• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The invention relates to a composition for preventing a hearing loss in a subject or for at least partially restoring the hearing of a subject having a reduced auditory function. The composition comprises at least one sterol compound inducing neuronal differentiation; this composition is brought into contact with at least a portion of the cochlea.
    公开号:FR3024361A1
    申请号:FR1401755
    申请日:2014-07-30
    公开日:2016-02-05
    发明作者:Medina Philippe De；Michael Paillasse；Mats Ulfendahl
    申请人:Affichem；
    IPC主号:
    专利说明:

    [0001] The present invention relates to the management of hearing loss. More specifically, the present invention relates to the use of a molecule of formula I or a pharmaceutically acceptable salt thereof; the composition according to the invention is administered to a subject to prevent his hearing loss or to restore his hearing. Hearing loss is a common affection that affects more than 360 million people worldwide for the World Health Organization (2012). The hearing loss taken into account by the World Health Organization is a loss greater than 25 dB. This pathology has important adverse consequences, both economic and emotional, for those affected and for society (de Graaf et al., Psychosom Med 64, 61-70), (Fellinger et al., Acta Psychiatr Scand 115,243 -5), (Fellinger et al., Psychiatry Psychiatric Psychiatr Epidemiol 40, 737-42), (Mohr et al., Policy Anal Brief H Ser 2, 1-4). Many factors, such as age (50% of humans over 65, 80% of those over 75 25 are affected), noise, physical or emotional trauma or genetic factors may be the cause dysfunction or loss of hair cells and degeneration of the auditory nerve leading to hearing loss. It is known that, in an uninjured auditory organ, the sound is transmitted to specialized brain cells by the vibration of the eardrum, which transmits the information mechanically to the inner ear. In the inner ear, hair cells (hereinafter referred to as HC) are found, which transform said mechanical signals into electrical signals, which generate electrical information transmitted to the brain by the neurons of a spiral ganglion (hereinafter referred to as "HC"). SGN). The hair cells are carried by a spiral organ called the "cochlea"; the cochlea has two spiral chambers arranged side by side and filled with liquids, perilymph for one and endolymph for the other; between these two chambers are housed the hair cells. A moderate or severe sensorineural hearing loss may be due to at least three types of dysfunction. On the one hand, dysfunction or partial loss of HC sensory cells, on the other hand, degeneration of axons of spiral ganglion neurons (hereinafter abbreviated as SGN), which transmit to the brain the signal of HC cells. (auditory neuropathy) and finally, the destructuration of synaptic connections between HC cells and SGN neurons (auditory synaptopathy). These various mechanisms leading to hearing loss are shown diagrammatically in FIG. 1, which will be detailed later in the present description. In case of loss of the hair cells, the signal can be transduced by a cochlear implant, whose electrodes replace the HC cells; in humans, in such a case, SGNs degenerate, notably losing their axons pointing to HC cells, but they do not die. The key to maintaining or recovering the hearing is therefore axonal regrowth, which enables the connections between the SGNs and the sound signal receiving transducers to be reconstituted, whether they are HC cells or a cochlear implant. For deafness related to the loss of HC cells, cochlear implants alone improve hearing, but their effectiveness is directly impacted by the integrity of SGN, they do not prevent the degeneration and axonal regrowth to reduce the distance between the nerve endings and the electrodes is an approach of interest for improving the efficiency of cochlear implants AShibata et al., Hear Res 281, 56-64). For all other forms, there is, so far, no satisfactory palliative or curative solution. Neurotrophic factors, the only molecules that have shown a beneficial effect on neuronal survival and axonal regrowth, can not be used because of side effects such as weight loss (Winkler et al., Ann Neurol 41, 82- 93), uncontrolled cell migration (Williams, Exp Neurol 113, 31-7) and cancer risk related to abnormal Schwann cell proliferation (Eriksdotter Jonhagen et al., Geriatr Disorder Cogn Disord 9, 246-57) . Despite intensive research, there is, so far, no satisfactory solution to the above-mentioned problems and a new approach is therefore necessary. Novel sterol derivatives have already been described which compounds the neuronal differentiation of pluripotent embryonic tumor cells, the survival of motoneurons in culture and the proliferation and differentiation of adult neuronal progenitors (from Medina et al., 2009, J Med Chem 52, 7765-77) and 2003) (Khalifa et al., Biochem Biophys Res Commun 446, 681-6). Those skilled in the art can not of course deduce that these compounds are of interest for pathologies, which, as indicated above, are related to a neuronal connection problem and not to a problem of number of neurons in the area. treated. Thus, a person skilled in the art would surely not seek to use the sterol derivatives in question to reform the connections between, on the one hand, SGN neurons and, on the other hand, a signal emitter constituted by at least partially ciliated cells. functional or cochlear implant electrodes.
    [0002] However, it has now been found, according to the invention, that if these compounds are used on a laboratory animal rendered deaf by stress, the transmission of the sound information translated in the form of an electrical pulse is maintained. (by the electrodes of a cochlear implant replacing the hair cells), the information being transmitted through the SGN to the brain, and without increasing the number of SGN said animal. The present invention accordingly relates to a pharmaceutical composition for preventing hearing loss in a subject or for achieving at least a partial therapeutic restoration of hearing of a subject having, prior to treatment, a hearing function reduced, by contacting said composition with at least a portion of the ear cochlea having a reduced auditory function, said composition being characterized in that it contains, in a pharmaceutically acceptable carrier, a significantly active dose of at least one compound of formula (I): wherein R1 = H or R-CO, with R = H, CH3 or C2H5; R2-1-1 or OH; R3 = -NR5R6 where R5 is H or (CH2) 3NH2 and R6 is taken from the group consisting of - (CH2) 4NH2; - (CH 2) 3 NH (CH 2) 4 NH 2; - (CH 2) 4 NH (CH 2) 3 NH 2; - (CH 2) 3 NH (CH 2) 4 NH (CH 2) 3 NH 2; - (CH 2) 3 NH 2 R - (CH 2) 2 - imidazol-4-yl and - (CH 2) 2 -indol-3-yl; R4 = H or OH at position 20,22,24,25,26 or 27, positioned to obtain an asymmetric center of R or S configuration; Z1 and Z2 are the double bond numbers (ie 0 or 1) between the C7 and C8 or C22 and C23 atoms respectively; T1, T2 and T3 = H or CH3, independently of each other; T4-H, CH3, or C2H5, positioned to obtain an asymmetric center of R or S configuration at position 24 and / or at least one pharmaceutically acceptable salt of at least one compound of formula (I).
    [0003] Among the compositions defined above, it has been found that the results obtained were particularly advantageous for the compounds of the subgroups in which: a) the compound (s) of formula (I), that it contains , is (are) defined by ZI: = 0; R1 = H; R2 = 0H; R3 = -NHR6 where R6 is - (CH2) 3NH (CH2) 4NH (CH2) 3NH2 OR - (CH2) imidazol-4-yl; T1 = T2 = T3 = H; b) the compound (s) of formula (I), which it contains, is (are) defined by Z1 = 0 or 1, RI H; R2 = OH; R3 = -NHR6 where R6 is - (CH2) 3NH (CH2) 4NH2 or - (CH2) 4NH (CH2) 3NH2 T1 = T2 = T3 = H; R4 = H or OH at position 22 or 27; c) the compound of formula (I), which it contains, is defined by Z1 = 0; R1 = acetyl; R2 = 0H; R4 = H; R3 = NH- (CH2) 2-imidazol-4-yl and T1 = T2 = T3 = H. According to a first aspect of the invention, the restoration caused by the composition according to the invention is an improvement in the effectiveness of a cochlear implant previously put in place in the treated subject. According to another aspect of the invention, the restoration obtained with the composition according to the invention improves the functionality of the neurons of the spiral ganglion in the subject treated, before practicing, on said subject, at least one therapy. for stimulating said neurons or inner and outer hair cells. According to another aspect of the invention, the restoration caused by the composition according to the invention benefits a subject who requires the placement of a cochlear implant due to auditory loss due to trauma or disease, said restoration now the functionality of neurons of the spiral ganglion before implantation of said cochlear implant. According to another aspect of the invention, the composition according to the invention is used to make a subject more likely to benefit later from a therapy aimed at restoring all or part of the inner ear, said therapy being chosen from the group formed by stem cell transplantation, regeneration of hair cells by transdifferentiation of supportive cells, gene tranfection or gene blockage in any part of the inner ear. According to another aspect of the invention, the composition according to the invention is administered orally, intravenously, intratympanically, intracochlear, on the round or oval window of the intracranial, nasal or tympanic cochlea. According to another aspect of the invention, the composition according to the invention is placed in the inner ear by an electrode impregnated with or brushed with said composition, or by an electrode comprising a cannula loaded with said composition or also by an electrode composed partially of one or more compounds of formula (I). According to another aspect of the invention, the restoration obtained by the composition according to the invention benefits a subject whose trauma has been generated by an ototoxic level of noise, ototoxic agents such as radiation, antibiotics, anti-inflammatory agents, -Inflammatory, chemotherapy agents, heavy metals or the age of the subject. According to another aspect of the invention, the composition according to the invention allows a restoration which benefits a subject whose hearing loss has been generated by a disease in the group consisting of otitis, Pendred's syndrome, Niemann's syndrome. -Pick, Smith-LemliOptiz, Stickler, Alport, Charge, Jervell and Lange-Nielsen, Norrie, Usher, Waardenburg and Perrault, neurofibromatosis type 2 or bronchiootorenal syndrome. The present invention also relates to the use of a composition as defined above to maintain and / or improve the quality of the connections between the SGNs, on the one hand, and the hair cells or electrodes of a cochlear implant, on the other hand.
    [0004] The implementation of the invention is illustrated by three examples to which corresponds a drawing comprising five figures. Figure 1 is a schematic diagram of the various inner ear conditions leading to the sensorineural hearing loss to which the present invention is amenable, and to the cellular effects relating thereto. This figure comprises three frames: the left frame shows the synaptic connection S of an HC 10 cell with an SGN in the case of a subject without affection of the inner ear. The middle frame shows the state of the SGN / HC bonds in three cases of dysfunction A, B, C: in the A dysfunction, the SGN neuron no longer receives information from its synapse S due to the non-functioning of the HC cell (dotted) previously connected to S; in malfunction B, the SGN no longer receives information from its synapse because the latter no longer assumes its liaison role (left column) and the SGN degenerates (right column); in the C dysfunction, the SGN no longer has an operational receiving synapse (left column) and the emission from the HC cell can therefore feed the SGN which, therefore, degenerates (right column). The right frame shows the result when the DA or DB products are acted on the elements concerned by the dysfunctions A (loss of HC), B (synaptopathy) and C (neuropathies) and the representations of the right column show the states after treatment and partial recovery of hearing (rectangle D schematizes electrical stimulation of the SGN). FIG. 2 is a graph showing the evolution curve over time of the electrically evoked auditory response of the brainstem (eABR) when the treatment with the composition according to the invention starts two days after the beginning of the induction of the ototoxicity by neomycin. Figure 3 is a graph showing the time course of the electrically evoked brainstem auditory response (eABR) when treatment with the composition starts sixteen days after the onset of neomycin induction of ototoxicity. .
    [0005] FIG. 4 is a bar graph showing the number of spiral ganglion neurons in the experiments relating to FIGS. 1 and 2 compared to what is obtained with an ear not exposed to neomycin (first bar on the left). in Figure 4). Figure 5 is a series of three cochlear lamella photographs taken at the level of the middle of the modiolus illustrating the quantification of the number of spiral ganglion neurons reported in Figure 4 as well as the axonal regrowth caused by the treatments. In each photograph, the nature of the product used for the treatment (AP, DB and GDNF) was indicated. In the figures, the following abbreviations have been used: AP: artificial perilymph (Ringer's acetate) DA: 6f3- [2- (1H-imidazol-4-yl) -ethylamino] -cholestane-3], 5a-diol DB: 6f3- [3- (4-aminobutylamino) propylamino] cholestane 30,5a-diol eABR: electrically evoked auditory response of the brainstem Neo: Neomycin GDNF: neurotrophic factor derived from glia SGC: spinal ganglion cell Table 1 summarizes the impact of the molecules used in Examples 1 to 3 on the density of SGN and the electrically evoked brainstem auditory response (eABR). Hereinafter, the terms "connection" and "synaptic connection" refer to a functional interaction between the spiral ganglion neurons and the hair cells or electrodes of a cochlear implant allowing appropriate stimulation of said spiral ganglion neurons. "Stress" refers to a cause of loss of functional synaptic connection and / or loss of projections of spiral ganglion neurons.
    [0006] The studies of Examples 1 to 3 were carried out on guinea pigs (250-500 g). All animals are equipped with a platinum-iridium electrode inserted into the cochlea to mimic a cochlear implant. The experiments were carried out according to the protocol described by Raphael and his collaborators (Shinohara et al., 2002, Proc Natl Acad Sci USA, 99, 1657-60). Example 1 Effect of early treatment with a derivative of formula (I) on the excitability of SGN spiral ganglion neurons The animals are anesthetized (10 mg / kg of xylazine and 40 mg / kg of ketamine intramuscularly) and the ear internal is open post-aurally. A pre-filled cannula containing 24 μl of 10% neomycin sulfate was connected to an osmotic mini-pump (ALZET 2002, DURECT Corp., CA, USA) having a flow rate of 0.5 μl / hour. The cannula enters the cochlea near the round window to reach the tympani scala. After 48 hours, the cannula was filled with either a solution of 63- [2- (11H-imidazol-4-yl) -ethylamino] -cholestane-3 (3,5u-diol (1gM), or with a solution of of 6f3- [3- (4-aminobutylamino) propylamino] cholestane-33,5a-diol (1pM), either with GDNF (lpg / ml) or with artificial perilymph which serves as a control. The pump is removed and replaced with a new identical pump similarly pre-filled After two weeks, the pump is removed and the cannula sealed for an additional two weeks This technique is described in detail on page 1658 of the Shinohara publication. The measurements of electrically evoked brainstem auditory thresholds (eABR) are measured using an iridium-platinum electrode (Pt-Ir 90% -10%, 250 μm in diameter) inserted from 1.5mm in the cochlea (scala tympani) via the round window at the time of setting up the pump, an electrode of return (Pt-Ir, 125 pin in diameter), being placed against the occipital bone, under the muscles of the neck. Measurement of eABR thresholds throughout the experiment did not show any significant difference between groups until the second week. From there, there is a significant decrease in eABR thresholds between the treated and control groups (p <0.05 at two weeks and p <0.001 beyond the fourth week), as shown in 25 Figure 2. From the sixth week, no eABR can be obtained in control animals. There is no possible stimulation of eABR on animals placed under the same conditions as defined above, but not treated with DA or DB products.
    [0007] EXAMPLE 2 Effect of a Delayed Treatment Performed with the DA or DB Derivatives Used in Example 1 on the Excitability of Spiral Ganglia Neurons The procedure used is the same as in Example 1, with the difference that following the infusion of neomycin sulphate, the pumps are filled with artificial perilymph for two weeks. When replacing, the pumps are replaced by identical pumps containing either a solution of 6F3- [2- (1H5 imidazol-4-yl) -ethylamino] -cholestane-3f3,5a-diol (1pM), or a solution of 6p [3- (4-Aminobutylamino) propylamino] cholestane-4,5a-diol (1pM), either GDNF (1 μg / ml) or artificial perilymph, which serves as a control. These pumps are replaced after two weeks by identical pre-filled pumps with the same solutions for two additional weeks. Measurement of electrically evoked auditory brainstem (eABR) hearing thresholds throughout the experiment showed significant differences between the treated and control groups up to the fourth week. From the fifth week on, there is no significant difference between the 613- [2- (11Iimidazol-4-yl) -ethylamino] -cholestane-3 [3,5u-diol group and the group whereas there is a significant difference between the 6f3- [3- (4-aminobutylamino) propylamino] -cholestane-4,5a-diol treated group and the control group (p <0.001) as shown in Figure 3. There is no possible stimulation of eABR on animals placed under the same conditions as defined above, but not treated with DA or DB products. Example 3: Quantification of SGN density in the Rosenthal canal After final measurement of the eABR threshold, the animals are deeply anesthetized, intraperitoneally, with sodium pentobarbital (25 mg / kg) and intracardially perfused by saline (37 ° C), which eliminates the blood, then by a solution of cold glutaraldehyde (2.5% in 0.1M phosphate buffer), which fixes the tissues. The temporal bone is removed and the bulla open to reveal the cochlea. A small window is open in the apex of the cochlea and the membrane of the round window so that the cochlea can be gently washed with the glutaraldehyde solution. The cochlea is then decalcified in an EDTA solution (0.1M in phosphate buffer) to allow slicing. After decalcification, the cochlea is dehydrated and included in "plastic JB-4" (Polyscience Inc., Warrington, PA). The cochlea is cut into slices 4 μm thick. In the middle of the modiolus, which is characterized by a lamella, in which six sections of the Rosenthal canal can be distinguished, one lamella in three is retained for analysis (which avoids counting several times the same neurons of the spiral ganglion). The slides are mounted on slides with "Paragon", stained with toluidine blue and prepared for microscopy. The six sections of the Rosenthal six-lamellae are analyzed for each group of animals (Sigma Pro Scan) to count spiral ganglion neurons. The criteria for an SGN are a cell diameter between 14 and 20 μm with a core diameter of 7 to 10 μm. The average density of SGN is thus calculated and presented in Figure 4; the sections of the Rosenthal channel are shown in Figure 5. For Example 1, only GDNF treatment induced a significant difference in the number of SGN compared to the control group treated with artificial perilymph (P <0.001). For example 2, it can be seen that no delayed treatment induces a significant difference compared to the control group. However, histological analysis reveals (see Figure 5), for animals treated with DB, that SGN axons appear thick and long while they are not distinguishable for animals treated with PA. This explains the effectiveness of the DB because the electrical resistance of the neuron is even lower as the size of the axon is large (reducing the distance between the signal transducer and the neuron).
    权利要求:
    Claims (14)
    [0001]
    CLAIMS1) Composition for preventing hearing loss in a subject or for achieving at least partial restoration of hearing of a treated subject having, before treatment, a reduced hearing function, by contacting said composition with at least a portion of the ear cochlea having a reduced auditory function, said composition being characterized in that it contains, in a pharmaceutically acceptable vehicle, at least one compound of formula (I): (I) wherein R1 = H or R-CO with R = H, CH3 or C2H5; R2 = H or OH; R3 = -NR5R6 where R5 is H or - (CH2) 3 NH2 and R6 is taken from the group consisting of - (CH2) 4 NH2, - (CH2) 3 NH (CH2) 4 NH2 - (CH2) 4 NH ( CH2) 3 NH2; - (CH 2) 3 NH (CH 2) 4 NH (CH 2) 3 NH 2; - (CH2) 3 NH2; - (CH2) 2-imidazol-4-yl and - (CH2) 2-indol-3-yl; R4 = H or OH at the 20, 22, 24, 25, 26 or 27 position, positioned to create an asymmetric center of R or S configuration; Z1 and Z2 each represents the number of double bonds between C7 and C8 carbon atoms and C22 and C23 respectively (ie 0 or 1); T1, T2 and T3 = H or CH3 independently of each other; T4 = H, CH3, C2H5 positioned to obtain an asymmetric center of configuration R or Sen position 24; and / or at least one pharmaceutically acceptable salt of at least one compound of formula (I).
    [0002]
    2) Composition according to claim 1, characterized in that the compound (s) of formula (I), which it contains, is (are) defined by Z1 = 0, R1 = H; R2 = OH; R3 = NHR6 where R6 is - (CH2) 3 NH (CH2) 4 NH (CH2) 3 NH2 or - (CH2) 2 -imidazol-4y1; T1 = T2 = T3 = H.
    [0003]
    3) Composition according to claim 1, characterized in that the compound (s) of formula (I), which it contains, is (are) defined by Z1 = 0 or 1; R1 = H; R2 = OH; R3 = -NHR6 where R6 is - (CH2) 3NH (CH2) 4NH2 or - (CH2) 4 NH (CH2) 3 NH2; T1 = T2 = T3 = H; R4 = H or OH in position 22 or 27.
    [0004]
    4) Composition according to claim 1, characterized in that the compound of formula (I), is defined by Z1 = 0; R1 = acetyl; R2 = OH; R4 = H; R3 = NH- (CH2) 2-imidazol-4-yl and T1 = T2 = T3 = H.
    [0005]
    5) Composition according to any one of claims 1 to 4, for improving the transmission of auditory signal to the brain from the signal transducer (ciliated cell or electrode).
    [0006]
    6. A composition according to claim 5 for improving the effectiveness of a cochlear implant previously set up in a treated subject.
    [0007]
    7) A composition according to claim 5, for improving the functionality of spiral ganglion neurons in a treated subject before practicing on said subject at least one therapy for stimulating the number and / or the functionality of said neurons or hair cells. internal and external.
    [0008]
    8. A composition according to claim 5 for maintaining the functionality of spiral ganglion neurons prior to implantation of a cochlear implant in a subject who requires placement of said cochlear implant as a result of trauma-induced hearing loss. a sickness.
    [0009]
    9) A composition according to claim 5, to make a subject more likely to benefit later therapy to restore all or part of his inner ear, said therapy belonging to the group formed by stem cell transplantation, regeneration of cells ciliated by transdifferentiation of supportive cells, gene transfection and gene blockage in all or part of the inner ear.
    [0010]
    10) A method for placing in the inner ear of a subject a composition according to any one of claims 1 to 4, characterized in that said composition is administered orally, intravenously, intratympanically, intracochlearly, intracranial or nasal, on the round or oval window of the cochlea or on the tympanum.
    [0011]
    11) Method for placing on the round or oval window of the cochlea or on the eardrum of a subject a composition according to any one of claims 1 to 4, characterized in that an electrode impregnated with or brushed with said composition, an electrode having a cannula loaded with said composition, or an electrode partially composed of one or more compounds of said composition.
    [0012]
    12) Composition according to one of claims 1 to 4, characterized in that the restoration benefits a subject whose trauma has been generated by an ototoxic level of noise, ototoxic agents, radiation, antibiotics, anti -Inflammatory, chemotherapy agents, heavy metals, or aging of the subject.
    [0013]
    13) Composition according to one of claims 1 to 4, characterized in that the restoration benefits a subject, whose hearing loss was generated by a disease taken in the group formed by otitis, Pendred syndrome, Niemann -Pick, Smith-LemliOpitz, Stickler, Charge, Jervell and LangeNielsen, Norrie, Usher, Waardenburg or Perrault, neurofibromatosis type 2 or bronchio-otorenal syndrome.
    [0014]
    14) Composition according to any one of claims 1 to 4, for maintaining and / or improving the quality of the connections between the SGN, on the one hand, and the hair cells or the cochlear electrodes, on the other hand.
    类似技术:
    公开号 | 公开日 | 专利标题
    EP3174543B1|2019-11-27|Sterol derivatives for treating neurosensory hearing loss, and corresponding composition
    Agterberg et al.2009|Enhanced survival of spiral ganglion cells after cessation of treatment with brain-derived neurotrophic factor in deafened guinea pigs
    Agterberg et al.2008|Morphological changes in spiral ganglion cells after intracochlear application of brain-derived neurotrophic factor in deafened guinea pigs
    Wise et al.2011|Combining cell-based therapies and neural prostheses to promote neural survival
    Leake et al.2011|Brain‐derived neurotrophic factor promotes cochlear spiral ganglion cell survival and function in deafened, developing cats
    Francis et al.2011|Celastrol inhibits aminoglycoside-induced ototoxicity via heat shock protein 32
    Duarte et al.2018|Ancestral adeno-associated virus vector delivery of opsins to spiral ganglion neurons: implications for optogenetic cochlear implants
    US20080275034A1|2008-11-06|Use of a Phenothiazine Derivative for Preventing and/or Treating Hearing Loss
    Chen et al.2010|The effect of cochlear-implant-mediated electrical stimulation on spiral ganglion cells in congenitally deaf white cats
    Agterberg et al.2010|Chronic electrical stimulation does not prevent spiral ganglion cell degeneration in deafened guinea pigs
    Wang et al.2003|Carboplatin-induced early cochlear lesion in chinchillas
    Eshraghi et al.2020|Recent advancements in gene and stem cell‐based treatment modalities: Potential implications in noise‐induced hearing loss
    Shibata et al.2020|Gene therapy for hair cell regeneration: Review and new data
    Song et al.2009|Delayed electrical stimulation and BDNF application following induced deafness in rats
    KR101893604B1|2018-08-30|Composition for preventing or treating hearing loss comprising an extract of Candida Utilis
    Leake et al.1987|Cochlear pathology of sensorineural deafness in cats: coadministration of kanamycin and aminooxyacetic acid
    Tang et al.2006|Sensorineural hearing loss: potential therapies and gene targets for drug development
    Yu et al.2014|Pattern of hair cell loss and delayed peripheral neuron degeneration in inner ear by a high-dose intratympanic gentamicin
    Worsøe et al.2010|Systemic steroid reduces long‐term hearing loss in experimental pneumococcal meningitis
    Tange1984|Differences in the cochlear degeneration pattern in the guinea pig as a result of gentamicin and cis‐platinum intoxication
    KR20220032936A|2022-03-15|Composition for preventing or treating hearing loss comprising Gingerone as an active ingredient
    Sayyid2018|Regeneration and Functional Recovery of the Adult Mouse Utricle
    Altschuler et al.2014|Protection and Repair of Hearing
    JP2004099537A|2004-04-02|Agent for preventing and treating deafness
    Li et al.2021|The circadian timing of noise exposure influences noise-induced inflammatory responses in the mouse cochlea
    同族专利:
    公开号 | 公开日
    US10092577B2|2018-10-09|
    EP3174543A2|2017-06-07|
    AU2015295184A1|2017-03-09|
    WO2016016518A3|2016-03-24|
    CN106852121B|2020-10-20|
    AU2015295184B2|2019-11-21|
    FR3024361B1|2017-11-24|
    JP6601882B2|2019-11-06|
    ES2770074T3|2020-06-30|
    CN106852121A|2017-06-13|
    CA2956192A1|2016-02-04|
    JP2017523240A|2017-08-17|
    US20170209465A1|2017-07-27|
    WO2016016518A2|2016-02-04|
    CA2956192C|2021-06-08|
    EP3174543B1|2019-11-27|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US20090076160A1|2007-09-17|2009-03-19|Balazs Lendvai|Use of R -N-propargyl-1-aminoindan to treat or prevent hearing loss|
    FR2838741B1|2002-04-19|2006-01-27|Inst Nat Sante Rech Med|STEROL DERIVATIVES, PROCESS FOR THEIR PREPARATION AND MEDICAMENTS COMPRISING THE SAME|WO2018005830A1|2016-06-29|2018-01-04|Otonomy, Inc.|Triglyceride otic formulations and uses thereof|
    US20210347810A1|2018-09-19|2021-11-11|Modernatx, Inc.|Sterol purification|
    EP3852764A1|2018-09-19|2021-07-28|ModernaTX, Inc.|Sterol analogs and uses thereof|
    BE1027157B9|2019-08-01|2020-11-03|Dendrogenix|Composition of sterol derivatives for its use in the treatment of neuronal pathology linked to hypoxia and / or hypoglycemia and corresponding composition|
    法律状态:
    2015-06-25| PLFP| Fee payment|Year of fee payment: 2 |
    2016-02-05| PLSC| Search report ready|Effective date: 20160205 |
    2016-06-22| PLFP| Fee payment|Year of fee payment: 3 |
    2017-06-21| PLFP| Fee payment|Year of fee payment: 4 |
    2018-08-21| PLFP| Fee payment|Year of fee payment: 5 |
    2020-06-23| PLFP| Fee payment|Year of fee payment: 7 |
    优先权:
    申请号 | 申请日 | 专利标题
    FR1401755A|FR3024361B1|2014-07-30|2014-07-30|USE OF STEROL DERIVATIVES FOR THE TREATMENT OF NEUROSENSORY HEARING LOSS AND CORRESPONDING COMPOSITION|FR1401755A| FR3024361B1|2014-07-30|2014-07-30|USE OF STEROL DERIVATIVES FOR THE TREATMENT OF NEUROSENSORY HEARING LOSS AND CORRESPONDING COMPOSITION|
    US15/329,190| US10092577B2|2014-07-30|2015-07-28|Sterol derivatives for treating neurosensory hearing loss, and corresponding composition|
    ES15775759T| ES2770074T3|2014-07-30|2015-07-28|Sterols derivatives for the treatment of sensorineural hearing loss and corresponding composition|
    CN201580041670.0A| CN106852121B|2014-07-30|2015-07-28|Sterol derivatives and corresponding compositions for the treatment of neurosensory hearing loss|
    PCT/FR2015/000164| WO2016016518A2|2014-07-30|2015-07-28|Use of sterol derivatives for treating neurosensory hearing loss, and corresponding composition|
    EP15775759.2A| EP3174543B1|2014-07-30|2015-07-28|Sterol derivatives for treating neurosensory hearing loss, and corresponding composition|
    CA2956192A| CA2956192C|2014-07-30|2015-07-28|Use of sterol derivatives for the treatment of sensorineural hearing loss and corresponding compound|
    JP2017526020A| JP6601882B2|2014-07-30|2015-07-28|Use of sterol derivatives for the treatment of sensorineural hearing loss and corresponding compositions|
    AU2015295184A| AU2015295184B2|2014-07-30|2015-07-28|Sterol derivatives for treating neurosensory hearing loss, and corresponding composition|
    [返回顶部]