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Journal: Development of TRIB3-Based Therapy as a Gene-Independent Approach to Treat Retinal Degenerative Disorders. (Pubmed Central) - May 11, 2024
and RHO staining, along with an elevation in total PDE activity in the retinas. Consequently, our study demonstrated the feasibility of a gene-independent strategy to target common signaling in degenerating retinas by employing a TRIB3-based therapeutic approach that delays retinal function and photoreceptor cell loss in two RD models.
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Trial completion date, Trial primary completion date: Oral Hydroxychloroquine (HCQ) for Retinitis Pigmentosa Caused by P23H- Rhodopsin (RHO) (clinicaltrials.gov) - Feb 9, 2023
P1/2, N=12, Recruiting,
Our finding suggests that using this or similar RNA replacement vectors in human gene therapy may provide clinical benefit to both eyes of patients with adRP. Trial completion date: Oct 2023 --> Oct 2025 | Trial primary completion date: Oct 2023 --> Oct 2025
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Journal: Galanin receptor 3 - a new pharmacological target in retina degeneration. (Pubmed Central) - Jan 25, 2023
These results indicate that GALR3 signaling contributes to acute light-induced and chronic RP-linked retinopathies. Together, this work provides the pharmacological knowledge base to evaluate GALR3 as a potential target for developing novel therapies to combat retinal degeneration.
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Preclinical, Journal: GADD34 Ablation Exacerbates Retinal Degeneration in P23H RHO Mice. (Pubmed Central) - Nov 27, 2022
Additionally, GADD34 controls cytokine expression and STAT3 activation. Perhaps these molecular events are particularly important in controlling the pace of retinal degeneration.
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Investigation of ABCA4 missense variant plasma membrane trafficking in cell models. (F0126) - Apr 29, 2022 - Abstract #ARVO2022ARVO_2941;
Reduced growth temperature can enhance the plasma membrane traffic of WT and missense variants of ABCA4 in cultured cells, suggesting that some of these variants are temperature sensitive misfolding variants that might be amenable to pharmacological rescue. The assay we developed is able to quickly and robustly detect plasma membrane localization, which could be used as a surrogate marker for correct folding and trafficking, and has potential use for high-throughput screening of small molecules able to restore ABCA4 folding.
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NANOBODY rescues adRP phenotype in a P23H adRP cell model, suggesting therapeutic potential (A0061) - Apr 29, 2022 - Abstract #ARVO2022ARVO_2645;
Intracellular expression of Nbs rescues the mutant RHO phenotype in an in vitro HEK293 adRP model, suggesting therapeutic potential of the nanobody technology. Since there are few treatment options for RHO-adRP, NANOBODY technology might offer a new treatment option regardless of a patient’s genetic background.
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GADD34 does not affect the translational rate in P23H RHO mouse retina ([Virtual]) - Apr 29, 2022 - Abstract #ARVO2022ARVO_1058;
Our results indicate that GADD34 deficiency does not affect the rate of protein synthesis during chronic ER stress, suggesting that p-eIF2α is not the major point of translational control in progressive RD. GADD34 may control the inflammatory response of P23H Rho retinas, and its deficiency may alter pro- and anti-inflammatory cytokine ratios, thus resulting in compromised photoreceptor homeostasis.
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Preclinical, Journal: Flavonoids improve the stability and function of P23H rhodopsin slowing down the progression of retinitis pigmentosa in mice. (Pubmed Central) - Apr 19, 2022
Thus, we hypothesized that flavonoids by binding to P23H Rho and enhancing its conformational stability could mitigate detrimental effects of this mutation on retinal health...In addition, treatment with quercetin resulted in downregulation of the UPR signaling and oxidative stress-related markers. This study unravels the pharmacological potential of quercetin to slow down the progression of photoreceptor death in Rho-related RP and highlights its prospective as a lead compound to develop a novel therapeutic remedy to counter RP pathology.
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Trial completion date, Trial primary completion date: Oral Hydroxychloroquine (HCQ) for Retinitis Pigmentosa Caused by P23H- Rhodopsin (RHO) (clinicaltrials.gov) - Feb 15, 2022
P1/2, N=12, Recruiting,
This study unravels the pharmacological potential of quercetin to slow down the progression of photoreceptor death in Rho-related RP and highlights its prospective as a lead compound to develop a novel therapeutic remedy to counter RP pathology. Trial completion date: Oct 2022 --> Oct 2023 | Trial primary completion date: Oct 2022 --> Oct 2023
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Preclinical, Journal: ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model. (Pubmed Central) - Nov 17, 2021
By contrast, older Atf6Rho mice developed significantly increased retinal degeneration in comparison to Atf6Rho mice in all retinal layers, accompanied by reduced rhodopsin protein levels. Our findings demonstrate that Atf6 is required for efficient clearance of rhodopsin protein in rod photoreceptors expressing P23H rhodopsin, and that loss of Atf6 ultimately accelerates retinal degeneration in P23H-KI mice.
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[VIRTUAL] Intravitreal triamcinolone acetate promotes rod and cone survival in Retinitis Pigmentosa () - Sep 15, 2020 - Abstract #RSLONDON2020RS_LONDON_221;
Chronic ER stress resulting from mutant misfolded protein in rods initiates activation of retinal microglia and removal of rods in RP. IVTA, a slow release intravitreal glucocorticoid, inhibits microglia by expression of a checkpoint inhibitor on rods, with surviving rods promoting glucose transport to cones for at least 60 days post-injection.
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A Hybrid Human/Mouse T4K Rhodopsin Transgene Causes Light Exacerbated Retinal Degeneration Indistinguishable from Human T4K Rhodopsin (Exhibit Hall: Posterboard# B0054) - Mar 9, 2020 - Abstract #ARVO2020ARVO_5180;
T4K-induced RD is mechanistically distinct from that caused by P23H RHO, in that the mutant rhodopsin does not mislocalize...This raises our confidence that a humanized mouse model based on a hybrid RHO strategy will retain a mechanistically similar RD. Our next step will be to develop and characterize the mouse model expressing the human T4K RHO, which can be used for both mechanistic studies and testing gene editing therapeutics that will be easily transferable to clinical studies.
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Advanced microscopy of wild-type and mutant rhodopsin trafficking at the basal body and connecting cilium of mouse rods (Ballroom III) - Mar 9, 2020 - Abstract #ARVO2020ARVO_3834;
Results from WT mice were compared to those from mice with human P23H-Rho-RFP knocked into the mouse rhodopsin locus.Results In the inner segment, Rho associates with the basal body (BB) at the distal tip of ciliary rootlet between the BB centrioles, as do ciliary trafficking proteins like Rab11a and intraflagellar transport (IFT) protein IFT88...Rho-IFT88 colocalization at the CC and the tethering of detergent resistant Rho to the microtubule axoneme support a model in which Rho actively traffics through the CC as cargo of IFT complexes. The P23H mutant rhodopsin is predominantly retained in the ER, likely in a misfolded form that overwhelms ER homeostasis, while a small fraction of the mutant protein successfully passes through the BB/CC trafficking machinery.
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Enrollment open: Oral Hydroxychloroquine (HCQ) for Retinitis Pigmentosa Caused by P23H- Rhodopsin (RHO) (clinicaltrials.gov) - Feb 28, 2020
P1/2, N=12, Recruiting,
The P23H mutant rhodopsin is predominantly retained in the ER, likely in a misfolded form that overwhelms ER homeostasis, while a small fraction of the mutant protein successfully passes through the BB/CC trafficking machinery. Not yet recruiting --> Recruiting
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