at a relatively advanced stage of disease (6 months old) (74). However, normalisation of visual acuity was only noted in mice treated at an earlier stage (2–4 weeks of age).