Early ERT initiation ameliorates hearing abnormalities in ADA-deficient mice

Early ERT initiation ameliorates hearing abnormalities in ADA-deficient mice

Published Date: 26/4/19

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medwireNews: Prompt initiation of enzyme replacement therapy (ERT) improves the hearing defects exhibited by mice deficient in adenosine deaminase (ADA), study results show.

Early treatment with polyethylene glycol (PEG)-modified ADA also had a positive effect on immune abnormalities, but “whether similar benefits can also be achieved in ADA-deficient patients remains to be determined”, say Eyal Grunebaum (Hospital for Sick Children, Toronto, Ontario, Canada) and co-researchers.

They assessed auditory brainstem evoked responses (ABR) in mice lacking ADA activity (ADA–/–) and littermate controls that were ADA-proficient (ADA+/–) at 17 days postpartum, and found that ADA-deficient mice exhibited significant hearing loss – as indicated by an increase in auditory thresholds – at 8, 16 and 32 kHz relative to control animals. However, the between-group difference was less pronounced at 32 kHz than at the lower frequencies, the team notes.

Administration of PEG-ADA at a dose of 1 unit/g twice a week from 7 to 21 days postpartum significantly improved the hearing abnormalities at all frequencies. Specifically, the mean auditory threshold decreased from 82.2 to 50.3 dB at 8 kHz and from 68.8 to 43.5 dB at 16 kHz, but the improvement was less prominent at 32 kHz.

Visualisation of the cochlea of ADA-deficient mice at 17 days postpartum by scanning electron microscopy revealed correlation with the hearing defects, such that the hair cells at the apical and mid-turn regions were splayed, short or missing, in line with the hearing loss at 8 and 16 kHz. By contrast, hair cells in the basal regions were not as damaged, which was consistent with the less severe hearing loss at 32 kHz.

And once again, early treatment with PEG-ADA resulted in amelioration of the damage, with no hair cell loss and normal-length hair cells.

The researchers were able to rule out hypoxia and delayed development as underlying causes for the hearing defects, and therefore believe that “ADA deficiency is a direct cause of the auditory abnormalities”.

They continue: “Hence, we add another non-infectious complication caused by ADA deficiency to the growing list of systemic effects of abnormal [adenosine] metabolism.”

Similar to the auditory results, ADA-deficient mice exhibited progressive immune abnormalities from 3–4 days postpartum, which were improved following the initiation of ERT from day 7 postpartum. For instance, ERT-treated ADA-deficient mice showed increases in the number of thymocytes and the proportion of CD4+CD8+ thymocytes at 17 days postpartum relative to their untreated counterparts; however, the levels remained below normal.

And despite early ERT, the levels of peripheral blood lymphocytes and CD4+ and CD8+ T cells in the spleen of ADA-deficient mice remained significantly lower than those of ADA-proficient controls at 17 days postpartum.

“Whether higher doses or longer duration of ERT will also reverse these abnormalities remains to be determined”, Grunebaum and colleagues write in Frontiers in Immunology. “Nevertheless, our study emphasizes again the important benefit of early ADA ERT for the T lineage development in ADA deficiency.”

© 2020 Springer Healthcare Ltd

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