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EP-4739300-A1 - MODULATORS OF IRON METABOLISM FOR TREATING CONDITIONS ASSOCIATED WITH CONE PHOTORECEPTOR DEGENERATION

EP4739300A1EP 4739300 A1EP4739300 A1EP 4739300A1EP-4739300-A1

Abstract

The present invention provides methods of treatment of conditions associated with cone photoreceptor degeneration, wherein the treatment comprises reduction of intracellular iron levels 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 (13)

  1. 1. A compound, preferably a ferroptosis inhibitor, for use in treating a condition associated with cone photoreceptor degeneration, wherein the treatment comprises reduction of intracellular iron levels in cone photoreceptors.
  2. 2. The compound for the use of claim 1 , wherein the activity of ferritin and/or nuclear receptor coactivator 4 (NCOA4) is decreased or inhibited.
  3. 3. The compound for the use of any one of claims 1 or 2, wherein the treatment comprises maintaining or increasing cone photoreceptor viability.
  4. 4. The compound for the use of any one of claims 1 to 3, wherein the treatment comprises preventing or reducing glial migration.
  5. 5. The compound for the use of any one of claims 1 to 4, wherein the treatment comprises preventing or reducing subretinal deposit formation.
  6. 6. The compound for the use of any one of claims 1 to 5, wherein the treatment comprises maintaining or increasing cone photoreceptor activity.
  7. 7. The compound for the use of anyone of claims 1 to 6, wherein the compound is selected in the group consisting of the Prominin2, miR-522, and/or RP11 -89 genes; an RNA inhibiting FTL, FTH1 , and/or NCO4; deferiprone, deferoxamine (DFO), gossypol acetic acid, histochrome, ciclopirox olamine (CPX), bafilomycin A1 , quercitrin, baicalein, dexrazoxane, 2, 2'- bi pyridine, 1 ,10-phenanthroline, mangiferin, astilbin, YL-939, deferasirox (DFX), Astilbin, CN128 (hydrochloride), Ginsenoside Rh3, Mangiferin, and Tricetin.
  8. 8. The compound for the use of any one of claims 1 to 7, 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.
  9. 9. The compound for the use of any one of claims 1 to 8, wherein the use comprises the administration of the compound intravitreally (e.g., in the subretinal space, the suprachoroidal space, the anterior chamber, the vitreous humour, the subconjunctival space, or on the corneal surface), by eye drop, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intra tracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intra tumourally, peritoneally, subcutaneously, subconjunctivally, intra vesicularly, mucosally, intrapericardially, intracardiacally intraumbilically, intraocularly, intraorbitally, orally, topically, transdermally, by inhalation, by injection, by implantation, by infusion, by continuous infusion, by localised perfusion bathing target cells directly, by catheter, by lavage, in cremes, or in lipid compositions.
  10. 10. The compound for the use of any one of claims 1 to 9, wherein the use comprises the administration of a further therapeutic agent.
  11. 11 . The compound for the use of claim 10, wherein the further therapeutic agent is a second ferroptosis inhibitor, pegaptanib, ranibizumab, bevacizumab, brolucizumab, faricimab, AKB-9778, nesvacumab, Bl 836880, AKST4290, or aflibercept.
  12. 12. The compound for the use of claim 11 , wherein administration of the second ferroptosis inhibitor results in activation of the Xc- transporter or the GPX4 enzyme in cone photoreceptors and/or reduction or inhibition of lipid peroxidation in cone photoreceptors.
  13. 13. The compound for the use of any one of claims 10 to 12, wherein the compound and the further therapeutic agent are administered simultaneously, sequentially, or separately.

Description

MODULATORS OF IRON METABOLISM 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 iron metabolism in cone photoreceptors prevents degeneration of these cells. In particular, reduction of intracellular iron levels 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 reducing, in particular specifically reducing, intracellular iron levels or sequesters, in particular specifically sequesters, intracellular iron molecules, in cone photoreceptors. More particularly, said ferroptosis inhibitor specifically reduces intracellular iron levels or specifically sequesters intracellular iron molecules, in cone photoreceptors. In an instance, the treatment comprises maintaining or increasing cone photoreceptor viability. In an instance, the treatment does not affect rod photoreceptor viability and/or the treatment does not affect retinal pigment epithelial cell viability at identical dose of treatment, in particular at identical concentration of ferroptosis inhibitor. In an instance, the treatment comprises preventing an increase in the cell membrane permeability to dyes in cone photoreceptors. More particularly, the treatment comprises specifically preventing an increase in the cell membrane permeability to dyes in cone photoreceptors, i.e. the treatment does not substantially prevent an increase in the cell membrane permeability to dyes in other retinal cell types, such as rod photoreceptors. In an instance, the treatment comprises maintaining or decreasing the activity of ferritin and/or nuclear receptor coactivator 4 (NCOA4), in particular specifically maintaining or decreasing the activity of ferritin and/or nuclear