Methods of treating, inhibiting and/or preventing an auditory impairment
Inventors
Assignees
US Department of Veterans Affairs
Publication Number
US-10124062-B2
Publication Date
2018-11-13
Expiration Date
2037-02-27
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Abstract
The present invention provides methods of treating an auditory impairment associated with outer hair cells of the cochlea in a subject. The method may comprise administering to said subject an effective amount of a composition comprising, as an active agent, an oligonucleotide sequence having a portion of a mammalian telomere sequence so as to reduce the auditory impairment thereby treating the auditory impairment in the subject.
Core Innovation
The invention provides methods for treating, inhibiting and/or preventing auditory impairments associated with outer hair cells of the cochlea in a subject by administering an effective amount of a composition comprising, as an active agent, an oligonucleotide sequence having a portion of a mammalian telomere sequence. The treatment aims to reduce auditory impairment by preserving or restoring outer hair cell function, retrocochlear function, and improving DNA repair in the subject.
The problem being addressed is the difficulty people suffer from when adjusting to hearing loss, which is a critical aspect of communication and relationships. Current treatments for auditory impairments are inadequate, and there is a need for new therapies that can alleviate or inhibit auditory impairments, particularly those associated with outer hair cells of the cochlea.
Claims Coverage
The patent contains one independent claim defining a method with several inventive features related to the treatment of auditory impairment using oligonucleotide sequences derived from mammalian telomeres. Four additional claims are dependent and define specific aspects or embodiments of the treatment.
Method of treating auditory impairment with mammalian telomere oligonucleotide
Administering to a subject an effective amount of a composition comprising an oligonucleotide sequence having a portion or variant of a mammalian telomere sequence to preserve or restore outer hair cell function, preserve or restore retrocochlear function, and improve DNA repair, thereby inhibiting or treating auditory impairment associated with outer hair cells of the cochlea.
Activation of p53 without inducing apoptosis
The composition increases activation of p53 protein without causing an increase in total p53 protein concentration sufficient to induce apoptosis of cochlear outer hair cells.
Treatment of various auditory impairments
The method is suitable for treating a range of auditory impairments including temporary, permanent, sensory, sensorineural hearing loss, tinnitus, loudness recruitment, hyperacusis, diplacusis, and speech intelligibility deficits.
Use of telomere-isolated oligonucleotides
The oligonucleotide sequence used in the method is isolated from a telomere.
Use of modified oligonucleotides and multiple administration routes
The oligonucleotide can be a modified oligonucleotide, and the composition can be administered by various routes including topical, injection, swab, patch, droplet, aerosol, implant, device with voltage, nanoparticle, projectile, aqueous or non-aqueous solutions, solids, micelles, salts, metal or lipid complexes, or conjugates with cell targeting agents.
Specific oligonucleotide sequences from mammalian telomeres
The oligonucleotide having a portion of a mammalian telomere sequence 100% homologous to direct hexanucleotide repeats (TTAGGG) is selected from sequences including GTTAGGGTT, TTAGGGTTA, GGGTTAGGG, GTTAGGGTTAG (SEQ ID NO. 1), GTTAGGGTTAGGGTT (SEQ ID NO. 5), and GTTAGGGTTAGGGTTA (SEQ ID NO. 4).
The claims cover a method of treating auditory impairments by administering oligonucleotide sequences derived from mammalian telomeres that preserve or restore cochlear functions and improve DNA repair, with particular focus on activation of p53 without apoptosis and multiple administration routes, using specific telomere-based nucleotide sequences.
Stated Advantages
The treatment with oligonucleotide sequences originating from mammalian telomeres can recover outer hair cell function after noise-induced injury.
The oligonucleotide treatment limits the magnitude of retrocochlear dysfunctions following damaging noise exposure.
The method induces activation of a protective p53/XPC pro-survival response in the cochlea that enhances DNA repair gene expression.
The oligonucleotide treatment has dose-dependent effects on DNA repair gene expression, providing durable protection over several days after noise exposure.
Documented Applications
Treatment, inhibition, and prevention of auditory impairments associated with outer hair cells of the cochlea, including noise-induced hearing loss, physical trauma, metabolic stress, temperature stress, hypoxia, chemical ototoxicants, and presbycusis.
Recovery or preservation of cochlear outer hair cell function and retrocochlear (brainstem) auditory functions after noise-induced injury.
Use in subjects suffering from auditory impairment due to noise injury, environmental toxins, toxic drugs, mutagens, chemotherapeutic agents, aging, diabetes, infections, cancer, antibiotics, or cancer therapy.
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