EP4608403A1 - Modulateurs et leurs utilisations - Google Patents

Modulateurs et leurs utilisations

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Publication number
EP4608403A1
EP4608403A1 EP23882103.7A EP23882103A EP4608403A1 EP 4608403 A1 EP4608403 A1 EP 4608403A1 EP 23882103 A EP23882103 A EP 23882103A EP 4608403 A1 EP4608403 A1 EP 4608403A1
Authority
EP
European Patent Office
Prior art keywords
smc
modulator
retinal
disease
ccr1
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23882103.7A
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German (de)
English (en)
Other versions
EP4608403A4 (fr
Inventor
Itay Chowers
Sarah ELBAZ-HAYOUN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hadasit Medical Research Services and Development Co
Original Assignee
Hadasit Medical Research Services and Development Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Hadasit Medical Research Services and Development Co filed Critical Hadasit Medical Research Services and Development Co
Publication of EP4608403A1 publication Critical patent/EP4608403A1/fr
Publication of EP4608403A4 publication Critical patent/EP4608403A4/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present disclosure relates to modulators and uses thereof.
  • AMD age-related macular degeneration
  • chemokine receptors are involved in AMD.
  • beta chemokine receptor inhibitors for the protection of photoreceptor cells medicament for the treatment of hereditary retinal degeneration [3].
  • expression of CCR1 in the photoreceptor cells was identified to be increased with the progress of retinal degeneration in rd mice [4]. Further, it was shown that retinal degeneration induces upregulation of a broad chemokine response whose expression is coordinated by Muller cells, microglia, and RPE [5].
  • the present disclosure provides in accordance with some aspects, an effective amount of at least one small molecule compound (SMC) modulator for use in a method for modulating activity of CCR1 in a Muller cell of a subject in need thereof.
  • SMC small molecule compound
  • the present disclosure provides in accordance with some other aspects, an effective amount of at least one SMC modulator for use in a method for inhibiting Muller cell activation of a subject in need thereof, wherein the SMC modulator modulates activity of CCR1 in the Muller cell.
  • an effective amount of at least one SMC for use in a method for modulating the activity of CCR1 in a Muller cell of a subject in need thereof, wherein the SMC is represented by Formula (I): pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • SMC small molecule compound
  • a pharmaceutical composition comprising the at least one SMC modulator and optionally at least one of pharmaceutically acceptable carrier/s, excipient/s, auxiliaries, and/or diluent/s.
  • the present disclosure provides with some other aspects a method of inhibiting activity of CCR1 in a Muller cell in a subject in need thereof, the method comprises contacting the cell with an effective amount of at least one SMC modulator.
  • the present disclosure provides with some other aspects a method of inhibiting Muller cell activation in a subject in need thereof, the method comprising contacting said cell with an effective amount of at least one SMC modulator, wherein the SMC modulator inhibits CCR1 activity in the Muller cell.
  • the present disclosure provides with some other aspects a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a retinal disease or condition in a subject in need thereof, the method comprises administering to said subject a therapeutically effective amount of at least one SMC modulator, wherein said SMC modulator is represented by Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof
  • FIGS. 1B-1E are images showing TUNEL (red) and DAPI (blue) staining of BALB/c mouse retinas two days after photic injury shows apoptotic photoreceptor cells (asterisk) and RPE cells (arrow) in the posterior retina (Fig. IB and Fig. 1C), and relatively few apoptotic cells (arrow) in the peripheral retina (Fig. ID and Fig. IE);
  • Figs. 1F-1G are optical coherence tomography images obtained 7 days after photic injury in control (Fig. IF) and in mice induced with photic injury (Fig. 1G), 1, 2, and 3 indicate the ganglion cell layer (GCL), inner nuclear layer (INL), and ONL, respectively;
  • Fig. IF optical coherence tomography images obtained 7 days after photic injury in control
  • Fig. 1G 1, 2, and 3 indicate the ganglion cell layer (GCL), inner nuclear layer (INL), and ONL, respectively;
  • Fig. IF
  • Fig. II is a graph showing relative photoreceptor number; *p ⁇ 0.05. Scale bars: 50 pm (Fig. IB- Fig. IE) and 200 pm (Fig. IF and Fig. 1G).
  • Figs. 2A-2F relate to in vitro characterization of human monocytes derived macrophages (hMdcjis) and in vivo cytotoxicity of M2a hMdcji cells
  • FIG. 2B are images from converted phasecontrast microscopy of M0, Ml, M2a, and M2c hMdcjis;
  • FIG. 2D are representative ERG recordings in control mice and in photic-injured mice in which the right eye (OD) was injected with Ml or M2a hMdcjis and the left eye (OS) was injected with PBS as vehicle, "a" and “b” in the graphs indicate the a-wave and the b-wave of the ERG, respectively;
  • Fig. 2E is a graph showing summary of the relative number of photoreceptor nuclei in the ONL measured at the indicated distances from the optic nerve head (in pm), the relative number of photoreceptor nuclei was calculated by comparing the number of photoreceptor nuclei present in the ONL of the mouse eye injected with hMdcji and the counterpart vehicle-injected eye; Fig.
  • 2F are representative immunofluorescence images of retinal slices prepared from the indicated mice following an injection of DiO-stained hMdcjis (green); the nuclei were counterstained with DAPI (blue), and the ONL is indicated (red brackets).
  • GCL ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer. *p ⁇ 0.05 and **p ⁇ 0.01. Scale bars: 50 pm (Yuan).
  • 3C-3E are inverted phase-contrast microscopy images of cryosections prepared from mouse eyes 7 days after photic retinal injury and intravitreal injection of DiO-labeled M2a hMdcjis, showing M2a hMdcjis in the vitreous (Fig. 3C) with a polarized profile and elongated cell morphology (Fig. 3D), as well as across the layers of the retina (Fig. 3E, asterisk), including the subretinal space (Fig. 3E, arrows);
  • Figs. 3F-3I are images of retinal flat-mount (Fig. 3F, Fig. 3H) and fundus autofluorescence images (Fig. 3G, Fig.
  • FIG. 4F is a Rhodopsin immunostaining (green) image of a retinal explant showing the association of macrophages with apoptotic photoreceptor cells, indicated by the co-localization of TUNEL and rhodopsin staining in a Z-stack (shown in arrow);
  • FIGs. 4G-4H are images of RPE-choroid explants co-cultured with M2a hMd ⁇ s, and the co-localization of TUNEL staining (red) and the expression of the RPE marker RPE65 (green) (Figs 4G), the presence of TUNEL-positive hexagonal and pigmented cells (shown by arrows) is visualized in Fig. 4H; Fig.
  • Figs 5A-5G relate to M2a hMdcjis cells that produce high levels of reactive oxygen species (ROS) and induce the infiltration of CDl lb + cells
  • Fig. SB is a HNE immunostaining (green) image showing similar levels of oxidative stress in mouse eyes following an intravitreal injection of either Ml hMdcjis (left) or M2a hMdcjis (right); Fig.
  • 5D is a CDl lb immunostaining image (red, arrows) showing increased presence of mononuclear phagocytes in the choroid tissue following photic injury (top right) and in eyes following an intravitreal injection of Ml hMdcjis (bottom left) or M2a hMdcjis (bottom right);
  • FIG. 5F are inverted phase-contrast microscopy images of the ONH showing migration of DiO-labeled M2a hMdcji cells (green) and co- localization with recruited CDl lb + cells (red), shown in the rectangles;
  • Figs 7A-7E relate to CCR1 expression, upregulated in a mouse model of photic injury
  • Figs 7A-7B are images of Albino BALB/c mice exposed to photic injury; 48 hours and 7 days later, retinal sections were prepared and immunostained for Ccrl (Fig. 7A; red) or TUNEL stained (Fig. 7A B, red); the nuclei were counterstained with DAPI (blue);
  • Fig. 7A-7E relate to CCR1 expression, upregulated in a mouse model of photic injury
  • Figs 7A-7B are images of Albino BALB/c mice exposed to photic injury; 48 hours and 7 days later, retinal sections were prepared and immunostained for Ccrl (Fig. 7A; red) or TUNE
  • FIG. 7D is a graph showing Ccrl expression plotted against the fa- wave amplitude measured using ERG in mice 7 days after photic injury, each dot represents an individual mouse, and the correlation coefficient and p- value are shown;
  • Fig. 7E show images of retinal sections prepared 7 days after photic injury and coimmunostained for CCR1 (red) and the glial cell marker GFAP (green); nuclei were counterstained with DAPI (blue).
  • GCL ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; ONL, outer nuclear layer. Scale bars: 50 pm (Fig. 7A, Fig. 7B, and Fig. 7E).
  • Figs. 8A-8E relate to expression of CCR2 and CCR5 in the mouse retina following photic injury
  • Figs. 8A-8B are images of retinal sections obtained from control and photic-injured mice immunostained for CCR2 (Fig. 8A) or CCR5 (Fig. 8B); nuclei were counterstained with DAPI (blue);
  • Fig. 8C are images of flat-mount retinal sections prepared from photic-injured mice and show recruited cells expressing CCR1 (left panel, arrows), CCR2 (middle panel, arrows), and CCR5 (right panel, arrows); Figs.
  • Figs. 9A-9H relate to upregulation of Ccrl in both rdlO mice and senescent mice
  • Fig. 9A are images showing retinal sections prepared from 1 -week-old, 3 -week- old, and 6-week-old rdlO mice and immunostained for CCR1; nuclei were counterstained with DAPI, increased expression of CCR1 (top row, shown by arrows) is observed at 3 and 6 weeks, corresponding to reduced ONL thickness (bottom row, shown by double-ended arrows); Fig.
  • FIGS. 9B are images of retinal sections from a 3-week- old rlO mouse co-immunostained for CCR1 (red) and GFAP (green); nuclei were counterstained with DAPI, and the co-localization of CCR1 and GFAP in the Muller cells is shown;
  • FIGS. 9E-9G are images of retinal sections prepared from 18-month-old (senescent) mice and co-immunostained for CCR1 (red) and GFAP (green); nuclei were counterstained with DAPI, colocalization of CCR1 and GFAP in the Muller cells is shown by arrows;
  • Figs. 10A-10G show inhibition of CCR1 resulting in the reduction of the effects of photic injury, Albino BALB/c mice were subjected to photic injury followed by subcutaneous injections of the CCR1 inhibitor BX471 or vehicle for 5 days;
  • Fig. 10A shows ERG recordings performed after 5 days, amplitude of the b-wave was measured and is plotted against flash intensity;
  • Fig. 10B is a graph showing the number of photoreceptor nuclei measured at the indicated distances from the optic nerve; Fig.
  • FIG. 10C are images of retinal sections prepared from vehicle- and BX471 -treated mice and immunostained for the microglial cell marker IBA-1; asterisks indicate amoeboidshaped cells in the ONL and subretinal layer, and arrows indicate elongated cells in the GCL and IPL, with one cell shown in a magnified view (inset);
  • FIGS. 10E are images showing retinal sections prepared from vehicle-treated photic-injured mice and BX471 -treated photic-injured mice and immunostained for CCR1;
  • Figs. 11A-11D relate to CCR1 inhibition that modulates the functional properties of M2a hMd$s
  • Fig. 11A are images of Ml and M2a hMdcjis immunostained for CCR1 (green); with magnified views are shown below
  • Fig. 11C is a graph showing ROS levels measured in untreated M2a hMdcjis and M2a hMdcjis treated with 0.5 or 5 pM BX471;
  • Fig. 11A are images of Ml and M2a hMdcjis immunostained for CCR1 (green); with magnified views are shown below
  • Fig. 11B is a graph showing the percentage of CCRl-postive cells measured using cell sorting analysis of
  • Figs. 12A-12O are auto- fluorescence images of the eye fundus
  • Figs. 13A-13F are graphs showing the results of real-time quantitative PCR (qPCR) analysis of CxcllO (Fig. 13A), Gfap (Fig. 13B), Vimentin (Fig. 13C), Cxcll (Fig. 13D), Ccl2 (Fig. 13E) and F4/80 (Fig.
  • Figs. 14A-14C show the effect of the CCRl-specific antagonist BX471 in rdlO mice;
  • Fig. 14A shows b-wave amplitude plotted against flash intensity, from fullfield electroretinography (ERG) measurements recorded for both (— ) vehicle-treated and ( TM «) BX471 -treated group, as well as a second ERG recording performed on day 5 of the experiment for both groups ((— ) vehicle-treated mice, and ( ) BX471 treated mice. ;
  • Fig. 14A shows b-wave amplitude plotted against flash intensity, from fullfield electroretinography (ERG) measurements recorded for both (— ) vehicle-treated and ( TM «) BX471 -treated group, as well as a second ERG recording performed on day 5 of the experiment for both groups ((— ) vehicle-treated mice, and ( ) BX471 treated mice. ;
  • Fig. 14A shows b-wave amplitude plotted against flash intensity, from full
  • FIG. 14B shows the average b-wave amplitudes (in pV) for the control and treated mice; ; Fig.l4C shows representative scotopic ERG signals of vehicle- and BX471 -treated mice, at post-natal day 21 (P21) and at post-natal day 25 (P25); data shown as mean ⁇ SEM. p-Values indicated by ns, not significant and Tp ⁇ 0.05. **p ⁇ 0.00004, ***p ⁇ 0.000004 (Student’s t-test).
  • Fig. 15 shows ERG measurements recorded at P21 for both, (-) rdlO mice and ( ⁇ ) rdlO mice with Ccrl deletion, represented by the b-wave amplitude plotted against flash intensity; data shown as mean ⁇ SEM. p-Values indicated by *p ⁇ 0.03, **p ⁇ 0.008 (Student’s t-test).
  • Retinal disease is characterized by a complex physiology involving multiple interrelated diverse cellular and molecular processes. Such diseases are often multifactorial disease influenced by both genetic and environmental factors.
  • the human retina comprises several types of glial cells among them, astrocytes, microglia and Muller cells, with the latter being the most common and predominate type cell.
  • Muller cells also denoted as Muller glial cells
  • Muller glial cells are known to participate in multiple and diverse retinal processes, including, for example, in retinal regeneration and in retinal neuroprotection, partially due to their unique morphology that enable their interaction with all neuronal cell types.
  • their stem cell potential suggests that these cells may be a target for regenerative therapies by replacing injured retinal neurons.
  • Muller cells may become reactive and might generate detrimental responses in the retina resulting in cell injury and loss.
  • the exact impact of Muller glia cells on the retina depends on the particular circumstances and the underlying pathology.
  • the inventors have identified a unique mechanism that involves M2 macrophages and photoreceptor cells death. Specifically, as shown in Example 1 below, photoreceptor cell death was associated with the presence of hMdcjis following photic retinal injury. As suggested in Example 2 below, M2a hMdcjis cells were shown to have a neurotoxic effect on retinal tissue.
  • the present disclosure provides in accordance with some aspects an effective amount of at least one small molecule compound (SMC) modulator for use in a method for modulating Muller cell activation in a subject in need thereof.
  • SMC small molecule compound
  • modulation encompasses either inhibition, or alternatively, enhancement.
  • the at least one SMC modulator inhibits Muller cell activation.
  • a small molecule compound (SMC) in the context of the present disclosure refers to a low molecular weight organic compound, having a molecular weight lower than 900 Daltons.
  • Muller cell activation refers to changes in these cells, for example, changes in morphology, protein expression and protein production, which may occur in response to pathological conditions such as a retinal disease. As shown in Example 6 and in Example 8, inhibition of Muller cells activation was associated with a reduction in the expression of genes encoding markers of activated Muller cells, Ccl2, Cxcll, CxcllO, Gfap and Vimentin.
  • the at least one SMC modulator may reduce expression of at least one chemokine associated with Muller cell activation. In some embodiments, the reduce expression of at least one chemokine may inhibit activation of the Muller cell.
  • Chemokines are classified into four main subfamilies: C-X-C Chemokines (CXC Chemokines), C-C Chemokines (CC Chemokines), CX3C Chemokines and C Chemokines and exert their biological effects by interacting with G protein-linked transmembrane receptors called chemokine receptors.
  • the SMC modulator may reduce expression of at least one CC chemokine. In some other embodiments, the SMC modulator may reduce the expression of at least one CXC chemokine. In some other embodiments, the SMC modulator may reduce the expression of at least one CX3C chemokine. In some other embodiments, the SMC modulator may reduce the expression of at least one C chemokine.
  • the SMC modulator may reduce expression of C-C Motif Chemokine Ligand 2 (CCL2).
  • CCL2 is a chemokine also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2.
  • the SMC modulator may reduce expression of one or more of C-X-C Motif Chemokine Ligand 1 gene (CXCL1), Chemokine (C-X-C motif) ligand 9 (CXCL9) gene or C-X-C Motif Chemokine Ligand 10 gene (CXCL10).
  • CXCL1 C-X-C Motif Chemokine Ligand 1 gene
  • CXCL9 Chemokine (C-X-C motif) ligand 9
  • CXCL10 C-X-C Motif Chemokine Ligand 10 gene
  • the SMC modulator may reduce expression of one or more of C-X-C Motif Chemokine Ligand 1 gene (CXCL1), or C-X-C Motif Chemokine Ligand 10 gene (CXCL10).
  • CXCL1 is a small peptide belonging to the CXC chemokine family.
  • CXCL10 also known as Interferon gamma-induced protein 10 (IP- 10) or small-inducible cytokine BIO is a small cytokine belonging to the CXC chemokine family.
  • CCL2 CXCL1, CXCL9 or CXCL10
  • the invention further encompasses genes and proteins as well as CCL2, CXCL1, CXCL9 or CXCL10 level and/or stability.
  • the SMC modulator may reduce the level of at least one CC chemokine. In some embodiments, the SMC modulator may reduce the level of at least one CC chemokine and hence inhibit Muller cell activation. In some embodiments, the SMC modulator may reduce the level of CCL2. In some embodiments, the SMC modulator may reduce the level of CCL2 and hence inhibit Muller cell activation.
  • the SMC modulator may reduce the level of at least one CXC chemokine. In some embodiments, the SMC modulator may reduce the level of at least one CXC chemokine and hence inhibit Muller cell activation.
  • the SMC modulator may reduce levels of CXCL1. In some embodiments, the SMC modulator may reduce levels of CXCL1 and hence inhibit Muller cell activation.
  • the SMC modulator may reduce levels of CXCL10. In some embodiments, the SMC modulator may reduce levels of CXCL10 and hence inhibit Muller cell activation.
  • the at least one SMC modulator may reduce expression of at least one intermediate filament (IF) protein associated with Muller cell activation.
  • the reduce expression of at least one intermediate filament may inhibit activation of the Muller cell.
  • Intermediate filament refers to one or more proteins that form an elaborate network in the cytoplasm of most cells, extending from a ring surrounding the nucleus to the plasma membrane.
  • the SMC modulator may reduce expression of at least one type III intermediate filament protein. In some embodiments, the SMC modulator may reduce expression of glial fibrillary acidic protein (GFAP). In some embodiments, the SMC modulator may reduce levels of GFAP and hence inhibit Muller cell activation. In some embodiments, the SMC modulator may reduce expression of vimentin. In some embodiments, the SMC modulator may reduce levels of vimentin and hence inhibit Muller cell activation.
  • GFAP glial fibrillary acidic protein
  • Example 4 nine cytokines were identified to be significantly higher in the conditioned medium of M2a hMd ⁇ j> cells with three of these cytokines (HCC-1, MCP-4, and MPIF-1) being ligands of CCR1.
  • HCC-1, MCP-4, and MPIF-1 three of these cytokines
  • the inventors surprisingly found that CCR1 is expressed primarily in Muller cells. Interestingly, the expression of CCR2 or CCR5 was not detected in Muller cells.
  • CCR1 expression was upregulated in Muller cells in models of retinal injury and aging, and that CCR1 expression was correlated with photoreceptor cell death and hence retinal damage. It was further found that inhibition of CCR1, significantly reduced the severity of retinal damage.
  • the present disclosure provides an effective amount of at least one small molecule compound (SMC) modulator for use in a method for modulating the activity of CCR1 in a Muller cell of a subject in need thereof.
  • SMC small molecule compound
  • the present disclosure provides in accordance with some other aspects an effective amount of at least one SMC modulator for use in a method for inhibiting Muller cell activation of a subject in need thereof, wherein the SMC modulator modulates activity of CCR1 in the Muller cell.
  • modulating the activity ofCCRl in Muller cell refers to reduction/inhibition of CCR1 expression, stability, level or any combination thereof.
  • CCR1 is a G protein-coupled receptor (GPCR) member of the CC chemokine subfamily of receptors.
  • GPCR G protein-coupled receptor
  • Human CCR1 is 355 amino acids in length and has a predicted molecular weight of 41 kDa and mouse and rat CCR1 share 80% amino acids sequence identity with the human protein.
  • CCR1 similar to other GPCR is characterized by a structure including even-transmembrane domain.
  • CCR1 may be a human CCR1.
  • human CCR1 may comprise the amino acid sequence as denoted by Accession number P32246.
  • the amino acid sequence of CCR1 is as denoted by SEQ ID NO: 1.
  • CCR1 is encoded by the cDNA of Accession number NC_000003.12.
  • said cDNA sequence of CCR1 is denoted by SEQ ID NO: 2.
  • the SMC modulator may be an antagonist of CCR1.
  • antagonist relates to a compound, agent or a drug that binds to a protein or a receptor and partially or totally blocks stimulation, decreases, prevents, delays activation, inactivates, desensitizes, down regulates the activity or dampens a biological response.
  • the antagonist or inhibitor may partially or completely block the activity of CCR1.
  • the antagonist may be directed to a specific binding site of CCR1.
  • the binding site may be determined by any known method in the field, for example by computational methods.
  • the antagonist binds to a binding site located between transmembrane domain 3, 4, 5, 6, and 7 of CCR1.
  • the antagonist binds to a binding site including amino acid residues from transmembrane domain 3 and 6 of CCR1.
  • the antagonist binds to a binding site including amino acid residues Tyr-113 and Tyr-114 on transmembrane domain 3 and Ile-259 on transmembrane 6 of CCR1.
  • CCR1 antagonist suitable for use can be determined based on their activity in at least one of the methods described in the Examples.
  • a CCR1 antagonist in accordance with the present disclosure is selected such that it is capable of at least one of (i) increasing b-wave amplitude on electroretinogram (ERG) and increased outer nuclear layer (ONL) thickness, (ii) elongated microglial cells; (iii) reduced recruitment of macrophages to the retina (based on increased retinal expression of the macrophage marker F4/80), (iv) reduction of expression of Muller cell activation markers or (v) any combination thereof.
  • the antagonist may be in some embodiments, as a direct antagonist, or an allosteric inhibitor.
  • the antagonist is a competitive antagonist.
  • a competitive antagonist directly and physically blocks access of the agonist to the receptor.
  • the at least one SMC modulator is at least one of the following:
  • SMC 10 a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • SMC 1 represented by Formula (I) is known as BX-471 having CAS# 217645- 70-0.
  • BX-471 represented by the chemical name N-[5-chloro-2-[2-[(2R)-4-[(4- fluorophenyl)methyl] -2-methyl- 1 -piperazinyl] -2-oxoethoxy]phenyl] -urea.
  • the at least one SMC modulator applicable for the present disclosure is a compound of Formula (I).
  • SMC 2 represented by Formula (II) is known as BI-638683 having a IUPAC name (2E,2'E)-dimethyl 4,4'-(benzylazanediyl)bis(but-2-enoate).
  • the at least one SMC modulator applicable for the invention is a compound of Formula (II).
  • SMC 3 represented by Formula (III) is known as BL-5923 having CAS# 868408-20-2.
  • BL-5923 is represented by the chemical name (E)-N-(5-chloro-2-(3-(9- (4-fluorobenzyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-3-oxoprop-l-en-l-yl)-4- methoxyphenyl)acetamidethe.
  • the at least one SMC modulator applicable for the invention is a compound of Formula (III).
  • SMC 4 represented by Formula (IV) is known as BMS-817399 having CAS# 1202400-18-7.
  • BMS-817399 is represented by the chemical name l-[(2R)-l-[(4S)-4- (4-chlorophenyl)-4-hydroxy-3 ,3-dimethylpiperidin- 1 -yl] -3-methyl- 1 -oxobutan-2-yl] - 3-(2-hydroxy-2-methylpropyl)urea.
  • the at least one SMC modulator applicable for the invention is a compound of Formula (IV).
  • SMC 5 represented by Formula (V) is known as AZD-4818 having CAS# 1003566-93-5.
  • AZD-4818 is represented by IUPAC name 2- ⁇ 2-chloro-5-[(2S)-3- ⁇ 5- chloro-3H-spiro [ 1 -benzofuran-2,4'-piperidin] - l'-yl ⁇ -2-hydroxypropoxy] -4- (methylcarbamoyl)phenoxy ⁇ -2-methylpropanoic acid.
  • the at least one SMC modulator applicable for the invention is a compound of Formula (V).
  • SMC 6 represented by Formula (VI) is known as CCX9588 having the chemical name 1 -(4-(4-chloro-3-methoxyphenyl)piperazin- 1 -yl)-2-(4-chloro-5-methyl-3-
  • the at least one SMC modulator applicable for the invention is a compound of Formula (VI).
  • SMC 7 represented by Formula (VII) is known as CCX354 having CAS# 1010073-75-2.
  • CCX354 has a chemical name 2-(3-(lH-Imidazol-2-yl)-lH- pyrazolo[3,4-b]pyridin- 1 -yl)- 1 -(4-(4-chloro-3-methoxyphenyl)piperazin- 1 -yl)ethan- 1-one.
  • the at least one SMC modulator applicable for the invention is a compound of Formula (VII).
  • SMC 8 represented by Formula (VIII) is known as CP-481715 having CAS# 212790-31-3.
  • CP-481715 has a chemical name N-((2S,3S,5R)-5-carbamoyl-l-(3- fluorophenyl)-3,8-dihydroxy-8-methylnonan-2-yl)quinoxaline-2-carboxamide.
  • the at least one SMC modulator applicable for the invention is a compound of Formula (VIII).
  • SMC 9 represented by Formula (IX) is known as MLN-3897 having CAS#1010731-97-l.
  • MLN-3897 has a chemical name (S,E)-4-(4-chlorophenyl)-l-(3- (7-(2-hydroxypropan-2-yl)-2,l l-dihydrobenzo[6,7]oxepino[3,4-b]pyridin-5(lH)- ylidene)propyl)-3,3-dimethylpiperidin-4-ol.
  • the at least one SMC modulator applicable for the invention is a compound of Formula (IX).
  • SMC 10 represented by Formula (X) is known as CP-865569 having CAS#1010731-97-l.
  • CP-865569 has a chemical name 5-chloro-2-(2-((2r,5s)-4-((4- fluorophenyl)methyl)-2,5-dimethyl- 1 -piperazinyl)-2- oxoethoxy)benzenemethanesulfonic acid.
  • the at least one SMC modulator applicable for the invention is a compound of Formula (I).
  • the at least one SMC modulator is at least one of AZD- 4818, BI-638683, BL-5923, BMS-817399, BX-471, CCX9588, CCX354, CP-481715, MLN-3897, CP-865,569, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the at least one SMC modulator applicable for the invention is a small molecule represented by Formula I.
  • the at least one SMC modulator applicable for the invention is a small molecule represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or any combinations thereof.
  • a small molecule compound e.g. any one of SMC1, SMC2, SMC3, SMC4, SMC5, SMC6, SMC 7, SMC 8, SMC 9, SMC 10
  • a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof e.g. any one of SMC1, SMC2, SMC3, SMC4, SMC5, SMC6, SMC 7, SMC 8, SMC 9, SMC 10
  • a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof in the context of the present disclosure are considered to have similar biological or physiological activity as the small molecule to which they relate or any small molecule related thereof, for example, in inhibiting Muller cell activation and/or neurotoxic effect of M2a hMd ⁇ s.
  • the present disclosure provides an SMC modulator represented by Formula (XI).
  • the SMC modulator is represented by Formula (XI), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein Ri is a halogen, R2 is an alkyl, R3 is a halogen and an ureido, Li is -(CH2)-, L2 is -C(0)-(CH2)-0-, n and m are each 1 and q is 2.
  • Formula (XI) Formula (XI), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein Ri is a halogen, R2 is an alkyl, R3 is a halogen and an ureido, Li is -(CH2)-, L2 is -C(0)-(CH2)-0-, n and m are each 1 and q is 2.
  • the SMC modulator is represented by Formula (XI), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein Ri is an F, R2 is an CH3, R3 is Cl and an ureido, Li is -(CH 2 )-, L 2 is -C(O)-(CH 2 )-O-.
  • Formula (XI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein Ri is an F, R2 is an CH3, R3 is Cl and an ureido, Li is -(CH 2 )-, L 2 is -C(O)-(CH 2 )-O-.
  • the SMC modulator represented by Formula (XI) is represented by Formula (Xia): wherein each one of Ri, R2, R3 is independently selected from each other to be an alkyl, a hydroxy alkyl, a halogen, ureido, aminocarbonyl, ureido or glycinamide, L2 is selected from -(CH 2 ) P -, -(CH 2 ) P -S, -,-(CH 2 ) P -O-, NH, -NH-(CH 2 ) P -, C(O)- (CH2) P -0-, each n, m, q, p is an integer being independently from each other selected from be 0 to 5.
  • the SMC modulator is represented by Formula (Xia), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein Ri is a halogen, R2 is an alkyl, R3 is a halogen and an ureido, L2 is -C(0)-(CH2)-0-, n and m are each 1 and q is 2.
  • Formula (Xia) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein Ri is a halogen, R2 is an alkyl, R3 is a halogen and an ureido, L2 is -C(0)-(CH2)-0-, n and m are each 1 and q is 2.
  • the SMC modulator is represented by Formula (Xia), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein Ri is an F, R2 is an CH3, R3 is Cl and an ureido, and L 2 is -C(O)-(CH 2 )-O-.
  • the SMC modulator represented by Formula (XI) is represented by Formula (Xlb): wherein each one of Ri, R2, R3 is independently selected from each other to be an alkyl, a hydroxy alkyl, a halogen, ureido, aminocarbonyl, ureido or glycinamide, Li is selected from -(CH 2 ) P -, -(CH 2 ) P -S, -,-(CH 2 ) P -O-, NH, -NH-(CH 2 ) P -, C(O)-(CH 2 ) P - O, each n, m, q, p is an integer being independently from each other selected from be 0 to 5.
  • the SMC modulator is represented by Formula (Xlb), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein Ri is a halogen, R2 is an alkyl, R3 is a halogen and an ureido, Li is -(CH2)-, n and m are each 1 and q is 2.
  • Formula (Xlb) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein Ri is a halogen, R2 is an alkyl, R3 is a halogen and an ureido, Li is -(CH2)-, n and m are each 1 and q is 2.
  • the SMC modulator is represented by Formula (Xlb), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein Ri is an F, R2 is an CH3, R3 is Cl and an ureido, and LI is -(CH2)-.
  • Formula (Xlb) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein Ri is an F, R2 is an CH3, R3 is Cl and an ureido, and LI is -(CH2)-.
  • the SMC modulator represented by Formula (XI) is represented by Formula (XII): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein each one of Ri, R2, R3 is independently selected from each other to be an alkyl, a hydroxy alkyl, a halogen, ureido, aminocarbonyl, ureido or glycinamide, each n, m, q is an integer being independently from each other selected from be 0 to 5.
  • the SMC modulator is represented by Formula (XII), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein Ri is a halogen, R2 is an alkyl, R3 is a halogen and an ureido, n and m are each 1 and q is 2.
  • the SMC modulator is represented by Formula (XII), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein Ri is an F, R2 is an CH3, R3 is Cl and an ureido.
  • the SMC modulator represented by Formula (XI) is represented by Formula (XIII): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein each one of Ri, R2, R3 is independently selected from each other to be an alkyl, a hydroxy alkyl, a halogen, ureido, aminocarbonyl, ureido or glycinamide.
  • the SMC modulator is represented by Formula (XIII), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein Ri is a halogen, R2 is an alkyl, R3 is a halogen and an ureido.
  • the SMC modulator is represented by Formula (XIII), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein Ri is an F, R2 is an CH3, R3 is Cl and an ureido.
  • an effective amount of at least one SMC modulator for use in a method for modulating the activity of CCR1 in a Muller cell of a subject in need thereof, wherein the SMC modulator is represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • an effective amount of at least one SMC modulator for use in a method for modulating the activity of CCR1 in a Muller cell of a subject in need thereof, wherein the SMC modulator is represented by at least one of Formula XI, Xia, Xlb, XII, XIII or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • SMC represented by at least one of Formula XI refers to one or more of Formula XI, Formula Xia, or Formula Xlb.
  • an effective amount of at least one SMC modulator for use in a method for inhibiting the activity of CCR1 in a Muller cell of a subject in need thereof, wherein the SMC modulator is represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • an effective amount of at least one SMC modulator for use in a method for inhibiting the activity of CCR1 in a Muller cell of a subject in need thereof, wherein the SMC modulator is represented by at least one of Formula XI, XII, XIII or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • an effective amount of at least one SMC modulator for use in a method for modulating the activity of CCR1 in a Muller cell of a subject in need thereof, wherein the SMC modulator is represented by a Formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • an effective amount of at least one SMC modulator for use in a method for inhibiting the activity of CCR1 in a Muller cell of a subject in need thereof, wherein the SMC modulator is represented by a Formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • an effective amount of at least one SMC modulator for use in a method for inhibiting Muller cell activation of a subject in need thereof, wherein the SMC modulator inhibits activity of CCR1 in the Muller cell and is represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • an effective amount of at least one SMC modulator for use in a method for inhibiting Muller cell activation of a subject in need thereof, wherein the SMC modulator inhibits activity of CCR1 in the Muller cell and is represented by at least one of Formula XI, XII, XIII or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • an effective amount of at least one SMC modulator for use in a method for inhibiting Muller cell activation of a subject in need thereof, wherein the SMC modulator is represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • an effective amount of at least one SMC modulator for use in a method for inhibiting Muller cell activation of a subject in need thereof, wherein the SMC modulator is represented by at least one of Formula XI, XII, XIII or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • an effective amount of at least one SMC modulator for use in a method for inhibiting Muller cell activation of a subject in need thereof, wherein the SMC modulator inhibits activity of CCR1 in the Muller cell and is represented by a Formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • an effective amount of at least one SMC modulator for use in a method for inhibiting Muller cell activation of a subject in need thereof, wherein the SMC modulator is represented by a Formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the SMC modulator does not modulate CCR2 and/or CCR5 activity and/or expression in the Muller cell. In accordance with some embodiments, the SMC modulator does not inhibit CCR2 activity and/or expression in the Muller cell. In accordance with some other embodiments, the SMC modulator does not inhibit CCR5 activity and/or expression in the Muller cell.
  • CCR1 is expressed in Muller cells.
  • the at least one SMC modulator inhibit CCR1 activity in Muller cell. In some other examples, the at least one SMC modulator inhibit Muller cell activation.
  • the level of CCR1 expression can be measured by any method known in the art.
  • CCR1 expression can be measured by using flow cytometry or immunofluorescence assay by employing specific CCR1 antibody such as those described herein below.
  • Muller cells form part of the glial cells in the retina and play an important role in retinal physiological activities.
  • Muller cell activation refers to changes in these cells, for example, changes in morphology, protein expression and protein production, which may occur in response to pathological conditions such as a retinal disease.
  • the at least one SMC modulator that reduces expression of the at least one chemokine is represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the at least one SMC modulator that reduces expression of the at least one chemokine is represented by Formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the at least one SMC modulator that reduces expression of the at least one intermediate filament is represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the at least one SMC modulator that reduces expression of the at least one intermediate filament is represented by Formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the inventors have identified unique mechanism that involves M2 macrophages and photoreceptor cells death and specifically a connection between photoreceptor cell death and the presence of hMdcjis following photic retinal injury.
  • the SMC modulator reduces neurotoxic effects of M2a macrophages.
  • the SMC modulator reduces M2a hMdcjis neurotoxicity.
  • the effects of M2a hMdcjis such as their neurotoxicity can be determined by any method known in the art, for example, those described herein below.
  • the at least one SMC modulator that reduces neurotoxic effects of M2a macrophages is represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X.
  • the at least one SMC modulator that reduces neurotoxic effects of M2a macrophages is represented by at least one of Formula XI, XII, XIII, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the at least one SMC modulator that reduces neurotoxic effects of M2a macrophages is a compound represented by formula I (denoted herein SMC 1).
  • Macrophages are a type of white blood cell that engulfs and digests cellular debris, foreign substances, microbes, cancer cells, and anything else that does not have the types of proteins specific to healthy body cells on its surface in a process called phagocytosis.
  • the SMC inhibit recruitment of neurotoxic macrophages to the retina.
  • neurotoxic macrophages are considered cause a detrimental effect.
  • Inhibition of activity of the neurotoxic macrophages may in turn reduce activity of Muller cells thus may directly inhibit the death of photoreceptor cells.
  • the SMC modulator reduces M2a hMdcjis neurotoxicity to thereby inhibit photoreceptor cell damage.
  • a photoreceptor cell as used herein refers to a type of neuroepithelial cell found in the retina that is capable of visual phototransduction.
  • the photoreceptor cell damage as used herein refers to harm or injury in these cells that may result in vision symptoms such as blurred vision, loss of peripheral vision, etc.
  • the photoreceptor cell damage as used herein encompasses photoreceptor cell death, e.g. photoreceptor cell apoptosis and/or photoreceptor cell degeneration.
  • the SMC modulator inhibits photoreceptor cell death. In some embodiments, the SMC modulator inhibits photoreceptor cell apoptosis.
  • photoreceptor cell apoptosis refers to programmed cell death of photoreceptor cells that may be triggered by various factors, including genetic mutations, environmental stressors, or age-related processes. Photoreceptor cell apoptosis may be associated with development of various retinal degenerative diseases.
  • the SMC modulator inhibits photoreceptor cell degeneration.
  • photoreceptor cell degeneration refers to a process of deterioration, damage, or loss of photoreceptor cells in the retina.
  • the SMC modulator inhibits photoreceptor cell degeneration, photoreceptor cell death, or any combination thereof.
  • the SMC modulator reduces macrophage-mediated photoreceptor cell death.
  • the present disclosure provides a SMC modulator for use in inhibiting one or more of Muller cell activation, photoreceptor cell damage or any combination thereof, wherein the SMC modulator inhibits the expression of CCR1 in Muller cell and is represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the present disclosure provides a SMC modulator for use in inhibiting one or more of Muller cell activation, photoreceptor cell damage or any combination thereof, wherein the SMC modulator is represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the present disclosure provides a SMC modulator for use in inhibiting one or more of Muller cell activation, photoreceptor cell damage or any combination thereof, wherein the SMC modulator inhibits the expression of CCR1 in Muller cell and is a compound represented by formula I (denoted herein SMC 1).
  • the present disclosure provides a SMC modulator for use in inhibiting one or more of Muller cell activation, photoreceptor cell damage or any combination thereof, wherein the SMC modulator is a compound represented by formula I (denoted herein SMC 1).
  • Muller cell activation and photoreceptor cell damage are processes often associated with retinal damage, hence, as described herein, targeted inhibition of Muller cell activation is useful in disease associated with retinal damage.
  • any subject suffering from one or more of a retinal damage, a retinal inflammation, a photoreceptor cell damage, retinal inflammation or any combination thereof may benefit from the at least one SMC modulator described herein.
  • the Muller cell may be of a subject suffering from a retinal damage and/or a photoreceptor cell damage.
  • Retinal damage as defined herein encompasses any process/mechanism/pathway that cause damage to any part of the retina and may result in worsening of vision, vision loss and even blindness. Such process includes at least one of retinal cells death, retinal injury, retinal aging, retinal degeneration, retinal inflammation, photoreceptor cells apoptosis, macular degeneration, photic injury or any combination thereof. Retinal damage can occur in various cells in the retina including, inter alia, in photoreceptor cell and in retinal glial cells.
  • Retinal glial cell as known in the art is important for maintaining normal retinal function, having important roles in neurotransmitter uptake and recycling, potassium siphoning, shuttling of energy metabolites and maintenance of the blood retinal barrier.
  • retina refers to a layer of photoreceptors cells and glial cells that process light to perceive a visual picture.
  • the Muller cell may be of a subject in need of restoring retinal function.
  • the Muller cell may be of a subject in need of inhibiting Muller cell and/or decreasing M2a hMdcjis neurotoxicity.
  • the Muller cell may be of a subject suffering from a retinal disease or any associated condition, such as retinal inflammation.
  • the Muller cell may be of a subject suffering from a retinal disease.
  • the Muller cell may be of a subject suffering from a retinal disease associated with activation of Muller cell. In accordance with some embodiments, the Muller cell may be of a subject suffering from a retinal disease associated with neurotoxicity of M2a hMdcjis.
  • the retinal disease is associated with damage to photoreceptor cell. In some embodiments, the retinal disease is associated with photoreceptor cell death.
  • an effective amount of at least one SMC modulator for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of retinal disease or condition in a subject in need thereof, wherein the retinal disease is associated with activation of Muller cell and/or neurotoxicity of M2a hMdcjis.
  • the at least one SMC modulator may be used for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of retinal disease or condition by inhibiting Muller cell and/or decreasing M2a hMdcjis neurotoxicity.
  • an effective amount of at least one SMC modulator for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of retinal disease or condition in a subject in need thereof, wherein the retinal disease is associated with activation of Muller cell and/or neurotoxicity of M2a hMdcjis and wherein the at least one SMC modulator is represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • an effective amount of at least one SMC modulator for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of retinal disease or condition in a subject in need thereof, wherein the retinal disease is associated with activation of Muller cell and/or neurotoxicity of M2a hMdcjis and wherein the at least one SMC modulator is represented by Formula I (denoted herein SMC 1) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • At least one SMC modulator for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of retinal disease or condition in a subject in need thereof by inhibiting Muller cell activation and/or decreasing M2a hMdcjis neurotoxicity, wherein the at least one SMC modulator is is represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • At least one SMC modulator for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of retinal disease or condition in a subject in need thereof by inhibiting Muller cell activation and/or decreasing M2a hMdcjis neurotoxicity
  • the at least one SMC modulator is a compound represented by formula I (denoted herein SMC 1) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • At least one SMC modulator for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of retinal disease or condition in a subject in need thereof by inhibiting damage of photoreceptor cell, wherein the at least one SMC modulator is represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • At least one SMC modulator for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of retinal disease or condition in a subject in need thereof by inhibiting damage of photoreceptor cell
  • the at least one SMC modulator is a compound represented by formula I (denoted herein SMC 1) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • an effective amount of at least one SMC modulator for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of retinal disease or condition in a subject in need thereof, wherein the at least one SMC modulator is described herein.
  • retinal disease when referring to a "retinal disease” or an “ocular disease” it is to be understood to encompass any abnormal condition primarily affecting the normal integrity and/or functionality of retina or choroid specifically interfering with the ability of the eye to function properly and/or that negatively affects the visual acuity.
  • Such disease may be caused by any one of angiogenesis, inflammation, trauma, oxidative stress, hypoxia, undesired immune response, diabetes, vascular occlusion, structural, atrophy, prematurity, toxicity (including light toxicity), inherited degeneration, radiation, developmental retardation/defect, oncologic, hematologic, metabolic, vitamins deficiency, infectious, senile (aging) or different combination between them.
  • retinal disease as used herein encompasses any conditions or complications associated therewith.
  • the retinal disease is one or more of an inherited retinal degeneration (IRD) disease, a retinal vascular disease, choroidal vascular disease, inflammatory disease, posterior non-infectious uveitis disease, a retinal detachment disease, glaucoma or any associated disorders.
  • IBD inherited retinal degeneration
  • the retinal disease is a retinal degenerative and dystrophies disease. In some examples, the retinal disease is a retinal degenerative disease. In some examples, the retinal disease is a retinal dystrophies disease. In some examples, the retinal disease is inherited retinal degeneration (IRD) disease.
  • IFD retinal degeneration
  • the retinal degenerative disease is one or more of macular dystrophies, retinitis pigmentosa (RP) and allied disorders, abnormalities of rod and cone function, hereditary vitreoretinal degeneration, hereditary choroidal dystrophies or any combination thereof.
  • macular dystrophies retinitis pigmentosa (RP) and allied disorders, abnormalities of rod and cone function, hereditary vitreoretinal degeneration, hereditary choroidal dystrophies or any combination thereof.
  • RP retinitis pigmentosa
  • the retinal degenerative disease is macular dystrophies.
  • macular dystrophies refers to a group of genetic disorders, primarily affecting the macula, being a central part of the retina in the eye.
  • the retinal degenerative disease is retinitis pigmentosa and allied disorders.
  • Retinitis pigmentosa and allied disorders as used herein refer to heterogeneous clinically and genetically disease.
  • the retinal degenerative disease is retinitis pigmentosa.
  • the term retinitis pigmentosa as used herein refers to a group of retinal degeneration genetic eye conditions leading to chronic retinal degeneration, accompanied by abnormal deposits of pigment, causing a progressive decrease in peripheral or side vision.
  • the retinitis pigmentosa is a non-syndromic disease.
  • the retinitis pigmentosa is a syndromic disease.
  • the retinal degenerative disease is an abnormality of rod and cone function.
  • Abnormalities of rod and cone function as used herein refer to disorders that affect the functioning of the two main types of photoreceptor cells in the retina: rods and cones.
  • the retinal degenerative disease is hereditary vitreoretinal degeneration.
  • Hereditary vitreoretinal degeneration also known as hereditary vitreoretinopathy, as used herein refers to disease characterized by early-onset cataracts, vitreous anomalies, coarse fibrils and membranes, and retinal detachment.
  • the retinal degenerative disease is hereditary choroidal dystrophies.
  • hereditary choroidal dystrophies refers to a disease or disorder involving the choroid.
  • the retinal degenerative disease or any associated condition thereof is one or more of retinitis pigmentosa (RP), cone or cone-rod dystrophy, Leber congenital amaurosis, Fundus flavimaculatus, Stargardt disease (STGD), Congenital stationary night blindness, North Carolina macular dystrophy, Sorsby’s macular dystrophy, Pattern macular dystrophy, Vitelliform macular dystrophy (Best's disease), Choroideremia, X-linked retinoschisis (XLRS), Gyrate atrophy.
  • the retinal degenerative disease or any associated condition thereof is one or more of Usher syndrome, Bardet-Biedl syndrome, Senior-Locken syndrome, Alport syndrome, Alrnstron syndrome, Joubert Syndrome, Nephronophtbisis, Cockayne syndrome, Refsum disease, Autosomal dominant cerebellar ataxia type 7 , Norrie disease.
  • the retinal disease is a retinal vascular disease.
  • the retinal vascular disease is one or more of diabetic retinopathy, retinal artery and capillary occlusions, acquired retinal macroaneurysm (RAM), branch retinal vein occlusion, central retinal vein occlusion, macular telangiectasia type 2, radiation retinopathy or any combination thereof.
  • the retinal vascular disease is diabetic retinopathy.
  • Diabetic retinopathy refers to a condition in which damage occurs to the retina due to diabetes mellitus and may cause vision loss and blindness. Diabetic retinopathy may affect blood vessels in the retina.
  • the term Diabetic retinopathy as used herein may encompasses non-proliferative diabetic retinopathy, proliferative diabetic retinopathy and diabetic macular edema (DME).
  • DME refers to retinal thickening caused by the accumulation of intraretinal fluid, primarily in the inner and outer plexiform layers.
  • the retinal vascular disease is non-proliferative diabetic retinopathy. In some examples, the retinal vascular disease is proliferative diabetic retinopathy. In some examples, the retinal vascular disease is DME.
  • the retinal vascular disease is Retinal artery occlusion and capillary occlusions.
  • Retinal artery occlusions (RAO) and capillary occlusions refers to a condition associated with visual loss.
  • Retinal artery occlusions is associated with vascular transient monocular vision loss (TMVL), branch retinal arterial occlusion (BRAO), central retinal arterial occlusion (CRAO) and ophthalmic arterial occlusion (OAO).
  • TMVL vascular transient monocular vision loss
  • BRAO branch retinal arterial occlusion
  • CRAO central retinal arterial occlusion
  • OAO ophthalmic arterial occlusion
  • the retinal vascular disease is acquired retinal macroaneurysm.
  • Acquired Retinal Macroaneurysm refers to a condition formed when arteriosclerosis leads to weakening of the arteriolar wall and consequently, the arterial wall develops an outpouching that results in a macroaneurysm.
  • the retinal vascular disease is branch retinal vein occlusion (BRVO).
  • Branch retinal vein occlusion refers to a situation when branches of the retinal vein become blocked. The most common symptom of branch retinal vein occlusion is vision loss or blurry vision in part or all of one eye.
  • the retinal vascular disease is retinal vein occlusion (RVO).
  • RVO retinal vein occlusion
  • Retinal vein occlusion refers to a condition associated with vision loss, typically in older individuals.
  • the retinal vascular disease is central retinal vein occlusion.
  • Central retinal vein occlusion refers to a condition associated with occlusion at or proximal to the lamina cribrosa of the optic nerve, where the central retinal vein exits the eye.
  • the retinal vascular disease is macular telangiectasia type 2.
  • Macular telangiectasia type 2 as used herein refers to a bilateral disease with characteristic alterations of the macular capillary network and neurosensory atrophy.
  • the retinal vascular disease is radiation retinopathy. Radiation retinopathy as used herein refers to a chronic progressive vasculopathy developing secondary to ionizing radiation to the retina.
  • the retinal disease is a choroidal vascular disease.
  • the retinal disease is a Bruch’s membrane disease.
  • Choroidal vascular disease or Macular neovascularization (MNV) disease refers to a condition associated with growth of new, abnormal blood vessels originating in the choroid or retina, that is a vessel-containing layer under the retina.
  • the choroidal vascular disease is one or more of age-related macular degeneration (AMD), pathologic myopia, pachychoroid disease and polypoidal choroidal vasculopathy.
  • AMD age-related macular degeneration
  • pathologic myopia pathologic myopia
  • pachychoroid disease polypoidal choroidal vasculopathy.
  • Age-related macular degeneration is a medical condition which may result in blurred or no vision in the center of the visual field.
  • the severity of the disease can be divided into early, intermediate, and late types, with the late type also divided into "atrophic” and “neovascular” forms.
  • age-related macular degeneration encompasses non- neovascular early AMD, intermediate AMD, and geographic atrophy and neovascular AMD.
  • Dry form AMD also known as Atrophic AMD (aAMD) is usually associated with drusen, cellular debris in the macula and is characterized by the progressive loss of retinal pigment epithelial (RPE) cells and photoreceptor cells, which can coalesce and cause geographic atrophy in the macular region.
  • RPE retinal pigment epithelial
  • neovascular AMD also known as neovascular AMD (nvAMD)
  • CNV neovascular AMD
  • Pathologic myopia refers to is highly myopic eyes with degenerative macular changes.
  • Polypoidal choroidal vasculopathy (PVC) as used herein refers to an eye disease primarily affecting the choroid that may cause sudden blurring of vision or a scotoma in the central field of vision.
  • the retinal disease is an inflammatory disease.
  • the term retinal inflammatory disease also is an eye condition that causes dysfunction of the retina and, in advance case, substantial vision loss.
  • the retinal inflammatory disease in some examples is uveitis.
  • the retinal inflammatory disease is Anterior Uveitis (Iritis). - Anterior Uveitis (Iritis), affects the front portion of the eye.
  • the retinal inflammatory disease is Intermediate Uveitis (Cyclitis). Intermediate Uveitis (Cyclitis) affects the ciliary body, which is responsible for releasing aqueous humor into the eye.
  • the retinal inflammatory disease is Posterior Uveitis (Choroiditis and Retinitis).
  • Posterior Uveitis affects the back portion of the eye.
  • the retinal inflammatory disease is Diffuse Uveitis (Panuveitis).
  • Diffuse Uveitis affects the middle portions of the eye located under the sclera (the white of the eye).
  • the retinal disease is a posterior non-infectious uveitis.
  • Posterior non-infectious uveitis as used herein are often the cause of vision loss.
  • the inflammatory disease/uveitis posterior non-infectious uveitis is or photic retinal injury.
  • the retinal disease is a retinal detachment.
  • Retinal detachment refers to a condition in which a thin layer of tissue (the retina) at the back of the eye pulls away from its normal position. Retinal detachment separates the retinal cells from the layer of blood vessels that provides oxygen and nourishment to the eye.
  • the retinal detachment is non-rhegmatogenous retinal detachment, rhegmatogeneous retinal detachment (RRD) or degenerative retinoschisis.
  • Rhegmatogenous Retinal Detachment is a disease associated with accumulation of subretinal fluid in the potential space between the neurosensory retina and the underlying retinal pigment epithelium (RPE).
  • RTD retinal pigment epithelium
  • RTD Retinal traction detachment
  • TRD tractional retinal detachment
  • RPE retinal pigment epithelium
  • Exudative (or serous) retinal detachment is associated with fluid accumulation in the subretinal space between the sensory retina and the retinal pigmented epithelium (RPE) resulting in retinal detachment.
  • RPE retinal pigmented epithelium
  • the retinal disease is glaucoma.
  • Glaucoma is a group of eye diseases which result in damage to the optic nerve and cause vision loss.
  • the most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye remains open, with less common types including closed-angle (narrow angle, acute congestive) glaucoma and normal-tension glaucoma.
  • compositions of the invention may comprise an effective amount of the at least one SMC modular.
  • the pharmaceutical composition comprises the at least one SMC modulator as described herein or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the pharmaceutical composition comprises the at least one SMC modulator represented by one or more of Formula I, II, III, IV, V, VI, VII, VIII, IX, X.
  • the pharmaceutical composition comprises the at least one SMC modulator represented by one or more of Formula XI, XII, XIII or any combinations thereof.
  • the pharmaceutical composition comprises the at least one SMC modulator represented by Formula I.
  • compositions of the invention can be administered and dosed by the methods of the invention, in accordance with good medical practice, systemically, for example intravenous. It should be noted however that the invention may further encompass additional administration modes.
  • the pharmaceutical composition can be introduced to a site by any suitable route including oral, intranasal, or intraocular administration, intraperitoneal, subcutaneous, transcutaneous, topical, intramuscular, intraarticular, subconjunctival, or mucosal.
  • the at least one SMC disclosed herein being for example a SMC denoted herein as SMC 1, may be formulated into a delivery system, preferably with a pharmaceutically acceptable carrier.
  • Such delivery systems typically control the rate at which a drug is released and the location in the body where it is released.
  • composition disclosed herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject in need by employing procedures known in the art.
  • the pharmaceutical composition is formulated using intravitreal biodegradable polymeric implant, or implanted device for sustained, slow release.
  • the composition is formulated for controlled delivery thereof.
  • controlled delivery denotes any one of slow release, delayed release, immediate/burst release, triggered release, and any other controlled delivery form as known to those versed in the pharmaceutical art.
  • the delivery system is one or more of liposome, niosome, microsponge, microemulsion, microsphere, solid lipid nanoparticles (SLN), aerosol or combination thereof.
  • a "pharmaceutically acceptable carrier” means a carrier that is useful in preparing a composition or formulation that is generally safe, non-toxic and neither biologically nor otherwise undesirable.
  • the carrier is one that is acceptable for use on a living body, preferably mammals (humans and non-humans).
  • suitable carriers or excipients for delivery of the combination disclosed herein include, without being limited thereto, polylactic acid (PLA), poly-lactic-co-glycolic acid (PLGA), polyvinyl alcohol (PVA), polyethyleneimine (PEI), lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • PLA polylactic acid
  • PLGA poly-lactic-co-glycolic acid
  • PVA polyvinyl alcohol
  • PEI polyethyleneimine
  • lactose lactose
  • dextrose sucrose
  • sorbitol mannitol
  • starches gum acacia
  • calcium phosphate alginates
  • tragacanth gelatin
  • calcium silicate calcium silicate
  • the composition can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl-and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending agents such as methyl-and propylhydroxy-benzoates
  • sweetening agents such as methyl-and propylhydroxy-benzoates
  • flavoring agents such as talc, magnesium stearate, and mineral oil.
  • the composition is formulated for injection. In some examples, the composition is formulated for intravenous (IV) injection, intramuscular (IM) injection.
  • IV intravenous
  • IM intramuscular
  • the pharmaceutical composition is formulated for topical (local) application/ administration e.g., for topical delivery, to the eye, e.g., as eye drops, or eye ointment and by local/intravitreal or suprachoroidal injection.
  • topical administration or “topical application” means directly laying on or spreading on an eye tissue, especially a cornea, or on tissues surrounding the eye.
  • the topically administrable compositions may be formulated into a suitable formulation or composition with at least one carrier.
  • the at least one carrier may be selected from powders, oils, creams, foams, ointments, lotions, gels, pastes, mousiness, hydrogels or combination thereof.
  • the composition is in the form of a solution, a suspension, a paste, a cream, a foam, gel or an ointment.
  • the composition is an ocular solution or an ocular suspension.
  • the composition is an aqueous solution or an aqueous suspension.
  • the composition is in the form of eye drops, eye spray or eye cream.
  • the composition is in the form of eye drops of a suspension or solution.
  • the composition is applied to the eye in a form of topical drop.
  • the eye drops may be in isotonic, pH-adjusted, sterile saline.
  • Administration of the eye drops into the eye may be using a dropper, or a container with a dropper nozzle or a tube with a nozzle.
  • the composition is an ocular solution.
  • solution as used herein encompasses a range of viscosities, ranging from low viscosity solution to high viscosity solutions (forming a gel-like solution).
  • the pH of ocular composition is an important feature for controlling for example the ocular acceptability of the composition and the absorption of the compound across the cornea. Ideally the pH of the composition should be adjusted to maximize the chemical stability and/or absorption of the compounds (the first compound and the second compound). In some embodiments, the pH of the ocular composition is about 7.4 as this is the pH of tear fluid.
  • compositions may be used to treat subjects in need thereof according to the invention, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general formulations are prepared by uniformly and intimately bringing into association the active ingredients, specifically, the SMC modulator with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • the compositions may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas.
  • compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media.
  • Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran.
  • the suspension may also contain stabilizers.
  • the pharmaceutical compositions of the present invention also include, but are not limited to, emulsions and liposome-containing formulations.
  • formulations may also include other agents conventional in the art having regard to the type of formulation in question.
  • composition/s of the invention and any components thereof may be applied as a single daily dose or multiple daily doses.
  • the SMC modulator of the present disclosure and/or pharmaceutical compositions comprising the same may be used in various methods as described herein. According with some aspects of the present disclosure, it is provided a method of inhibiting Muller cell activation in a subject in need thereof. The method comprises the step of contacting the cell with an effective amount of at least one SMC modulator as described herein.
  • a method of modulating activity of CCR1 in a Muller cell in a subject in need thereof comprises the step of contacting the cell with an effective amount of at least one SMC modulator as described herein.
  • a method of inhibiting Muller cell activation in a subject in need thereof comprises the step of contacting the with an effective amount of at least one SMC modulator, wherein said SMC modulator inhibits CCR1 activity in the Muller cell.
  • the present disclosure provides a method for reducing loss of photoreceptor cell and/or inhibiting Muller cell activation.
  • the method may comprise in some embodiments the step of contacting a cell the with an effective amount of at least one SMC modulator as described herein.
  • the SMC modulator inhibits CCR1 activity in the Muller cell.
  • the at least one SMC modulator applicable by the methods of the present disclosure is is represented by at least one of Formula XI, XII, XIII or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the at least one SMC modulator applicable by the methods of the present disclosure is a compound represented by formula I (denoted herein SMC 1) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • contacting means to bring, put, incubates or mix together. As such, a first item is contacted with a second item when the two items are brought or put together, e.g., by touching them to each other or combining them.
  • the term “contacting” includes all measures or steps which allow interaction between the at least one SMC modulator and a cell, being in accordance with some embodiments a Muller cell.
  • the methods of the invention may be in vitro methods, ex vivo methods and/or in vivo methods.
  • the method is an in vitro method.
  • the method is an in in vivo method.
  • the method is an ex vivo method.
  • the at least one SMC modulator (being in some examples a compound denoted as SMC 1) was found to be effective at different animal (mice) models in which retina damage was induced or present and hence is considered to be useful for various retinal diseases.
  • the method is for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of one or more retinal disease.
  • a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a retinal disease in a subject in need thereof comprises administering to the subject a therapeutically effective amount of at least one SMC modulator or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the at least one SMC modulator applicable by the methods of the present disclosure for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a retinal disease in a subject in need thereof is represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the at least one SMC modulator applicable by the methods of the present disclosure for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a retinal disease in a subject in need thereof is represented by at least one of Formula XI, XII, XIII or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the at least one SMC modulator applicable by the methods of the present disclosure for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a retinal disease in a subject in need thereof is a compound represented by formula I (denoted herein SMC 1).
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying an inherited retinal degeneration (IRD) disease.
  • the methods of the invention for treating, inhibiting, arresting or delaying IRD disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying IRD disease comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by at least one of Formula XI, XII, XIII or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying an inherited retinal degeneration (IRD) disease.
  • IRD retinal degeneration
  • the methods of the invention for treating, inhibiting, arresting or delaying IRD disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying IRD disease comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying an inherited retinal degeneration (IRD) disease.
  • the methods of the invention for treating, inhibiting, arresting or delaying IRD disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying IRD disease comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying one or more of macular dystrophies, retinitis pigmentosa (RP) and allied disorders, abnormalities of rod and cone function, hereditary vitreoretinal degeneration, hereditary choroidal dystrophies.
  • macular dystrophies retinitis pigmentosa (RP) and allied disorders
  • abnormalities of rod and cone function abnormalities of rod and cone function
  • hereditary vitreoretinal degeneration hereditary choroidal dystrophies.
  • the methods of the invention for treating, inhibiting, arresting or delaying one or more of macular dystrophies, retinitis pigmentosa (RP) and allied disorders, abnormalities of rod and cone function, hereditary vitreoretinal degeneration, hereditary choroidal dystrophies comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying one or more of macular dystrophies, retinitis pigmentosa (RP) and allied disorders, abnormalities of rod and cone function, hereditary vitreoretinal degeneration, hereditary choroidal dystrophies comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying retinitis pigmentosa (RP).
  • the methods of the invention for treating, inhibiting, arresting or delaying RP comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying RP comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying a retinal vascular disease.
  • the methods of the invention for treating, inhibiting, arresting or delaying a retinal vascular disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying a retinal vascular disease comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying a retinal vascular disease.
  • the methods of the invention for treating, inhibiting, arresting or delaying a retinal vascular disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying a retinal vascular disease comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying diabetic retinopathy.
  • the methods of the invention for treating, inhibiting, arresting or delaying diabetic retinopathy comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying a diabetic retinopathy disease comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying a choroidal vascular disease.
  • the methods of the invention for treating, inhibiting, arresting or delaying a choroidal vascular disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying a choroidal vascular disease comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying a choroidal vascular disease.
  • the methods of the invention for treating, inhibiting, arresting or delaying a choroidal vascular disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying a choroidal vascular disease comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying dry AMD.
  • the methods of the invention for treating, inhibiting, arresting or delaying dry AMD comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying dry AMD comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying an inflammatory disease.
  • the methods of the invention for treating, inhibiting, arresting or delaying an inflammatory disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying an inflammatory disease comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying an inflammatory disease.
  • the methods of the invention for treating, inhibiting, arresting or delaying an inflammatory disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying an inflammatory disease comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying retinal detachment disease.
  • the methods of the invention for treating, inhibiting, arresting or delaying retinal detachment disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying retinal detachment disease comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by at least one of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying retinal detachment disease.
  • the methods of the invention for treating, inhibiting, arresting or delaying retinal detachment disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying retinal detachment disease comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying RRD.
  • the methods of the invention for treating, inhibiting, arresting or delaying RRD comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying RRD comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the method of the invention may be applicable for treating, inhibiting, arresting or delaying exudative retinal detachment.
  • the methods of the invention for treating, inhibiting, arresting or delaying exudative retinal detachment comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying RRD comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying exudative retinal detachment comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the method of the invention may be applicable for treating, inhibiting, arresting or delaying RTD.
  • the methods of the invention for treating, inhibiting, arresting or delaying RTD comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying RTD comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the method of the invention may be applicable for treating, inhibiting, arresting or delaying glaucoma.
  • the methods of the invention for treating, inhibiting, arresting or delaying glaucoma comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying glaucoma comprises topically administering to the subject in need thereof a therapeutically effective amount of at least one SMC modulator represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • alkyl refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, and no atoms other than carbon and hydrogen.
  • Pr or isopropyl -CH2CH2CH2CH3 (n-Bu), -CH(CH 3 )CH 2 CH3 (sec-butyl), -CH 2 CH(CH 3 )2 (isobutyl), -C(CH 3 ) 3 (tertbutyl, t-butyl, t-Bu or 'Bu), and -CH2C(CH3)3 are non-limiting examples of alkyl groups.
  • Hydroxy alkyl refers to a linear monovalent hydrocarbon radical of one or more carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both on the same carbon atom.
  • the SMC modulator, compositions comprising the SMC, methods may be applicable using an effective amount such that the methods of the invention involve the administration of a therapeutically effective amount of at least one SMC modulator.
  • effective amount or “therapeutically effective” for purposes disclosed herein indicates that the amount of formulation is effective to treat, inhibit or delay one or more symptoms of a disease as described herein. Specifically, such terms relate to the amount of an active agent present in a composition, that is needed to provide a desired level of active agent in the bloodstream or at the site of action in an individual to be treated to give an anticipated physiological response when such composition is administered.
  • an "effective amount" of the at least one SMC modulator in the composition of the present invention is meant any amount effective for the inhibitory effect on Muller cell activation, and/or photoreceptor cell death and/or therapeutic effect on any of the disclosed retinal disease as disclosed herein.
  • “Expression”, as used herein generally refers to the process by which gene- encoded information is converted into the structures present and operating in the cell. Therefore, according to the invention “expression” of a gene, specifically, may refer to transcription into a polynucleotide, translation into a protein, or even posttranslational modification of the protein.
  • Protein stability refers to the physical (thermodynamic) stability, and chemical stability of the protein and relates to the net balance of forces, which determine whether a protein will be in its native folded conformation or a denatured state. More specifically, the levels of proteins within cells are determined not only by rates of synthesis as discussed above, but also by rates of degradation and the half-lives of proteins within cells that vary widely, from minutes to several days.
  • “Expression” generally refers to the process by which gene-encoded information is converted into the structures present and operating in the cell. Therefore, according to the invention “expression” of a gene, specifically, may refer to transcription into a polynucleotide, translation into a protein, or even posttranslational modification of the protein.
  • Protein stability refers to the physical (thermodynamic) stability, and chemical stability of the protein and relates to the net balance of forces, which determine whether a protein will be in its native folded conformation or a denatured state.
  • the levels of proteins within cells are determined not only by rates of synthesis as discussed above, but also by rates of degradation and the half-lives of proteins within cells that vary widely, from minutes to several days.
  • rates of synthesis as discussed above, but also by rates of degradation and the half-lives of proteins within cells that vary widely, from minutes to several days.
  • ubiquitin-proteasome pathway mentioned herein before, and lysosomal proteolysis.
  • a small molecule as used herein may encompass at least one of solvate, a hydrate, a stereoisomer, a pharmaceutically acceptable prodrug, a pharmaceutically active metabolite, a pharmaceutically acceptable salt, a crystalline form, an amorphous form, a physiologically functional derivative.
  • a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof is included in a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • salts refers to salts derived from organic and inorganic acids of a compound described herein.
  • Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, napthalenesulfonate, propionat
  • solvate refers to an aggregate of a molecule with one or more solvent molecules, such as hydrate, alcoholate (aggregate or adduct with alcohol), and the like.
  • hydrate refers to a compound formed by the addition of water.
  • the hydrates may be obtained by any known method in the art by dissolving the compounds in water and recrystallizing them to incorporate water into the crystalline structure.
  • stereoisomer as used herein encompasses an "enantiomer”, the enantiomer refers to a compound that is superposable with respect to its counterpart only by a complete inversion/reflection (mirror image) of each other.
  • the small molecule in accordance with the present disclosure encompass any enantiomers (i.e. R or S).
  • physiologically functional derivative used herein relates to any physiologically acceptable derivative of a compound as described herein.
  • the physiologically functional derivatives also include prodrugs of the compounds of the invention. As noted herein, such prodrugs may be metabolized in vivo to a compound of the invention. These pro-drugs may or may not be active themselves and are also an object of the present invention. It should be noted that in accordance with some embodiments, the compounds defined by Formulas XI, Xia, Xlb, XII, XIII may be considered as physiologically functional derivative of the SMC modulator of Formula I denoted herein as SMC 1.
  • derivative in accordance with the small molecule of the present invention also encompasses chemically modified small molecule derived from a parent compound of the invention that differs from the parent compound by one or more elements, substituents and/or functional groups such that the derivative has the same or similar biological properties/activities as the parent compound.
  • prodrug or “pharmaceutically acceptable prodrug” as used herein refers to a compound that may be converted under physiological conditions to the specified compound or to a pharmaceutically acceptable salt of such compound. Prodrugs may be useful for facilitating the administration of a parent drug.
  • metabolite or “pharmaceutically acceptable metabolite” as used herein refers to a compound that is formed under physiological conditions to of degrading and eliminating the compounds. Oxidative metabolite may be an example.
  • a crystalline and/or amorphous forms of the small compounds described herein include, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • disease As used herein, “disease”, “disorder”, “condition” and the like, as they relate to a subject's health, are used interchangeably and have meanings ascribed to each and all of such terms. It is understood that the interchangeably used terms "associated” and “related”, when referring to pathologies herein, mean diseases, disorders, conditions, or any pathologies which at least one of: share causalities, co-exist at a higher than coincidental frequency, or where at least one disease, disorder, condition or pathology causes a second disease, disorder, condition or pathology.
  • treatment refers to the administering of a therapeutic amount of the formulation of the present invention which is effective to improve one or more undesired symptoms associated with a disease or condition as described herein.
  • the term “subject” refers to a living organism that is treated with the formulation as described herein, including, but not limited to, any mammal, such as a human.
  • inhibitors relate to the reduction for example in expression/level/stability of CCR1 activity or CCR1 expression in Muller cell or Muller cell activation or at least one CC chemokine by any one of about 1% to 99.9%, specifically, about 1% to about 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, about 75% to 80%, about 80% to 85% about 85% to 90%, about 90% to 95%, about 95% to 99%, or about 99% to 99.9% as compared to a suitable control.
  • antagoist includes one or more antagoionst.
  • composition include the recited components, e.g. at least one SMC modulator.
  • Consisting of shall thus mean excluding more than trace amounts of other components. Embodiments defined by each of these transition terms are within the scope of this invention.
  • mice used in these studies were purchased from Jackson laboratory, (Bar Harbor, ME, US).
  • PBMCs were separated from the whole blood using a Histopaque- Ficoll gradient (Sigma-Aldrich, Munich, Germany) and washed twice by centrifugation at 1500 rpm for 10 minutes to remove the platelets; live cells were counted using a hemocytometer with the trypan blue exclusion method.
  • PBMCs were isolated from the whole blood samples as described above, stimulated with M-CSF (macrophage colony-stimulating factor; PeproTech, Rocky Hill, NJ) to produce non-activated (M0) macrophages, and then activated with either IFN-y and LPS (to produce Ml hMdcjis), IL-4 and IL-13 (to produce M2a hMdcjis), or IL- 10 (to produce M2c macrophages) as previously described (Mantovani et al. 2002; Fernando O Martinez 2009).
  • M-CSF macrophage colony-stimulating factor
  • IFN-y and LPS to produce Ml hMdcjis
  • IL-4 and IL-13 to produce M2a hMdcjis
  • IL- 10 to produce M2c macrophages
  • PBMCs were suspended in RPMI 1640 medium (Biological Industries, Kibbutz Beit-Haemek, Israel) and seeded at 3xl0 7 cells/cm 2 in 6-well plates.
  • the monocytes were then incubated at 37°C in 5% CO2 for 2 hours, washed with phosphate-buffered saline (PBS), and then cultured for 7 days in RPMI 1640 supplemented with 10% (v/v) fetal calf serum (FCS), 1% non-essential amino acids, 2 mmol/L L-glutamine, 1 mM sodium pyruvate, 100 units/ml penicillin, 100 pg/ml streptomycin, and 50 ng/ml M-CSF; M-CSF was included in the growth medium to drive maturation of the monocytes into macrophages.
  • RPMI 1640 medium Biological Industries, Kibbutz Beit-Haemek, Israel
  • Ml hMdcjis were obtained by the addition of 20 ng/ml IFN-y (PeproTech) and 100 ng/ml LPS (Sigma- Aldrich) on day 6, M2a hMdcjis were obtained by the addition of 50 ng/ml IL- 13 (PeproTech) and 20 ng/ml IL-4 (PeproTech) on day 5, and M2c hMdcjis were obtained by the addition of 50 ng/ml IL- 10 (PeproTech) on day 5. hMdcji cells that were not activated were classified as unpolarized HMdcjis (M0).
  • Ml macrophages require 24 hours for polarization, whereas M2a and M2c cells require 48 hours; therefore, the hMdcjis were polarized on different days so that the in vitro and in vivo experiments could be performed on the same day.
  • Macrophage co-cultures with mouse retinal explants
  • hMdcjis The various groups of polarized hMdcjis were harvested and seeded for a minimum of 2 hours on a polycarbonate filter in serum-free DMEM (Biological Industries) supplemented with glutamine and penicillin-streptomycin.
  • serum-free DMEM Biological Industries
  • the retinas were gently detached from the choroid tissue and immediately placed on the polycarbonate filter so that the hMdcjis were in contact with the photoreceptor layer.
  • PF A paraformaldehyde
  • Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was then performed using an In Situ Cell Death Detection Kit, TMR red (La Roche, Basel, Switzerland) in accordance with the manufacturer’s instructions.
  • retinal explants were incubated with either mouse antirhodopsin (10 pg/ml; ab3267, Abeam, Cambridge, UK) or mouse anti-RPE65 (10 pg/ml; abl3826, Abeam) overnight at 4°C, washed, and then incubated with donkey anti-mouse IgG- Alexa Fluor 488 (Abeam) for 1 hour at RT.
  • a Zeiss LSM 710 confocal microscope was used to visualize the TUNEL-stained cells in 11 randomly selected retinal fields.
  • the RNA quality and quantity were measured using a NanoDrop spectrophotometer (Thermo Scientific, Waltham, MA) and a bioanalyzer (Agilent Technologies, Santa Clara, CA), and RNA was reverse transcribed to create cDNA using the qScript cDNA Synthesis Kit (Quantabio, Beverly, MA) in accordance with the manufacturer’s instructions.
  • qPCR was then performed using the PerfeCTa SYBR Green FastMix kit (Quantabio); the gene-specific primers (Sigma- Aldrich) used in this study are listed in Table 1.
  • Each gene was amplified in triplicate, and the expression level of each gene was normalized to human GAPDH or mouse Gapdh as an endogenous control using the standard 2(AACT) method.
  • EMR1 EMR-like module-containing mucin-like hormone receptor-like 1).
  • Photic injury was then induced as follows, according to the appropriate circadian rhythm: the pupils were dilated with Cyclogyl (one drop per eye, Sandoz Farmaceutica S.A., Madrid, Spain) and 5% phenylephrine (Fisher Scientific, Tel Aviv, Israel) at 9:30 am under a red light; the light level was adjusted at 9:45 am, and photic injury was induced for 3 hours (from 10:00 am to 1:00 pm), during which the mice were placed in a cage (maximum two mice per cage) lined with aluminum foil, and the temperature was maintained below 30°C.
  • mice Immediately after photic injury, the mice received an intravitreal injection of either human monocytes or hMdcjis that were labeled with the Vybrant DiO tracer (Invitrogen-Molecular Probes, Carlsbad, CA), and then returned to the standard light/dark cycle.
  • the intravitreal route was chosen over the subretinal route in order to avoid triggering an immune response due to RPE immunogenicity and the potentially higher risk of RPE and/or Bruch’s membrane breakthrough; moreover, intravitreal injection allows the injected cells to distribute across the entire retina, creating a wider and less-biased effect on ONL thickness.
  • mice 10 5 human monocytes or hMdcjis suspended in PBS were injected into the right eye, while the left eye received an injection of PBS as a control. As an additional control, some mice were not exposed to light and did not receive an intravitreal injection of monocytes or hMdcjis. An antibiotic ointment (5% chloramphenicol) was applied after each intravitreal injection.
  • mice received subcutaneous injections of either the CCRl-specific antagonist BX471 (50 mg/kg body weight; Tocris, Bristol, UK) or vehicle (40% cyclodextrin in saline) every 12 hours for 7 days.
  • BX471 was dissolved at a final concentration of 10 mg/ml in saline containing 40% (w/v) cyclodextrin (Sigma- Aldrich); the solution was mixed thoroughly and dissolved overnight at 4°C, after which the pH was adjusted to 4.5 with NaOH, and the solution was filtered through a 0.45-pm filter.
  • Electroretinography recording and in vivo retinal imaging Seven days after photic injury, the pupils were dilated with tropicamide (Fisher Scientific) and phenylephrine (Fisher Scientific), and the corneas were kept moist by application of carboxymethylcellulose (Fisher Scientific). Retinal images were obtained using a Spectralis Optical Coherence Tomography device and a Micron III retinal microscope (Phoenix Research Labs, San Francisco, CA). Blue autofluorescence images were obtained using an excitation wavelength of 488 nm, and full-field electroretinography (ERG) was performed in dark-adapted mice. During ERG recording, the eyes were anesthetized with oxybuprocaine hydrochloride drops (Fisher Scientific).
  • ERG data were recorded inside a Faraday cage using an Espion computerized system (Diagnosys LLC, Littleton, MA). Dark-adapted ERG responses to a series of white flashes at increasing intensity (from 0.000006 to 9.6 cd-sec/m 2 ) were recorded at inter-stimulus intervals increasing from 10 sec (for the lowest-intensity flashes) to 90 sec (for the highest-intensity flashes). Light adaptation was performed using a background illumination of 30 cd/m 2 . For analysis, the b-wave amplitude was measured from the trough of the a-wave to the peak of the b-wave.
  • mice Seven days after photic injury, the mice were euthanized, the eyes were enucleated and sectioned at 10 pm using a cryostat, and the sections were immunostained as previously described (Hagbi-Levi et al. 2016).
  • the eyes were fixed in 4% PFA for 2 hours and then placed in 30% sucrose overnight at 4°C.
  • OCT optimal cutting temperature
  • the eyes were then placed in optimal cutting temperature (OCT) compound (Scigen Scientific, Gardena CA), and 10 pm sections were cut and placed in blocking solution (PBS containing 10% serum and 0.1% Triton X-100) for 1 hour at RT.
  • OCT optimal cutting temperature
  • PBS containing 10% serum and 0.1% Triton X-100
  • the nuclei were counterstained with DAPI, and the sections were visualized using a fluorescence microscope.
  • hMd ⁇ j> labeling after polarization the cells were washed once with PBS and then fixed with 4% PFA for 30 min at RT; after three washes with PBS, the cells were incubated in blocking solution and immunostained with primary and secondary antibodies as described above.
  • rabbit anti- 4 hydroxynonenal (HNE) antibody (10 pg/ml; ab46545, Abeam)
  • rat anti-cdl lb antibody 0.5 pg/ml; ab64347, Abeam
  • mouse anti-human CCR1 25 pg/ml; mabl45, R&D Systems, Minneapolis, MN
  • rat anti-mouse CCR1 25 pg/ml; mab5986, R&D Systems
  • rat anti-mouse-CCR5 (10 pg/ml; abl l466, Abeam
  • rabbit anti-mouse CCR2 (5 pg/ml; NBP2-67700, Novus Biologicals, Littleton, CO
  • rabbit anti-mouse GFAP 0.5 pg/ml; ab64347, Abeam
  • rabbit anti-mouse Ibal 5 pg/ml; abl53696, Abeam
  • TUNEL staining was performed using the In Situ Cell Death Detection Kit, TMR red (La Roche, Basel, Switzerland) in accordance with the manufacturer’s instructions.
  • the sections were stained with DAPI and the number of photoreceptor nuclei was counted at fixed distances from the optic nerve head (ONH).
  • ROS reactive oxygen species
  • hMdcjis Human hMdcjis were cultured in 6-well plates for 6 days and polarized as described above. To block CCR1, 0.5 pM or 5 pM BX471 was added to M2a hMd ⁇ j> cultures for 1 hour at 37°C. ROS production was measured using the DCFDA Cellular ROS Detection Assay (abl l3851; Abeam) and a fluorescence microplate reader (Tecan Group, Mannedorf, Switzerland) in accordance with the manufacturers’ instructions.
  • DCFDA Cellular ROS Detection Assay abl l3851; Abeam
  • a fluorescence microplate reader Tecan Group, Mannedorf, Switzerland
  • the culture medium was collected and stored at -80°C. A panel of 120 cytokines was then measured in the culture medium using the Human Cytokine Array GS2000 (RayBiotech Life, Inc., Norcross, GA) in accordance with the manufacturer’s instructions.
  • CD14 ++ CD16" and CD14 + CD16 + monocytes were isolated as described above, and their migration was measured using a 24- well Boyden chamber assay (Corning, 5- pm pore size).
  • conditioned medium obtained from 10 5 Ml hMdcjis or 10 5 M2a hMdcjis was harvested, centrifuged to remove cell debris, and placed in the bottom chamber of the plate.
  • 1.2xl0 5 previously isolated monocytes suspended in 100 pl RPMI with 1 % FCS were placed in the upper chamber.
  • retinal explants that were either in contact with or not in contact with polarized hMdcjis were fixed, TUNEL stained as described above, and digested using a homogenizer in 500 ml PBS containing 100 mg/ml collagenase/dispase (10-269-638; La Roche). Samples (100 ml each) were then placed in tubes, washed twice with 2 ml FACS washing buffer containing 0.5% (w/v) BSA in PBS, and centrifuged at 1500 g for 5 min to collect the cells. The cells were then filtered through a 60-micron mesh, and fluorescence intensity was immediately read using an LSR-II flow cytometer (BD Biosciences, Franklin Lakes, NJ) in accordance with the manufacturer’s instructions.
  • LSR-II flow cytometer BD Biosciences, Franklin Lakes, NJ
  • the cells were fixed in 4% PFA for 20 min at RT and washed twice with PBS. The cells were then stained with mouse anti-human CCR1 antibody (2.5 pg/10 6 cells; mabl45, R&D Systems) for 20 min at RT, followed by donkey anti-mouse IgG- Alexa Fluor 488 antibody (1 pg/ml; abl50109, Abeam) for 20 min in the dark at RT. Each sample was then washed twice with PBS containing 0.5% (w/v) BSA and centrifuged at 1500 rpm for 5 minutes to collect the cells. The cells were then filtered through a 60-micron mesh, and fluorescence intensity was immediately read using an LSR-II flow cytometer (BD Biosciences) in accordance with the manufacturer’s instructions.
  • LSR-II flow cytometer BD Biosciences
  • rdlO mice received subcutaneous injections of either the CCR1 -specific antagonist BX471 (50 mg/kg body weight; Tocris, Bristol, UK) or vehicle (40% cyclodextrin in saline) every 8 hours for 4 days.
  • BX471 was dissolved at a final concentration of 10 mg/ml in saline containing 40% (w/v) cyclodextrin (Sigma- Aldrich); the solution was mixed thoroughly and dissolved overnight at 4°C, after which the pH was adjusted to 4.5 with NaOH, and the solution was filtered through a 0.45-pm filter.
  • Full-field electroretinography (ERG) measurements were recorded before the first administration of the treatment and five days after it.
  • mice were placed in dark adaptation overnight.
  • ERG recording the mice were anesthetized, their pupils were dilated with tropicamide (Fisher Scientific) and phenylephrine (Fisher Scientific), and the corneas were kept moist by application of carboxymethylcellulose (Fisher Scientific). All procedures were performed in dim red lighting or in total darkness, and the mice were kept warm throughout the recording.
  • the mouse was positioned facing the center of a Ganzfeld bowl, ensuring equal, simultaneous illumination of both eyes.
  • ERG data were recorded inside a Faraday cage using an Espion computerized system (Diagnosys LLC, Littleton, MA).
  • Electroretinography recording in rdlO mice and rdlO mice with Ccrl deletion was performed at P21 in rdlO mice and in rd 10 mice with Ccrl deletion. ERG procedure was the described above.
  • Example 1 M2a hMd ⁇
  • Optical coherence tomography images obtained 7 days after photic injury in control (Fig. 1G) and in mice induced with photic injury (Fig. 1G). revealed a marked reduction in ONL thickness (red asterisks) in a mice induced with photic injury mouse compared to a control mouse.
  • mice received an intravitreal injection in one eye of human monocytes derived from patients with AMD; the other eye was injected with vehicle (PBS) as a control (Fig. 1A).
  • PBS vehicle
  • the eyes that received an intravitreal injection of monocytes had significantly reduced/suppressed ERG b-wave amplitudes at various light intensities (Fig. 1H) and significantly increased photoreceptor cell loss per ONL thickness in the dorso-central retina ranging from -300 to - 1200 microns from the ONH (Fig. II) as evident from the reduced number of photoreceptor nuclei -i-found in eyes injected with monocytes from AMD patients at different distances from the ONH.
  • monocytes After reaching the site of inflammation, monocytes can differentiate into a variety of macrophage subtypes; the inventors therefore attempted to identify which subtype is associated with the neurotoxicity observed in the photic-injured retina. To that end, monocytes obtained from patients with AMD were polarized into MO, Ml, M2a, and M2c macrophages by stimulation with M-CSF, LPS + IFNy, IL-4 + IL-13, or IL- 10, respectively.
  • Ml hMdcjis which have been reported as pro-inflammatory cells in other organs had no effect on ERG b-wave amplitude or ONL thinning compared to control eyes (Figs. 2C-2F).
  • M2c hMdcjis nor M0 hMdcjis affected photoreceptor cell death (Fig. 2C and Fig. 2E).
  • the presence of DiO-positive M2a hMdcjis was observed in the ganglion cell layer (GCL).
  • the inventors monitored the spatial distribution of the injected cells for 7 days using histology.
  • the inventors identified the injected M2a hMdcjis by their typical elongated cell shape (Hagbi-Levi et al. 2016;) (Fig. 3B and Fig. 3D). Although most of the injected M2a hMdcjis were scattered throughout the vitreous (Fig. 3C), several of these cells migrated across the retina layers, reaching the subretinal space (Fig. 3E), with many cells present around the ONH and along the retinal vessels (Fig.
  • Example 2 M2a hMdcjis have a neurotoxic effect on retinal tissue ex vivo
  • the inventors also used HNE staining to evaluate the oxidative damage in a retinal section following photic injury and found that injection of either Ml or M2a hMdcjis was not associated with increased oxidative damage compared to control conditions (Fig. 5B and Fig. 5C). Together, these results suggest that M2a hMdcji-mcdiatcd neurotoxicity is driven only partially by increased ROS release from these cells.
  • M2a hMdcjis exerts a direct neurotoxic effect
  • additional indirect processes may also contribute to this effect in vivo.
  • the presence of M2a hMdcjis may drive the recruitment of mononuclear cells to the retina, and these cells may exert an additional neurotoxic effect.
  • the inventors measured cells expressing CDl lb-a broadly expressed integrin that serves as a marker of mononuclear phagocytes-in the choroid of photic-injured mice following an injection of either Ml or M2a hMdcjis.
  • an inflammatory response may have resulted from the xenograft; however, the eye is an immune -privileged site, and the inventors previously excluded the possibility that adoptive transfer of hMdcjis causes a cross-species reaction (Hagbi- Levi et al. 2016).
  • the inventors measured the in vitro chemotactic capacity of Ml and M2a hMdcjis on freshly isolated human monocytes. Using FACS analysis, the inventors found that chemokines released from M2a hMdcjis attracted more monocytes compared to chemokines released from Ml hMdcjis (Fig. 5G).
  • M2a hMdcjis differ from the other macrophage phenotypes with respect to their capacity to recruit additional immune cells to the site of injury and their ability to increase oxidative stress, thereby exacerbating photoreceptor cell death in the context of inflammation.
  • Example 4 CCR1 expression and apoptosis are increased in the retina following photic-induced damage
  • Table 2 Levels of various cytokines in Ml hMd ⁇ j>- and M2a hMd ⁇ -conditioned medium It was found that 9 cytokines were significantly higher in the M2a hMd ⁇ j>- conditioned medium (Table 3A), while 15 cytokines were significantly higher in the Ml hMd ⁇ -conditioned medium (Table 3B). Several of the 9 cytokines that were increased in the M2a hMd ⁇ -conditioned medium were previously reported to play a role in various inflammatory processes, including ocular inflammatory diseases and neurodegenerative diseases; these cytokines include eotaxin (Segal-salto et al. 2019; Shoji et al.
  • HCC-1, MCP-4, and MPIF-1 are ligands of the C-C chemokine receptor , including, CCR1.
  • qPCR real-time quantitative PCR
  • the inventors attempted to identify which cell type(s) in the retina express CCR1 and are therefore affected by the cytokines released by M2a hMdcjis and drive photoreceptor cell death in response to photic-induced injury.
  • increased levels of CCR1 protein were found in the mouse retina-primarily in the ONL — 48 hours after inducing photic injury (Fig. 7A, middle panel).
  • the inventors also measured robust CCR1 immunofluorescence in the inner nuclear layer (INL) and inner plexiform layer (IPL) seven days after photic injury (Fig. 7A, right panel).
  • CCR1 is expressed primarily in Muller cells, the only retinal cell type that spans all of the layers of the retina (Bringmann et al. 2006).
  • apoptotic photoreceptor cells 48 hours after photic injury Fig. 7B, middle panel
  • apoptotic photoreceptor cells were still present (Fig. 7B, right panel), albeit it to a lesser extent as previously reported.
  • Ccrl mRNA was measured using qPCR 7 days after photic injury and found significantly increased retinal expression of Ccrl compared to control mice (Fig. 7C).
  • the inventors also measured retinal function using ERG recordings and found a strong inverse correlation between retinal Ccrl mRNA levels and b-wave amplitude following photic injury (Fig. 7D), suggesting that Ccrl expression may play a role in determining the extent of retinal damage.
  • CCR1, CCR2, and CCR5 may be functionally redundant (Gladue et al. 2010).
  • the inventors therefore examined whether photic injury also increases the level of CCR2 and/or CCR5 protein in Muller cells in the mouse retina using immunofluorescence.
  • CCR2 Fig.8A
  • CCR5 Fig. 8B
  • Example 5 Increased expression of CCR1 in rdlO mice and senescent mice
  • the rdlO mouse is a model of autosomal recessive retinitis pigmentosa in which a mutation in the Pde gene (which encodes the enzyme phosphodiesterase in rod cells) causes degeneration of photoreceptor cells starting at around postnatal day 18.
  • the inventors measured extremely low levels of CCR1 in the retina (Fig. 9A, left panel).
  • Example 6 Inhibiting CCR1 reduces photic injury-induced retinal damage
  • qPCR analysis revealed that photic injury increased the recruitment of macrophages to the retina (based on increased retinal expression of the macrophage marker F4/80), and this recruitment was significantly reduced in BX471 -treated mice (Fig. 10D).
  • the inventors also found that BX471 reduced CCR1 expression in Muller cells in photic-injured mice compared to control-treated mice (Fig. 10E); this finding was confirmed using qPCR to measure Ccrl mRNA (Fig. 10F).
  • Example 7 Inhibiting CCR1 reduces the neurotoxic effects of M2a macrophages
  • CCR1 is a chemokine receptor expressed by a wide range of immune cells, including mononuclear cells (Mantovani et al. 2006), the inventors suggested that inhibiting this receptor can affect the functional properties of M2a hMdcjis via an autocrine signaling process.
  • the inventors found that both Ml and M2a hMdcjis express CCR1 (Fig. 11 A); however, cell sorting analysis revealed that a significantly larger percentage of M2a hMdcjis express CCR1 compared to Ml hMdcjis (Fig. 1 IB), suggesting that M2a hMdcjis may be more susceptible to the effects of inhibiting CCR1.
  • the inventors therefore examined whether inhibiting CCR1 could reduce M2a hMdcji-mediated neurotoxicity and found that treating M2a hMdcjis with either 0.5 pM or 5
  • Example 8 CCR1 knockout is associated with decreased lesions
  • Figs. 13A-13F show real-time quantitative PCR (qPCR) analysis of CxcllO, Gfap, Vimentin, Cxcll and Ccl2.
  • qPCR quantitative PCR
  • Fig. 14A shows the full-field electroretinography (ERG) measurements prior to the experiment and on day 5 of the experiment.
  • Fig. 14B shows the average b-wave amplitudes that were 57.33 ⁇ 4.75 and 119.45 ⁇ 9.51 pV for vehicle-treated mice and BX471-treated mice at P25, respectively, as the light intensity achieved 1.0 log cd s m -2 .
  • M2a hMdcjis mediate neurotoxicity in both in vitro and in vivo models of aAMD.
  • Ml macrophages likely underlie tissue damage during inflammation, the inventors found that Ml macrophages do not appear to play a major role in retinal damage in the context of aAMD.
  • M2a hMdcjis produce high levels of ROS ex vivo-, however, the in vivo effects of M2a hMdcjis may also be mediated by additional mechanisms such as increased production of cytokines that promote neurotoxicity and drive the recruitment of additional mononuclear cells.
  • oxidative stress particularly ROS-induced cellular damage
  • ROS-induced cellular damage was recently reported as a cause of retinal inflammation (Abokyi et al 2020), and the recruitment of other immune cell types can exacerbate inflammation in the eye, an immune-privileged organ in which overstimulation of the immune system can be detrimental (Buschini et al, 2011).
  • the inventors also found increased retinal expression of CCR1 in senescent mice, supporting the notion that this receptor is involved in age-related neurodegenerative diseases, including AMD. Finally, the inventors found that inhibiting CCR1 significantly reduced the severity of retinal damage induced by photic injury, suggesting that CCR1 antagonists may have therapeutic applications in aAMD.
  • Muller cells Although largely known for their structural role in the retina, Muller cells also play an essential role in maintaining metabolic homeostasis and function in the retina. For example, Muller cells can exchange ions, water, and bicarbonate molecules in order to regulate the composition of the extracellular fluid, and these cells use a variety of complex mechanisms to regulate synaptic activity, guide incoming light, and both support and protect neurons (Reichenbach et al. 2013). Importantly, Muller cells also serve as a source of cytokines and growth factors that drive neuronal and immune responses (Abcouwer et al.; 2017; Coughlin et al. 2017).
  • Muller cells are activated by a process known as gliosis, which allows them to interact with immune cells and microglial cells recruited to the site of inflammation (Bringmann et al. 2006). With respect to their role in pathogenesis, previous studies suggest that Muller cells are associated with the progression of several inflammatory eye diseases such as diabetic retinopathy (Capozzi et al. 2018) by activating the CD40 receptor ( Portillo et al. 2016, 2017) or by acting upon the microvascular to promote angiogenesis (Xin et al, 2013). Muller cells have also been shown to promote the development of glaucoma in an experimental model of chronic ocular hypertension (Zhong-feng et al. 2016).
  • both retinitis pigmentosa and AMD culminate in the loss of photoreceptor cells.
  • CCR1 expression in Muller cells is correlated with photoreceptor cell death.
  • previous studies have shown that Muller cells can directly cause the death of retinal ganglion cells (Xue et al, 2016) and endothelial cells (Portillo et al, 2016)
  • the notion that Muller cells can be activated by neurotoxic macrophages — and thus may directly cause the death of photoreceptor cells — is novel and warrants further study.
  • Muller cells were shown previously to induce photoreceptor cell death by recruiting immune cells (Matsumoto et al, 2018) and through crosstalk with microglial cells (Wang et al, 2011). Similarly, the inventors found that inhibiting CCR1 reduced macrophage infiltration and prevented activation of microglial cells. Interestingly, previous studies found that the chemokine receptor ligand CCL2 can act as an inflammatory cytokine, promoting photoreceptor cell death by recruiting macrophages (Nakazawa et al, 2007), while other studies found that the ligand CXCL10 can activate microglial cells via the CCR3 receptor (Clarner et al, 2015).
  • CCR1 was first identified as a chemokine receptor expressed in specific immune cell types such as monocytes (Chia-lin et al, 1998), which are recruited during photic injury (Rutar et al. 2015).
  • CCR1 -mediated photoreceptor cell death seems to include an intrinsic retinal process involving the activation of Muller cells, as well as the recruitment of neurotoxic macrophages to the retina and the functional modulation of M2a hMdcjis.
  • CCR1 - which include gliosis and the recruitment and polarization of macrophages in the retina-suggest that this receptor may serve as a promising new target for treating ocular degenerative diseases such as aAMD.
  • CCR1 C-C Chemokine Receptor 1
  • HCC Monocyte Hemofiltrate C-C Chemokine

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Abstract

La présente invention concerne des modulateurs de composés à petites molécules (SMC), des compositions contenant les modulateurs de SMC, leurs utilisations et des méthodes pour leur utilisation pour moduler l'activité de CCR1 dans une cellule de Müller et traiter une maladie rétinienne.
EP23882103.7A 2022-10-24 2023-10-24 Modulateurs et leurs utilisations Pending EP4608403A4 (fr)

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