Early Enzyme Replacement Therapy Improves Hearing and Immune Defects in Adenosine Deaminase Deficient-Mice

Abstract

Background: Inherited defects in adenosine deaminase (ADA) cause severe immune deficiency, which can be corrected by ADA enzyme replacement therapy (ERT). Additionally, ADA-deficient patients suffer from hearing impairment. We hypothesized that ADA-deficient (–/–) mice also exhibit hearing abnormalities and that ERT from an early age will improve the hearing and immune defects in these mice.Methods: Auditory brainstem evoked responses, organ weights, thymocytes numbers, and subpopulations, lymphocytes in peripheral blood as well as T lymphocytes in spleen were analyzed in ADA–/– and ADA-proficient littermate post-partum (pp). The cochlea was visualized by scanning electron microscopy (SEM). The effects of polyethylene glycol conjugated ADA (PEG-ADA) ERT or 40% oxygen initiated at 7 days pp on the hearing and immune abnormalities were assessed.Results: Markedly abnormal hearing thresholds responses were found in ADA–/– mice at low and medium tone frequencies. SEM demonstrated extensive damage to the cochlear hair cells of ADA–/– mice, which were splayed, short or missing, correlating with the hearing deficits. The hearing defects were not reversed when hypoxia in ADA–/– mice was corrected. Progressive immune abnormalities were detected in ADA–/– mice from 4 days pp, initially affecting the thymus followed by peripheral lymphocytes and T cells in the spleen. ERT initiated at 7 days pp significantly improved the hearing of ADA–/– mice as well as the number of thymocytes and T lymphocytes, although not all normalized.Conclusions: ADA deficiency is associated with hearing deficits and damage to cochlear hair cells. Early initiation of ERT improves the hearing and immune abnormalities.

Adenosine A2B receptor: A pathogenic factor and a therapeutic target for sensorineural hearing loss

“…To determine the pathogenic mechanisms of HL mediated by chronically elevated adenosine as seen ADA-deficient humans, we took advantage of using Ada −/− mice, which manifest most of the phenotypes observed in ADA-deficient humans including HL. 22 Although ADA-deficiency is a lethal condition for humans and mice, ADA-deficient humans and mice can survive indefinitely by enzyme replacement therapy that involves weekly injection of polyethylene glycol-ADA (PEG-ADA), an FDA-approved drug to reduce excessive levels of adenosine in ADA-deficient humans and mice. 23 Furthermore, the experimental ease with which adenosine levels can be regulated by administration of PEG-ADA represents a powerful investigative strategy.…”

“…4 Consistently, recent studies validated that ADA-deficient mice (Ada −/− ) mimicking ADA-deficient humans display the phenotype of HL and that polyethylene glycol-ADA (PEG-ADA) treated 7-day post-partum Ada −/− mice have improved hearing and immune abnormalities. 22 Thus, elevated cochlear adenosine is likely a common metabolic signaling molecule involved in SNHL in ADA-deficiency and other conditions such as aging, noise and drugs. To define the pathogenic mechanism of elevated cochlear adenosine in SNHL, we took advantage of adult Ada −/− mice and aged wild-type (WT) mice, two distinct animal models with SNHL, to probe cellular, molecular, and metabolic basis underlying elevated cochlear adenosine in SNHL with a goal to develop innovative therapies.…”

Comparison of elapegademase and pegademase in ADA-deficient patients and mice

“…Consequently, ADA activity in ADA‐KO mice treated with ELA–ADA remained above or within normal range for more than 4 days after injection, in contrast to fewer than 3 days after ADAGEN treatment. Body and thymus weights, the number of thymocytes and flow cytometry analysis of thymocyte subpopulation were assessed at 17–19 days pp in treated and non‐treated ADA‐KO and normal littermate mice, as previously reported . Both ELA–ADA and ADAGEN treatments significantly increased thymus weights and the number of thymocytes (Fig.…”

“…The mouse model was generated a decade after the approval of ADAGEN , and has since been instrumental in evaluating the different treatment options for ADA deficiency, including HSCT, HSC‐GT and ERT . In contrast to previous studies that explored ‘low’ and ‘high’ as well as ‘early’ and ‘late’ ERT , we examined regimens reminiscent of that used in ADA–SCID patients, initiating treatment at 7 days pp. Importantly, we found that ELA–ADA circulating half‐life, estimated at 24–28 h, was consistently longer than the 16–20 h estimated for ADAGEN.…”

“…ADAGEN was shown to rapidly correct the metabolic, immune and systemic abnormalities in ADA‐deficient patients , and recent guidelines recommend administering ADAGEN to all newly diagnosed ADA–SCID . In mice lacking ADA [ADA‐knock‐out (KO) mice], which recapitulate many of the features observed in the human condition including profound T and B cell deficiency, ADAGEN can correct the metabolic, immune and non‐immune abnormalities when treatment is initiated at an early age .…”