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- Paquet-Durand, F., et al.
(författare)
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Systemic and intraocular administration of the liposomal formulation of the cyclic GMP analogue CN03 : An exploratory safety and tolerability study in non-human primates
- 2019
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Ingår i: Investigative Ophthalmology and Visual Science. - : ASSOC RESEARCH VISION OPHTHALMOLOGY INC. - 0146-0404 .- 1552-5783. ; 60:9
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Tidskriftsartikel (refereegranskat)abstract
- Purpose : The cGMP analogue CN03 targets cGMP signalling, a disease driver common to different types of retinal degeneration. For efficient targeting to the neuroretina CN03 was combined with a liposomal (LP) drug delivery system. In rodents, LP-CN03 has shown significant photoreceptor protection and preservation of in vivo retinal function, without major adverse events. The objective of the study was to determine the toxicity of CN03 and LP-CN03, following intravitreal (IVT) or intravenous (IV) administration. IVT administration is the intended human therapeutic route, IV injection was tested to investigate systemic toxicity.Methods : Cynomolgus monkeys were assigned to five different groups, consisting of one male and one female (n=2). Group 1 served as saline control for IVT and IV dosing, group 2 served as liposome (LP) control. Groups 3 and 4 received IVT injections of either 1X or 10X of the intended therapeutic dose, of either LP-CN03 (left eye) or CN03 (right). Group 5 received 100X IV bolus injections of LP-CN03 (Day 1) and CN03 (Day 25). Toxicity was assessed based on clinical observations, body weights, ophthalmology, intraocular pressure (IOP), electroretinography (ERG), and clinical and anatomic pathology.Results : IVT administration of LP caused transient white opacity in the vitreous body of all treated eyes, related to the milky consistency of LP. IVT injection of 1X and 10X CN03 was well-tolerated and only showed temporary pupil dilation in one male. IVT injection of 1X and 10X LP-CN03 was additionally associated with particles in the anterior chamber and vitreous body. At 10X, pigmented dots were also noted in the anterior lens capsule. IV injection of 100X LP-CN03 and CN03 was well tolerated and did not cause systemic toxicity. Comparison of pre- and post-dosing ERG did not reveal significant differences (p>0.05) in any of the groups, nor were there any indications of pathological changes in retinal morphology.Conclusions : IVT injection of CN03 and LP-CN03 at the intended therapeutic dose was not associated with any changes in ophthalmoscopy, electroretinography or histopathology, and only revealed slight pupil dilation in one animal. IV slow bolus injection at 100X the intended therapeutic dose was well tolerated.
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| 3. |
- Jiao, K, et al.
(författare)
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Efficacy of PARP inhibition in Pde6a mutant mouse models for retinitis pigmentosa depends on the quality and composition of individual human mutations
- 2016
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Ingår i: Cell death discovery. - : Springer Science and Business Media LLC. - 2058-7716. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Retinitis pigmentosa (RP), an inherited blinding disease, is caused by a variety of different mutations that affect retinal photoreceptor function and survival. So far there is neither effective treatment nor cure. We have previously shown that poly(ADP-ribose)polymerase (PARP) acts as a common and critical denominator of cell death in photoreceptors, qualifying it as a potential target for future therapeutic intervention. A significant fraction of RP-causing mutations affect the genes for the rod photoreceptor phosphodiesterase 6A (PDE6A) subunit, but it is not known whether they all engage the same death pathway. Analysing three homozygous point mutations (Pde6a R562W, D670G, and V685M) and one compound heterozygous Pde6a (V685M/R562W) mutation in mouse models that match human RP patients, we demonstrate excessive activation of PARP, which correlated in time with the progression of photoreceptor degeneration. The causal involvement of PARP activity in the neurodegenerative process was confirmed in organotypic retinal explant cultures treated with the PARP-selective inhibitor PJ34, using different treatment time-points and durations. Remarkably, the neuroprotective efficacy of PARP inhibition correlated inversely with the strength of the genetically induced insult, with the D670G mutant showing the best treatment effects. Our results highlight PARP as a target for neuroprotective interventions in RP caused by PDE6A mutations and are a first attempt towards personalized, genotype-matched therapy development for RP. In addition, for each of the different mutant situations, our work identifies windows of opportunity for an optimal treatment regimen for further in vivo experimentation and possibly clinical studies.
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