Rescue of Outer Hair Cells with Antisense Oligonucleotides in Usher Mice Is Dependent on Age of Treatment

doi:10.1007/s10162-017-0640-x

. 2018 Feb;19(1):1-16.

doi: 10.1007/s10162-017-0640-x. Epub 2017 Oct 12.

Rescue of Outer Hair Cells with Antisense Oligonucleotides in Usher Mice Is Dependent on Age of Treatment

Abhilash Ponnath¹, Frederic F Depreux², Francine M Jodelka², Frank Rigo³, Hamilton E Farris^{1

4

5}, Michelle L Hastings⁶, Jennifer J Lentz^{7

8}

Affiliations

¹ Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier Street, 8th Floor, New Orleans, LA, 70112, USA.
² Department of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd, North Chicago, IL, 60064, USA.
³ Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA, 92010, USA.
⁴ Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, LA, 70112, USA.
⁵ Department of Otolaryngology and Biocommunications, Louisiana State University Health Sciences Center, 533 Bolivar Street, New Orleans, LA, 70112, USA.
⁶ Department of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd, North Chicago, IL, 60064, USA. [email protected].
⁷ Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier Street, 8th Floor, New Orleans, LA, 70112, USA. [email protected].
⁸ Department of Otolaryngology and Biocommunications, Louisiana State University Health Sciences Center, 533 Bolivar Street, New Orleans, LA, 70112, USA. [email protected].

PMID: 29027038
PMCID: PMC5783922
DOI: 10.1007/s10162-017-0640-x

Rescue of Outer Hair Cells with Antisense Oligonucleotides in Usher Mice Is Dependent on Age of Treatment

Abhilash Ponnath et al. J Assoc Res Otolaryngol. 2018 Feb.

. 2018 Feb;19(1):1-16.

doi: 10.1007/s10162-017-0640-x. Epub 2017 Oct 12.

Authors

Abhilash Ponnath¹, Frederic F Depreux², Francine M Jodelka², Frank Rigo³, Hamilton E Farris^{1

4

5}, Michelle L Hastings⁶, Jennifer J Lentz^{7

8}

Affiliations

¹ Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier Street, 8th Floor, New Orleans, LA, 70112, USA.
² Department of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd, North Chicago, IL, 60064, USA.
³ Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA, 92010, USA.
⁴ Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, LA, 70112, USA.
⁵ Department of Otolaryngology and Biocommunications, Louisiana State University Health Sciences Center, 533 Bolivar Street, New Orleans, LA, 70112, USA.
⁶ Department of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd, North Chicago, IL, 60064, USA. [email protected].
⁷ Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier Street, 8th Floor, New Orleans, LA, 70112, USA. [email protected].
⁸ Department of Otolaryngology and Biocommunications, Louisiana State University Health Sciences Center, 533 Bolivar Street, New Orleans, LA, 70112, USA. [email protected].

PMID: 29027038
PMCID: PMC5783922
DOI: 10.1007/s10162-017-0640-x

Abstract

The absence of functional outer hair cells is a component of several forms of hereditary hearing impairment, including Usher syndrome, the most common cause of concurrent hearing and vision loss. Antisense oligonucleotide (ASO) treatment of mice with the human Usher mutation, Ush1c c.216G>A, corrects gene expression and significantly improves hearing, as measured by auditory-evoked brainstem responses (ABRs), as well as inner and outer hair cell (IHC and OHC) bundle morphology. However, it is not clear whether the improvement in hearing achieved by ASO treatment involves the functional rescue of outer hair cells. Here, we show that Ush1c c.216AA mice lack OHC function as evidenced by the absence of distortion product otoacoustic emissions (DPOAEs) in response to low-, mid-, and high-frequency tone pairs. This OHC deficit is rescued by treatment with an ASO that corrects expression of Ush1c c.216G>A. Interestingly, although rescue of inner hairs cells, as measured by ABR, is achieved by ASO treatment as late as 7 days after birth, rescue of outer hair cells, measured by DPOAE, requires treatment before post-natal day 5. These results suggest that ASO-mediated rescue of both IHC and OHC function is age dependent and that the treatment window is different for the different cell types. The timing of treatment for congenital hearing disorders is of critical importance for the development of drugs such ASO-29 for hearing rescue.

Keywords: ABR; DPOAE; RNA; USH1C; Usher syndrome; antisense oligonucleotides; c.216G>A mutation; harmonin; hearing loss; inner hair cells; outer hair cells; splicing.

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Conflict of interest statement

Competing Interests

F.R. is an employee of Ionis Pharmaceuticals. M.L.H. receives funding from Ionis Pharmaceuticals. A.P., H.E.F., and J.J.L declare that they have no competing interests.

Figures

**Fig. 1**
Distortion product optoacoustic emission analysis in ASO-treated *Ush1c* mice. Representative power spectra for all tone pairs at the highest stimulus intensity of 75 dB SPL from a a 216GA control littermate (black) and b *Ush1c* 216AA mouse (red). Power spectrum of the tone pairs at primary frequency tones of 6363 and 7630 Hz for *Ush1c* 216AA mice treated with 300 mg/kg of ASO-29 at P1–3 (e, pink line) and untreated 216AA (d, red line) and 216GA control (c, black line) mice at 1 month of age. The primary tones f1 and f2 and 2f1-f2 distortion product (black arrow) peaks are indicated. Response at 2f1-f2 increases with stimulus intensity for 216GA mice and 216AA mice treated with ASOs at P1–3 but not for untreated 216AA mice. f Average 2f1-f2 distortion product at 75 dB SPL for the tone pairs in 216AA mice treated with 300 mg/kg of ASO-29 with one dose at P1 (purple) or P5 (blue), two doses at P1 and 3 (P1, 3; pink), or four doses at P1, 3, 5, and 7 (P1, 3, 5, 7; green); 216AA untreated (red) and control littermates (black). The number of mice assayed is indicated in bars. Error bars represent SEM. For each frequency, asterisks indicate significant difference (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ANOVA with Tukey-Kramer post-test) from control mutant thresholds (red). P values, specific test, test value, and degrees of freedom for all comparisons in this dataset are shown in Supplemental Table Comparison 1. dB, decibel; SPL, sound pressure level, kHz, kilohertz; Het, heterozygote; f, frequency

**Fig. 2**
Analysis of DPOAE signal to noise ratios in *Ush1c* mice treated with a single dose of ASOs. Signal to noise ratio (SNR) plots at the primary tone pairs tested at 1 month (a), 3 months (b), and 6 months (c) of age for *Ush1c* 216AA mice treated with 300 mg/kg of ASO-29 one time at P1 (purple line, n = 8, 6, and 6 at 1, 3, and 6 months of age, respectively) or P5 (blue line, n = 5) and untreated 216AA (red line, n = 15, 12, and 7 at 1, 3, and 6 months of age, respectively) and untreated 216GA (black line, n = 11, 11, and 8 at 1, 3, and 6 months of age, respectively) control mice. Frequency tone pairs: f1 = 6363 Hz, f2 = 7630 Hz (2f1-f2 = 5096 Hz); f1 = 6672 Hz, f2 = 8000.5 Hz (2f1-f2 = 5243 Hz); f1 = 10,008 Hz, f2 = 12,001 Hz (2f1-f2 DP at 8015 Hz); f1 = 13,342.5 Hz, f2 = 15,999 Hz (2f1-f2 DP at 10685 Hz); f1 = 16,000 Hz, f2 = 19,186 Hz (2f1-f2 DP at 12814 Hz); f1 = 24,500 Hz, f2 = 29,378.5 Hz (2f1-f2 DP at 19621). SNRs are increased at some frequencies at all ages tested with a single ASO treatment at P1, but not P5. Error bars represent SEM. For each frequency, asterisks indicate significant difference (**P ≤* 0.05, ***P ≤* 0.01, ***P ≤ 0.001, ANOVA with Tukey-Kramer post-test) from control mutant thresholds (red). P values, specific test, test value, and degrees of freedom for all comparisons in this dataset are shown in Supplemental Table Comparison 1. f, frequency; DP, distortion product; DPOAE, distortion product otoacoustic emission; Hz, Hertz; dB, decibel; SPL, sound pressure level; Het, heterozygote

**Fig. 3**
Analysis of DPOAE signal to noise ratios in *Ush1c* mice treated with multiple doses of ASOs. Signal to noise ratio (SNR) plots at the primary tone pairs tested at 1 month (a), 3 months (b), and 6 months (c) of age for *Ush1c* 216AA mice treated with 300 mg/kg of ASO-29 twice at P1 and 3 (P1, 3, pink line, n = 9, 8, and 7 at 1, 3, and 6 months of age, respectively) or four times at P1, 3, 5, and 7 (P1, 3, 5, 7, green line, n = 17, 13, and 12 at 1, 3, and 6 months of age, respectively) and untreated 216AA (red line, n = 15, 12, and 7 at 1, 3, and 6 months of age, respectively) and 216GA (black line, n = 11, 11 and 8 at 1, 3 and 6 months of age, respectively) control mice. Frequency tone pairs: f1 = 6363 Hz, f2 = 7630 Hz (2f1-f2 = 5096 Hz); f1 = 6672 Hz, f2 = 8000.5 Hz (2f1-f2 = 5243 Hz); f1 = 10,008 Hz, f2 = 12,001 Hz (2f1-f2 DP at 8015 Hz); f1 = 13,342.5 Hz, f2 = 15,999 Hz (2f1-f2 DP at 10685 Hz); f1 = 16,000 Hz, f2 = 19,186 Hz (2f1-f2 DP at 12814 Hz); f1 = 24,500 Hz, f2 = 29,378.5 Hz (2f1-f2 DP at 19621). SNRs are increased at some frequencies at 1 and 3 months of age with multiple ASO treatments in the first week of life. The number of treatments (doses) is indicated. Error bars represent SEM. For each frequency, asterisks indicate significant difference (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ANOVA with Tukey-Kramer post-test) from control mutant thresholds (red)*. P* values, specific test, test value, and degrees of freedom for all comparisons in this dataset are shown in Supplemental Table Comparison 1 . f, frequency; DP, distortion product; DPOAE, distortion product otoacoustic emission; Hz, Hertz; dB, decibel; SPL, sound pressure level; Het, heterozygote

**Fig. 4**
Distortion product otoacoustic emissions analysis in *Ush1c* mice treated with ASOs. Average DPOAE thresholds (dB SPL) at 1 month (a), 3 months (b), and 6 months (c) of age to tone pairs ranging from 6363 to 29,378.5 kHz from 216AA mice treated with 300 mg/kg of ASO-29 one time at P1 (purple line, n = 8, 6, and 6 at 1, 3, and 6 months of age, respectively) or P5 (blue line, n = 5) or multiple times at P1–3 (pink line, n = 9, 8, and 7 at 1, 3, and 6 months, respectively) or P1–7 (green line, n = 17, 13, 12 at 1, 3 and 6 months of age, respectively); 216AA mice treated with ASO-C or untreated (red line, n = 15, 12, 7 at 1, 3 and 6 months of age, respectively); and 216 untreated GA mice (black line, n = 11, 11, 8 at 1, 3, and 6 months of age, respectively). DPOAE thresholds are reduced with some ASO treatments in 216AA mice. Total number of treatments (doses) is indicated. Error bars indicate SEM. For each frequency, asterisks indicate significant difference (**P ≤* 0.05, ***P ≤* 0.01, ***P ≤ 0.001, ANOVA with Tukey-Kramer post-test) from control mutant thresholds (red). P values, specific test, test value, and degrees of freedom for all comparisons in this dataset are shown in Supplemental Table Comparison 2. dB, decibels; SPL, sound pressure level; kHz, kilohertz; BBN, broad-band noise; GA, *Ush1c* c.216GA littermate controls, AA, *Ush1c* c.216AA

**Fig. 5**
Auditory evoked brainstem analysis in Ush1c mice treated with a single dose of ASOs. Average ABR thresholds (dB SPL) at 1 month (a), 3 months (b), and 6 months (c) of age to pure tones ranging from 8 to 32 kHz or BBN from 216AA mice treated with 300 mg/kg of ASO-29 one time at P1 (purple line, n = 6, 6, and 6 at 1, 3, and 6 months of age, respectively), P5 (blue line, n = 9, 9, and 9 at 1, 3, and 6 months of age, respectively) or P7 (orange line, n = 7, 7 and 6 at 1, 3, and 6 months of age, respectively); 216AA mice treated with ASO-C or untreated (red line, n = 27, 23 and 11 at 1, 3 and 6 months of age); and 216GG/GA mice treated by IP injection with ASO-29, ASO-C, and untreated (black line, n = 31, 28, and 24 at 1, 3, and 6 months of age, respectively). ABR thresholds are reduced at some frequencies at all ages in 216AA mice treated with a single dose of ASOs in the first week of life. Error bars indicate SEM. For each frequency, asterisks indicate significant difference (**P ≤* 0.05, ***P ≤* 0.01, ***P ≤ 0.001, ANOVA with Tukey-Kramer post-test) from control mutant thresholds (red). P values, specific test, test value, and degrees of freedom for all comparisons in this dataset are shown in Supplemental Table Comparisons 3 and 4. dB, decibels; SPL, sound pressure level; kHz, kilohertz; BBN, broad-band noise; GG/GA, *Ush1c* c.216GG/GA littermate controls, AA, *Ush1c* c.216AA

**Fig. 6**
Auditory evoked brainstem analysis in *Ush1c* mice treated with multiple doses of ASOs. Average ABR thresholds (dB SPL) at 1 month (a), 3 months (b), and 6 months (c) of age to pure tones ranging from 8 to 32 kHz or BBN from 216AA mice treated with 300 mg/kg of ASO-29 twice at P1 and 3 (P1–3, pink line, n = 9, 7, and 7 at 1, 3 and 6 months of age) or four times at P1, 3, 5, and 7 (P1–7, green line, n = 16, 13, and 12 at 1, 3, and 6 months of age); 216AA mice treated with ASO-C or untreated (red line, n = 27, 23, and 11 at 1, 3, and 6 months of age, respectively); and 216GG/GA mice treated by IP injection with ASO-29, ASO-C, and untreated (black line, n = 31, 28, and 24 at 1, 3, and 6 months of age, respectively). ABR thresholds are reduced at some frequencies at all ages in 216AA mice treated with multiple doses of ASOs in the first week of life. Error bars indicate SEM. For each frequency, asterisks indicate significant difference (**P ≤* 0.05, ***P ≤* 0.01, ***P ≤ 0.001, ANOVA with Tukey-Kramer post-test) from control mutant thresholds (red). P values for additional comparisons in this dataset shown in Supplemental Table Comparisons 3 and 4. Total number of treatments (doses) is indicated. dB, decibels; SPL, sound pressure level; kHz, kilohertz; BBN, broad-band noise; GG/GA, *Ush1c* c.216GG/GA littermate controls, AA, *Ush1c* c.216AA

**Fig. 7**
ASO-mediated correction of *Ush1c* c.216A pre-mRNA splicing 6 months post-injection. a RT-PCR analysis of cochlear RNA isolated from 6-month-old mice treated with 300 mg/kg of ASO-29 at indicated post-natal day(s). Spliced products are labeled. b Quantitation of PCR products shown in a. Asterisks indicate significant difference (***P ≤ 0.001, one-way ANOVA, Tukey’s multiple comparison test)

**Fig. 8**
Localization of ASOs in auditory hair cells at P12 after systemic treatment in *Ush1c* mice. Immunofluorescent labeling of ASO-29 (red) in HCs (green) at the a, b apex, c, d middle turn, and e, f base at P12 after ASO treatment at P1 or P5. Distance from the apex tip is indicated. Scale bars indicate 10 μm. IHC, inner hair cell; OHC, outer hair cell; ASO, antisense oligonucleotide

**Fig. 9**
Localization of ASOs in auditory hair cells at P30 after systemic treatment in *Ush1c* mice. Immunofluorescent labeling of ASO-29 (red) in HCs (green) at the a, b apex-mid turn at P30 after ASO treatment at P1 (a) or P5 (b). c Immunofluorescent image at the apex-middle turn of P5 vehicle-treated (saline), control littermate 1 week after P5 ASO treatment (P12). Scale bars indicate 10 μm. IHC, inner hair cell; OHC, outer hair cell; ASO, antisense oligonucleotide

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References

1. Ahmed M, Wong EYM, Sun JB, Xu JS, Wang F, Xu PX. Eya1-Six1 interaction is sufficient to induce hair cell fate in the cochlea by activating Atoh1 expression in cooperation with Sox2. Dev Cell. 2012;22:377–390. doi: 10.1016/j.devcel.2011.12.006. - DOI - PMC - PubMed
1. Bitner-Glindzicz M, Lindley KJ, Rutland P, Blaydon D, Smith VV, Milla PJ, Hussain K, Furth-Lavi J, Cosgrove KE, Shepherd RM, Barnes PD, O’Brien RE, Farndon PA, Sowden J, Liu XZ, Scanlan MJ, Malcolm S, Dunne MJ, Aynsley-Green A, Glaser B. A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene. Nat Genet. 2000;26:56–60. doi: 10.1038/79178. - DOI - PubMed
1. Boeda B, El-Amraoui A, Bahloul A, Goodyear R, Daviet L, Blanchard S, Perfettini I, Fath KR, Shorte S, Reiners J, Houdusse A, Legrain P, Wolfrum U, Richardson G, Petit C. Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle. EMBO J. 2002;21:6689–6699. doi: 10.1093/emboj/cdf689. - DOI - PMC - PubMed
1. Burns JC, On D, Baker W, Collado MS, Corwin JT. Over half the hair cells in the mouse utricle first appear after birth, with significant numbers originating from early postnatal mitotic production in peripheral and striolar growth zones. Jaro-J Assoc Res Otolaryngol. 2012;13:609–627. doi: 10.1007/s10162-012-0337-0. - DOI - PMC - PubMed
1. Clark W, Clark C, Moody D, Stebbins W. Noise-induced hearing loss in the chinchilla, as determined by a positive-reinforcement technique. J Acoust Soc Am. 1974;56:1202–1209. doi: 10.1121/1.1903409. - DOI - PubMed

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[1] Ahmed M, Wong EYM, Sun JB, Xu JS, Wang F, Xu PX. Eya1-Six1 interaction is sufficient to induce hair cell fate in the cochlea by activating Atoh1 expression in cooperation with Sox2. Dev Cell. 2012;22:377–390. doi: 10.1016/j.devcel.2011.12.006. - DOI - PMC - PubMed

[2] Ahmed M, Wong EYM, Sun JB, Xu JS, Wang F, Xu PX. Eya1-Six1 interaction is sufficient to induce hair cell fate in the cochlea by activating Atoh1 expression in cooperation with Sox2. Dev Cell. 2012;22:377–390. doi: 10.1016/j.devcel.2011.12.006. - DOI - PMC - PubMed

[3] Bitner-Glindzicz M, Lindley KJ, Rutland P, Blaydon D, Smith VV, Milla PJ, Hussain K, Furth-Lavi J, Cosgrove KE, Shepherd RM, Barnes PD, O’Brien RE, Farndon PA, Sowden J, Liu XZ, Scanlan MJ, Malcolm S, Dunne MJ, Aynsley-Green A, Glaser B. A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene. Nat Genet. 2000;26:56–60. doi: 10.1038/79178. - DOI - PubMed

[4] Bitner-Glindzicz M, Lindley KJ, Rutland P, Blaydon D, Smith VV, Milla PJ, Hussain K, Furth-Lavi J, Cosgrove KE, Shepherd RM, Barnes PD, O’Brien RE, Farndon PA, Sowden J, Liu XZ, Scanlan MJ, Malcolm S, Dunne MJ, Aynsley-Green A, Glaser B. A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene. Nat Genet. 2000;26:56–60. doi: 10.1038/79178. - DOI - PubMed

[5] Boeda B, El-Amraoui A, Bahloul A, Goodyear R, Daviet L, Blanchard S, Perfettini I, Fath KR, Shorte S, Reiners J, Houdusse A, Legrain P, Wolfrum U, Richardson G, Petit C. Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle. EMBO J. 2002;21:6689–6699. doi: 10.1093/emboj/cdf689. - DOI - PMC - PubMed

[6] Boeda B, El-Amraoui A, Bahloul A, Goodyear R, Daviet L, Blanchard S, Perfettini I, Fath KR, Shorte S, Reiners J, Houdusse A, Legrain P, Wolfrum U, Richardson G, Petit C. Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle. EMBO J. 2002;21:6689–6699. doi: 10.1093/emboj/cdf689. - DOI - PMC - PubMed

[7] Burns JC, On D, Baker W, Collado MS, Corwin JT. Over half the hair cells in the mouse utricle first appear after birth, with significant numbers originating from early postnatal mitotic production in peripheral and striolar growth zones. Jaro-J Assoc Res Otolaryngol. 2012;13:609–627. doi: 10.1007/s10162-012-0337-0. - DOI - PMC - PubMed

[8] Burns JC, On D, Baker W, Collado MS, Corwin JT. Over half the hair cells in the mouse utricle first appear after birth, with significant numbers originating from early postnatal mitotic production in peripheral and striolar growth zones. Jaro-J Assoc Res Otolaryngol. 2012;13:609–627. doi: 10.1007/s10162-012-0337-0. - DOI - PMC - PubMed

[9] Clark W, Clark C, Moody D, Stebbins W. Noise-induced hearing loss in the chinchilla, as determined by a positive-reinforcement technique. J Acoust Soc Am. 1974;56:1202–1209. doi: 10.1121/1.1903409. - DOI - PubMed

[10] Clark W, Clark C, Moody D, Stebbins W. Noise-induced hearing loss in the chinchilla, as determined by a positive-reinforcement technique. J Acoust Soc Am. 1974;56:1202–1209. doi: 10.1121/1.1903409. - DOI - PubMed

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Rescue of Outer Hair Cells with Antisense Oligonucleotides in Usher Mice Is Dependent on Age of Treatment

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Rescue of Outer Hair Cells with Antisense Oligonucleotides in Usher Mice Is Dependent on Age of Treatment

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