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In this work, we use structure-based drug design to further improve the potency of the original CMA activators and medicinal chemistry optimization to make them suitable for in vivo use. The derivatives demonstrate good biodistribution and pharmacokinetic properties favorable for peripheral and central nervous system targeting. We have found that these compounds stabilize the interaction of RARα with its corepressor N-CoR1. This unique mechanism of action of the CMA activators leads to the selective regulation of only a discrete subset of the RARα transcriptional program, thus conferring selectivity for CMA. We provide evidence that the compounds efficiently activate CMA in vivo without noticeable toxicity. Lastly, taking into consideration the important contribution of CMA to retinal proteostasis10, we have used an experimental mouse model of retinal degeneration of clinical relevance for retinitis pigmentosa, an incurable devastating condition that results in blindness, and demonstrate that in vivo administration of the CMA activators, either systemically or locally through intravitreal injection, efficiently reduces retinal degeneration and preserves visual function. This work provides proof of concept for pharmacologically targeting the transcriptional mechanism of CMA regulation in a retinal degenerative setting.
To confirm that the CA77-mediated improvement in the retinal structure is associated with preserved visual function, we performed electroretinograms (ERG). Mice receiving CA77 from P18 displayed significantly higher amplitude of their mixed (rod and cone) scotopic responses (b-mixed), and cone photopic responses (b-phot and flicker waves) (Fig. 6h, i), which corroborate the beneficial effect of the intervention on retinal function. No significant differences in other light responses measured were observed between mice receiving CA77 or not.
In light of the growing number of connections linking CMA malfunctioning and disease4, we anticipate that molecules such as the CA compounds developed in this study, could have translational value in treatment of an array of degenerative conditions. In this work, we present evidence of their protective effect against retinal degeneration using a pre-clinical model of retinitis pigmentosa. Although a rare genetic disorder, the severity of the visual deficiency and rapid progression to blindness, along with the fact that there are no currently effective treatments for this type of retinal degeneration, justify our interest in further exploring the suitability of these CA compounds or additional derivatives in the treatment of this detrimental retinal condition. We have previously shown that CMA has a key role in preserving retinal proteostasis10. Here, we wanted to investigate whether the protective effect of CMA in retina extended also to other types of stressors, beyond proteotoxicity. To this effect, we selected the rd10 mouse model of retinitis pigmentosa where degeneration is associated with an abnormal increase in the levels of cGMP that results in photoreceptor cell death. Moreover, and in contrast to other Pde6 mutations that degenerate very fast after the time of eye opening (i.e., rd1 mice), the rd10 mouse model provides a suitable therapeutic window and eliminates the confounding effects of the naturally occurring cell death associated to postnatal retinal development22. Using this model, we now show that both systemic as well a single intravitreal injection of CA77 provide strong preservation of retinal histology and visual function. In addition, our observation that NCOR1 expression was reduced in retinas from RP patients bearing different mutations suggests that dysregulation of the N-CoR1/RARα axis could be a common pathogenic feature in this group of diseases and supports the possible translational value of our CA compounds. Furthermore, the cytoprotective effect of the pharmacological activation of CMA in the retina opens the possibility of expanding testing of the CA compounds to common retinal degenerative disorders such as diabetic retinopathy or age-related macular degeneration.
Primary antibodies were from the following sources: (dilution for use in immunoblot (IB) or immunofluorescence (IF) and clone indicated in brackets): rabbit anti LC3B (1/1000 IB, MBL pm036), mouse anti β-actin (1/10000 IB, Sigma, A4700), chicken anti MAP2 (1/2000 IF, Biolegend, 822501), mouse anti-GFAP (1/1000 IF, Millipore, MAB360), rabbit anti-GFAP (1/500 IF, DAKO, Z0334), mouse anti S100 (1/1000 IF, Abcam, ab7852), goat anti Iba1 (1/100 IF, Abcam, ab5076), rabbit anti-RARα (1/1000 IF and IB, Cell Signaling, 2554), mouse anti visual (rod) arrestin (1/200 IF, Santacruz Biotechnologies, C-3, Sc-166383), rabbit anti-Opsin R/G (1/1000 IF, Millipore, AB5405), rabbit anti transducin (1/200 IF, Santacruz Biotechnologies, sc-389), rabbit anti cone arrestin (1/1000 IF, Millipore, AB15282), rabbit anti-N-CoR1 (1/100 IF and IB, Cell Signaling, 5948) and rabbit anti L2A (1/2000 IB, Invitrogen, 51-2200). Secondary antibodies were from the following sources (dilution, source, and catalogue number): Anti-mouse IgG secondary antibody Alexa Fluor 568 (1/500 IF, Invitrogen, A-11004), Anti-mouse IgG secondary antibody Alexa Fluor 647 (1/500 IF, Invitrogen, A-32728), Anti-goat IgG secondary antibody, Alexa Fluor 594 (1/500 IF, Invitrogen, A-11012), Anti-rabbit IgG secondary antibody, Alexa Fluor 568 (1/500 IF Invitrogen, A-11011), Anti-chicken IgY secondary antibody, Alexa Fluor 488 (1/500 IF, Invitrogen, A-11039), Anti-rabbit secondary antibody, HRP (1:5000 IB, ThermoFisher, 31460), Anti-mouse secondary antibody, HRP (1:5000 IB, ThermoFisher, 31430). 153554b96e
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