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EP-4739298-A1 - ACTIVATORS OF THE XC- SYSTEM AND/OR GPX-4 FOR TREATING CONDITIONS ASSOCIATED WITH CONE PHOTORECEPTOR DEGENERATION

EP4739298A1EP 4739298 A1EP4739298 A1EP 4739298A1EP-4739298-A1

Abstract

The present invention provides methods of treatment of conditions associated with cone photoreceptor degeneration, wherein the treatment comprises activating the Xc- transporter or the GPX4 enzyme in cone photoreceptors. In particular, the present invention provides compounds, preferably ferroptosis inhibitors, for use in such methods.

Inventors

  • PICAUD, SERGE
  • Sahel, José Alain
  • FRADOT, Valérie
  • LECLERCQ, Manon
  • DENTEL, Alexandre

Assignees

  • SORBONNE UNIVERSITE
  • Institut National de la Santé et de la Recherche Médicale
  • Centre National de la Recherche Scientifique (CNRS)

Dates

Publication Date
20260513
Application Date
20240705

Claims (16)

  1. 1 . A compound, e.g., a ferroptosis inhibitor, for use in treating a condition associated with cone photoreceptor degeneration, wherein the treatment comprises activating the Xc- transporter or the GPX4 enzyme in cone photoreceptors.
  2. 2. The compound for the use of claim 1 , wherein the activity of the Xc- transporter or the GPX4 enzyme is increased or decreased.
  3. 3. The compound for the use of any one claims 1 or 2, wherein the expression of the Xc- transporter or the GPX4 enzyme is increased.
  4. 4. The compound for the use of any one of claims 1 to 3, wherein the treatment comprises maintaining or increasing cone photoreceptor viability.
  5. 5. The compound for the use of any one of claims 1 to 4, wherein the treatment comprises maintaining or increasing intracellular glutathione level in cone photoreceptors.
  6. 6. The compound for the use of any one of claims 1 to 5, wherein the treatment comprises maintaining or decreasing intracellular NADP/NADPH ratio in cone photoreceptors.
  7. 7. The compound for the use of any one of claims 1 to 6, wherein the treatment comprises preventing or reducing glial migration.
  8. 8. The compound for the use of any one of claims 1 to 7, wherein the treatment comprises preventing or reducing subretinal deposit formation.
  9. 9. The compound for the use of any one of claims 1 to 8, wherein the treatment comprises maintaining or increasing cone photoreceptor activity.
  10. 10. The compound for the use of any one of claims 1 to 9, wherein the ferroptosis inhibitor is selected in the group consisting of cystine, B-mercaptoethanol, selenium, bardoxolone, carvacrol (CAR), rehmanniosideA, bioflavonoids including galangin, xanthohumol, naringenin, britanin, entacapone, capsiate, resveratrol, dexmedetomidine, irisin, kaempferol, fluoflavine, GKT136901 hydrochloride, and ML171.
  11. 11 . The compound for the use of any one of claims 1 to 10, wherein the condition is selected in the group consisting of age-related macular degeneration (AMD), cone dystrophies, cone-rod dystrophies, rod-cone dystrophies, macular dystrophy (e.g. Stargardt disease), central serous chorioretinopathy, Best disease and bestrophinopathies, retinal detachment including rhegmatogenous, serous and fractional causes, solar retinopathy, laser-induced retinopathy, achromatopsia, Stargardt disease, Usher syndrome, Leber congenital amaurosis (LCA), Alstrom disease, and Refsum disease, preferably AMD or retinitis pigmentosa, more preferably AMD.
  12. 12. The compound for the use of any one of claims 1 to 11 , wherein the use comprises the administration of the component in the subretinal space, the suprachoroidal space, the anterior chamber, the vitreous humor, the subconjunctival space, on the corneal surface, through systemic administration (inhalator, intravenous, intramuscular or intraperitoneal) or under solution, gel or implant.
  13. 13. The compound for the use of any one of claims 1 to 12, wherein the use comprises the administration of a further therapeutic agent.
  14. 14. The compound for the use of claim 13, wherein the further therapeutic agent is a second ferroptosis inhibitor, pegaptanib, ranibizumab, bevacizumab, brolucizumab, faricimab, AKB-9778, nesvacumab, Bl 836880, or aflibercept.
  15. 15. The compound for the use of claim 14, wherein administration of the second ferroptosis inhibitor results in reduction or inhibition of lipid peroxidation in cone photoreceptors and/or reduction of intracellular iron levels in cone photoreceptors.
  16. 16. The compound for the use of any one of claims 13 to 15, wherein the component and the further therapeutic agent are administered simultaneously, sequentially, or separately.

Description

ACTIVATORS OF THE Xc- SYSTEM AND/OR GPX-4 FOR TREATING CONDITIONS ASSOCIATED WITH CONE PHOTORECEPTOR DEGENERATION. INTRODUCTION The retina is a light-sensitive neuronal tissue located at the posterior part of the eyeball. Retinas of humans have two distinct regions. The retinal periphery has low spatial acuity and is responsible for night-vision and different aspects of motion vision. The fovea (or macula) is at the retinal centre and drives high spatial acuity vision that is essential for reading and face recognition. Primates are the only mammals with a fovea. Retina is arranged in three layers of cells, namely the outer nuclear layer (ONL), the inner nuclear layer (INL), and the retinal ganglion cell (RGC) layer. The ONL harbours photoreceptors, which are unique neurons dedicated to converting light into electrochemical signals and as such essential for vision. Two different types of photoreceptors are distinguished: rod photoreceptors respond to dim light and enable vision at night, whereas cone photoreceptors respond to bright daylight and mediate high-resolution and colour vision. Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Photoreceptor death is the common cause in many retinal disorders, such as age-related macular degeneration (AMD), and retinitis pigmentosa (RP). In most of these diseases (e.g., AMD), the pathology appears to be linked primarily to a loss of cones. It is thus particularly important to be able to prevent cone photoreceptors degeneration. It would enable therapeutic intervention at the earliest stages to stop the disease developing, thereby ultimately preventing loss of vision. To this day, there is no effective therapy for retinal degenerative diseases which remain poorly treatable, presenting an urgent need for developing novel treatment strategies. There are few approved therapies for these diseases, but they only address the eye neovascularisation subsequent to cone photoreceptor degeneration. On the other hand, no molecules capable of preventing or treating the earliest stages of the pathologies, i.e., the death of the cone photoreceptors, have yet been identified. Further understanding of the mechanisms leading to cone photoreceptor death is essential for the development of these treatments. Most of the earliest stages of retinal diseases are still not understood, notably the molecular and cellular mechanisms which result in cone photoreceptor death. Several mechanisms of cell death have been suggested to be implicated in ocular diseases, including apoptosis, pyroptosis, necrosis, and ferroptosis (Yang et al., Int J Mol Sci. 21 (19):7279, 2020; Lin et al. J Ophthalmol. 2022:2695212, 2022; Zhang et al. Front Nutr. 9:844757, 2022). However, none of these mechanisms has been shown to specifically drive death of the cone photoreceptors. There is thus still an urgent need for molecules that can effectively treat conditions associated with cone photoreceptor degeneration. SUMMARY OF THE DISCLOSURE In a first aspect, the present disclosure relates to a method of treating a condition associated with cone photoreceptor degeneration. The present disclosure shows that modulation of the Xc- transporter and/or the GPX4 enzyme in cone photoreceptors prevents degeneration of these cells. Hence, a first aspect of the disclosure relates to a compound, e.g., a ferroptosis inhibitor, for use in treating a condition associated with cone photoreceptor degeneration, wherein the treatment comprises modulating, in particular specifically modulating, the Xc- transporter or the GPX4 enzyme in cone photoreceptors. More particularly, said ferroptosis inhibitor specifically modulates the Xc- transporter or the GPX4 enzyme in cone photoreceptors, i.e., the Xc- transporter or the GPX4 enzyme are modulated by said ferroptosis inhibitor in cone photoreceptors but are not substantially affected in other retinal cell types, such as rod photoreceptors or retinal pigment epithelial cells, at identical concentrations of ferroptosis inhibitor. Preferably, the activity of the Xc- transporter and/or of the GPX4 enzyme is increased, in particular is specifically increased, in cone photoreceptors. More particularly, said ferroptosis inhibitor specifically increases the activity of the Xc- transporter and/or of the GPX4 enzyme in cone photoreceptors, i.e., the activity of the Xc- transporter or the GPX4 enzyme is increased by said ferroptosis inhibitor in cone photoreceptors but is not substantially affected in other retinal cell types, such as rod photoreceptors or retinal pigment epithelial cells, at identical concentrations of ferroptosis inhibitor. In another preferred instance, the expression of the Xc- transporter and/or the GPX4 enzyme is increased, in particular is specifically increased, in cone photoreceptors. In an instance, the treatment comprises maintaining or increasing cone photoreceptor viability. In an instance, th