Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/18—Growth factors; Growth regulators
  • A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • 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
  • A61P27/16—Otologicals

Definitions

• the present invention relates to the prevention and treatment of sensorineural hearing loss.
• Hearing loss is the fourth leading cause of disability worldwide, affecting 430 million people, over 5% of the of the world’s population. It is estimated that by 2050 over 700 million people will have disabling hearing loss (World Health Organization, 2021 https://www.who.int/news-room/fact-sheets/detail/deafness-and-hearinq-loss.).
• hearing loss refers to a vast array of hearing disorders that can be classified into two main classes: (i) conductive hearing loss, wherein the hearing loss results from obstruction or disease of the outer or middle ear that prevents transmission of sound energy to the inner ear, and (ii) sensorineural hearing loss (SNHL), which constitute 90% of all cases of hearing loss, wherein the hearing loss results from damage to the inner ear and the auditory nerve.
• conductive hearing loss wherein the hearing loss results from obstruction or disease of the outer or middle ear that prevents transmission of sound energy to the inner ear
• SNHL sensorineural hearing loss
• sensorineural hearing loss is mainly characterized by the degeneration of two types of cells: cochlear hair cells, which are the primary mechanoreceptors converting sound energy into neural signals, and/or auditory nerve neurons, the spiral ganglion cells (SGCs), that transmit signals from cochlear hair cells to the auditory nuclei of the brain stem through the auditory nerve.
• cochlear hair cells which are the primary mechanoreceptors converting sound energy into neural signals
• auditory nerve neurons the spiral ganglion cells (SGCs)
• SGCs spiral ganglion cells
• the degeneration of hair cells in sensorineural hearing loss may have genetic or non- genetic etiology.
• Non-genetic factors include noise exposure, viral or bacterial infections, ototoxic chemicals such as the chemotherapeutic drug cisplatin or aminoglycoside antibiotics, autoimmune diseases and aging (Liu et al, Front. Neurosci. 2022, 16: art. 867453).
• cochlear cochlear implant which functions by directly stimulating spiral ganglion cells (SGCs) soma and probably their central axons, delivering partial restoration of sensory organ function in patients.
• SGCs spiral ganglion cells
• no pharmacological therapies that have been approved by FDA for the prevention and treatment of this family of disorders.
• non-genetic SNHL is usually treated by administration of corticosteroids, in particular dexamethasone and prednisolone. However, this treatment has not proven to lead to satisfactory outcomes.
• Nerve growth factor is a member of the neurotrophin family that is essential for viability, differentiation, and maintenance of nerve cells.
• NGF has been identified in a number of preclinical and clinical studies as a promising therapeutic approach for the treatment of SNHL (Gao et al, Clinical and Experimental Otorhinolaryngology 2017, 10(4): 303-308).
• NGF neurotrophic and neuroprotective properties of wild-type NGF but show a reduced algogenic activity, thereby avoiding the side effect of increased nociception encountered with wild type NGF.
• NGF neurotrophic factor
• the blood labyrinth barrier which separates the inner ear fluids from blood circulation, limits the possibility of systemic delivery.
• delivery by local administration into the ear is hindered by the barriers between different compartments of the ear, the tympanic membrane (TM), between the outer and middle ear and the round window membrane (RWM), between the middle and inner ear.
• TM tympanic membrane
• RWM round window membrane
• intratympanic injection has been used to deliver active molecules directly into the middle ear for subsequent diffusion into the inner ear across the RWM.
• this delivery route requires an invasive surgical procedure, which may distress patients and carries the risk of permanent tympanic membrane perforation.
• NGF or its biologically active muteins can be delivered at effective concentrations into the inner ear by intranasal administration.
• a first object of the invention is NGF or a mutein thereof for use in the prevention or treatment of sensorineural hearing loss in a subject, wherein said NGF or mutein is administered intranasally to said subject.
• a further object of the invention is a pharmaceutical composition comprising NGF or a mutein thereof, for use in the prevention or treatment of sensorineural hearing loss in a subject, wherein said composition is administered intranasally to said subject.
• Figure 1 shows the concentration of NGF in cochlear perilymph at 2 hours post-treatment in rhNGF- treated (NGF treated animals) and PBS-treated (No treated animals) animals, measured as described in Example 1 .
• Figure 2 shows the concentration of NGF in cochlear perilymph at 12 hours in PBS- treated (PBS) animals and at 12 hours, 24 hours, and 48 hours post-treatment in rhNGF- treated (rhNGF) animals, measured as described in Example 1.
• Figure 3 shows the baseline ABRs threshold frequencies, measured before any treatment at different in the three experimental groups of mice: group 1 (SAMR1 ), group 2 (SAMP8+ vehicle) or group 3 (SAMP8 +rhNG F), as described in Example 2.
• Figure 4 shows the baseline DPOAE amplitudes at different frequencies, measured before any treatment in the three experimental groups of mice: group 1 (SAMR1 ), group 2, (SAMP8+ vehicle) or group 3 (SAMP8 +rhNG F) , as described in Example 2.
• Figure 5 shows the ABRs threshold at different frequencies, measured after 2 months of treatment in the three experimental groups of mice: group 1 (SAMR1 ), group 2 (SAMP8+ vehicle) or group 3 (SAMP8 +rhNG F), as described in Example 2.
• Figure 6 shows the DPOAE amplitudes at different frequencies, measured after 2 months of treatment in the three experimental groups of mice: group 1 (SAMR1 ), group 2 (SAMP8+ vehicle) or group 3 (SAMP8 +rh NGF), as described in Example 2.
• Figure 7 shows the plasma prestin concentration, measured after 2 months of treatment in the three experimental groups of mice: group 1 (SAMR1 ), group 2 (SAMP8+ vehicle) or group 3 (SAMP8 +rh NG F), as described in Example 2.
• Figure 8 shows the total number of inner hair cells (IHC), measured by the immunohistology analysis of the mid turn of each cochlea in the three experimental groups of mice: group 1 (SAMR1 ), group 2 (SAMP8+ vehicle) or group 3 (SAMP8 +rhNGF), as described in Example 2.
• IHC inner hair cells
• Figure 9 shows the total number of outer hair cells (OHC), measured by immunohistology analysis of the mid turn of each cochlea in the three experimental groups of mice: group 1 (SAMR1 ), group 2 (SAMP8+ vehicle) or group 3 (SAMP8 +rhNGF), as described in Example 2.
• SAMR1 SAMR1
• SAMP8+ vehicle SAMP8+ vehicle
• SAMP8 +rhNGF SAMP8 +rhNGF
• a first object of the invention is nerve growth factor (NGF) or a mutein thereof for use in the prevention or treatment of sensorineural hearing loss in a subject, wherein said NGF or mutein is administered intranasally to said subject.
• NGF nerve growth factor
• treatment refers to the eradication/amelioration or prevention/delay in onset, respectively, of a disorder or of one or more of the symptoms associated thereof.
• said subject is a human subject.
• said subject has been diagnosed with a sensorineural hearing loss and said NGF or mutein thereof is for use in the treatment of said sensorineural hearing loss by intranasal administration to said subject.
• said subject has been identified as being at risk of developing a sensorineural hearing loss and said NGF or mutein thereof is for use in the prevention of said sensorineural hearing loss by intranasal administration to said subject.
• said sensorineural hearing loss is a sensorineural hearing loss of non-genetic etiology.
• said sensorineural hearing loss of non genetic etiology is caused by noise exposure, a bacterial or viral infection, the treatment with an ototoxic drug, an autoimmune disease or aging.
• said ototoxic drug is selected from chemotherapeutic drugs and aminoglycoside antibiotics, more preferably it selected from cisplatin, caroboplatin and gentamicin.
• said NGF is human NGF.
• said human NGF has the aminoacid sequence of SEQ. ID NO.1 below SEQ. ID N0.1 :
• said human NGF has the aminoacid sequence of SEQ ID NO. 2 below: SEQ ID NO. 2: SSSHPIFHRGEFSVCDSVSVWVGDKTTATDIKGKEVMVLGEVNINNSVFKQYFFETKC RDPNPVDSGCRGIDSKHWNSYCTTTHTFVKALTMDGKQAAWRFIRIDTACVCVLSRK AVRRA
• said human NGF is a mixture of NGFs having sequences of SEQ ID NO. 1 and and SEQ ID NO. 2.
• the human NGF of SEQ ID NO. 2 have an aminoacid sequence that only differ from the NGF of SEQ ID NO. 1 for the presence of two additional amminoacids at the C-terminus. Both forms of NGF are found in human cells and therefore are considered as wild type human NGF.
• human NGF or wild type human NGF in the present application, it is meant a human NGF of SEQ ID NO. 1 or SEQ ID NO. 2.
• said NGF is produced by recombinant DNA technology, preferably it is a human recombinant NGF (rhNGF).
• rhNGF human recombinant NGF
• Methods of producing rhNGF are known to the person skilled in the art, for example those described in WQ0022119A1 and WQ2013092776A1 .
• said NGF has a purity higher than 70%, more preferably higher than 80%, higher than 90%, higher than 95%, higher than 98% or higher than 99%.
• the purity of NGF may be determined by conventional means known to those skilled in the art, for example by HPLC analysis.
• mutein of NGF refers to a biologically active mutein of NGF, meaning a NGF protein having an aminoacid sequence with one or more aminoacid mutations, preferably substitutions, such that the therapeutic activity of wild type NGF is maintained.
• said mutein is a mutein of wild type human NGF.
• mutein of NGF is characterized by more than 70 %, more preferably more than 80 %, even more preferably more than 90 %, and most preferably more than 95 % sequence identity with wild type human NGF.
• the mutein is a mutein of wild type human NGF characterized by at least one mutation, preferably aminoacid substitution of proline at position 61 by another amino acid, in the sequence of wild type human NGF.
• proline at position 61 is substituted by serine.
• the mutein is a mutein of human NGF, characterized by at least one mutation of the amino acid sequence associated with reduced nociceptive activity. More preferably said mutein is characterized by at least one mutation, preferably amino acid substitution, at any of positions 95-101 of wild type human NGF. Even more preferably, said mutein is characterized by substitution of the arginine in position 100 of wild type human NGF. Most preferably, arginine at position 100 of wild type human NGF is substituted by glutamic acid.
• Particularly preferred muteins according to the invention have the aminoacid sequences of SEQ ID NO. 3-6 below
• muteins are particularly advantageous for use according to the invention since they maintain the same bioactivity than wild type human NGF but are able to induce a lower nociceptive sensitivity compared to the corresponding wild type human NGF.
• said mutein of human NGF is produced by recombinant DNA technology. Methods of producing muteins of rhNGF according to the invention by recombinant DNA technology are known to the person skilled in the art, for example those described in WO2019/207106.
• the NGF or mutein for use according to the invention is administered to the subject from one to three times a day for a period of treatment of between 7 and 300 days, preferably between 60 and 240 days, more preferably between 100 and 200 days.
• the amount of NGF or mutein thereof per each administration is between 5 pg and 1 mg, more preferably between 10 pg and 400 pg, even more preferably between 15 pg and 200 pg.
• the effective amount of said NGF or mutein used in each administration, the duration of the treatment and the number of administrations for day are selected by the skilled person on the basis of the characteristics of the subject to be treated, the severity of the SNHL and on the basis of the auditory tests carried out during the treatment.
• the effective amount of said NGF or mutein used in each administration, the duration of the treatment and the number of administrations per day are selected by the skilled man on the basis of the characteristics of the subject at risk of developing SNHL and the clinical evaluation of the entity and duration of the risk of developing hearing loss as a result of one of said causes.
• a further object of the present invention relates to a pharmaceutical composition for intranasal administration comprising the NGF or mutein as described above and at least one pharmaceutically acceptable excipient suitable for intranasal use.
• the pharmaceutical composition for intranasal administration of the invention is a liquid intranasal composition.
• the pharmaceutical composition according to the present invention comprises an effective amount of the NGF or mutein as described above and at least one pharmaceutically acceptable excipient suitable for intranasal use, preferably selected from solvents, thickening agents, mucoadhesive agents, buffers, antioxidants, preservatives, and penetration enhancers.
• the concentration of said NGF or mutein in the liquid intranasal composition according to the invention is between 5 pg/ml and 1 mg/ml, more preferably between 10 pg/ml and 400 pg/ml, even more preferably between 15 pg/ml and 200 pg/ml.
• said solvent is water.
• said mucoadhesive agent is glycerol, more preferably at a concentration between 0.05 % w/v and 0.2% w/v, more preferably of 0.1 % w/v.
• said antioxidant is methionine, more preferably at a concentration between 0.005 mg/ml and 0.02 mg/ml, more preferably of 0.01 mg/ml.
• said surfactant is Kolliphor P188 (Poloxamer 188), more preferably at a concentration between 0.05 % w/v and 0.2% w/v, more preferably of 0.1% w/v.
• Kerphor P188 refers to Poloxamer 188, a block copolymer that is a synthetic copolymer of ethylene oxide and propylene oxide represented by the following chemical structure: where in a and b blocks have the following values:
• said buffer is phosphate buffer.
• said penetration enhancer is n-Dodecyl-p-D-maltoside, more preferably at a concentration between 0.1 % w/v and 1% w/v, more preferably of 0.5% w/v.
• a particularly preferred liquid intranasal composition according to the invention comprises, preferably consists of, said NGF or mutein thereof, sodium chloride, phosphate buffer and water.
• Another particularly preferred liquid intranasal composition according to the invention comprises, preferably consists of, said NGF or mutein thereof as described above, sodium chloride, phosphate buffer, Kolliphor P188 (Poloxamer 188), L-Methionine, and water.
• Another particularly preferred liquid intranasal composition according to the invention comprises, preferably consists of said NGF or mutein, sodium chloride, phosphate buffer, Kolliphor P188 (Poloxamer 188), L-Methionine, Glycerol, n-Dodecyl-p-D-maltoside and water.
• the liquid intranasal composition according to the invention comprises, preferably consists of, the following components:
• -NGF or a mutein thereof, as described above preferably at a concentration between 5 pg/ml and 1 mg/ml, more preferably between 10 pg/ml and 400 pg/ml, even more preferably between 15 pg/ml and 200 pg/ml,
• -NaCI preferably at a concentration between 5 and 6.5 mg/ml, more preferably of 5.84 mg/mL,
• -Poloxamer 188 preferably at a concentration between 0.05 % w/v and 0.2% w/v, more preferably of 0.1% w/v,
• -L-Methionine preferably at a concentration between 0.005 mg/ml and 0.02 mg/ml, more preferably of 0.01 mg/ml,
• n-Dodecyl-p-D-maltoside preferably at a concentration between 0.1 % w/v and 1% w/v, more preferably of 0.5% w/v, and/or glycerol, preferably at a concentration between 0.05 % w/v and 0.2% w/v, more preferably of 0.1 % w/v, -Water.
• composition according to the invention may be suitably formulated using appropriate methods known in the art or by the method disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton Pa.
• the pharmaceutical composition of the invention is for use in the prevention or treatment of sensorineural hearing loss in a subject, as above described, wherein said composition is administered intranasally to the subject.
• the present invention relates to a method for the prevention or treatment of sensorineural hearing loss in a subject comprising intranasally administering to the subject NGF or a mutein thereof, as described above, in a therapeutically effective amount.
• said NGF or mutein is administered as described above.
• said NGF or mutein used in the method of the invention is in form of a pharmaceutical composition, as above described.
• the invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.
• the tip of the filled pipette was placed near the mouse's left nostril, kept at 45 degree angle, and a droplet of the content released so that it was immediately inhaled by the mouse. A second droplet was released to the mouse so that it could be inhaled through the same nostril about 2-3 sec later. After administration, the mice were held in this position for 15 sec.
• mice All mice were sacrificed by cervical dislocation and the tympanic bullas were isolated. Each tympanic bulla was opened, the cochlea was cleaned with PBS and 1 pl of cochlear perilymph was sampled from each bulla using a capillary micropipette and immediately frozen in a low-bidding Eppendorf tube and stored at -20 °C before ELISA analysis.
• the cochlear perilymph samples were diluted at 1/10 and analyzed by ELISA (Novus Biological, Ref. NBP2-62776). Duplicates were performed with the right and left cochlea The manufacturer’s protocol provided was optimized. Standard references were diluted at 1000, 500, 250, 125, 62.5, 31.25, 15.63 and 0 pg/mL to perform the standard curve. The Standard working solution of different concentrations was added to the first two columns: Each concentration of the solution was added into two wells side by side and the samples to other wells (10 pl/well). The plate was covered with sealer provided in the kit and incubated for 90 min at 37°C.
• Descriptive statistics by groups are expressed as mean ⁇ SEM for continuous variables. Statistical significances were determined using t-test to compare treated versus control non-treated animals. Statistical analyses were performed using GraphPad Prism version 5.02 for Windows (GraphPad Software, La Jolla California USA). A P value of less than 0.05 was considered significant.
• rhNGF having the sequence of SEQ ID NO.1
• SAMP8 Senescence Accelerated Mouse Prone
• This strain has been widely used in aging research to study phenotypes such as peripheral neuropathy, hearing loss, immune dysfunction, osteoporosis, blindness and brain atrophy.
• the premature SAMP8 senescence involves oxidative stress, altered levels of antioxidant enzymes and increase of senescent cells, leading to chronic inflammation closely mimicking human senescence.
• SAMR1 Senescence-Accelerated Resistant mice were used in the experiments as normal aging control.
• mice were then divided in three groups, each treated as follows:
• ABRs auditory brainstem response
• DPOE distortion product otoacoustic emission
• the intranasal administration was carried out once a day following the same procedure described in Example 1 starting at one month of age of the animals for 60 days.
• ABRs Auditory brainstem responses
• ABRs are electric potentials recorded from scalp electrodes, and the first ABR wave represents the summed activity of the auditory nerve fibers contacting the inner hair cells.
• mice were anesthetized using ketamine/xylazine mixture, and body temperature was regulated using a heating pad at 37 °C. Then, earphones were placed in the left ear of each mouse, an active electrode was placed in the vertex of the skull, a reference electrode under the skin of the mastoid bone and a ground electrode in the neck skin.
• the stimuli consisted of tone pips of five frequencies (2 kHz, 4 kHz, 6 kHz, 12 kHz, 16 kHz and 24 kHz) at various sound levels (from 0 to 90 dB) ranging to cover the mouse auditory frequency range.
• ABR measures of each animal were performed individually and using OtoPhyLab system. Evoked potentials were extracted by the signal averaging technique for each noise level and ABR thresholds for each frequency were determined using OtoPhyLab software.
• DPOAE Distortion product otoacoustic emission
• DPOAEs are acoustic signals created and amplified by the cochlear epithelium, offering an index of cochlear functions. They are related to outer hair cell (OHGs) health which amplifies sound-evoked cochlear vibrations. They do not depend on IHCs or auditory nerve fibers.
• OOGs outer hair cell
• mice were anesthetized using ketamine/xylazine mixture and a probe (OtoPhyLab) was inserted into the external left ear canal.
• the primary tone F2 was set at five frequencies (4 kHz, 6 kHz, 12 kHz, 16 kHz and 24 kHz) at 58 dB.
• the frequency ratio F2/F1 was set at 1 .2.
• F2 the input of DPOAE systems was received, digitized, and evaluated using the output of the microphone. The amplitudes of the frequency component at the distortion product frequency were determined and represented.
• Prestin is a protein recognized as biomarker for cochlear damage. Therefore, the level of this protein was evaluated in the animals at the end of the treatment. For each animal, 2 mL of blood was sampled by cardiac puncture and collected in a tube containing EDTA as anticoagulant. Samples were centrifuged for 15 minutes at 1000 x g (or 3000 rpm) at 2 - 8 °C within 30 minutes of collection. The supernatant (plasma) was stored at -80 °C until analysis. Prestin quantification for each animal was performed in duplicated by ELISA method (Mybiosource. Ref. SLC26A5. Cat Number. MBS286559).
• IHC inner hair cells
• OOC outer hair cells
• Outer and inner hair cell stereocilia morphology was determined by scanning electron microscopy in the mid turn of the cochlea. Outer hair cell loss was confirmed in the SAMP8 animals treated with vehicle whereas no cell loss was observed in SAMR1 control animals or in SAMP8 animals treated with rhNGF. Inner hair cells stereocilia fusion was observed in the SAMP8 animals treated with vehicle whereas normal stereocilia morphology was observed in the SAMP8 animals treated with rhNGF. Morphology of stereocilia of SAMP8+rhNGF group was close that of SAMR1 control animals confirming the protective effect of the intranasal administration of nerve growth factor also from a histological point of view.
• the inventors have prepared the following example pharmaceutical compositions, obtained according to the below-disclosed preparation methods.
• composition was filtered with 0.22pm filter.
• composition 2 The neurotrophin was added to the composition at final concentration 0.6 mg/mL.
• composition was filtered with 0.22pm filter.
• the neurotrophin was added to the composition at final concentration 0.6 mg/mL.
• Composition 3 rhNGF having the sequence of SEQ ID NO.1 (0.6 mg/mL)
• composition was filtered with 0.22pm filter.
• the neurotrophin was added to the composition at final concentration 0.6 mg/mL.
• composition was filtered with 0.22pm filter.
• the neurotrophin was added to the composition at final concentration 0.6 mg/mL.

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