Enzyme Replacement Therapy May Improve Hearing in ENPP1 Deficiency
ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) deficiency is a rare but devastating genetic disorder that affects bone and vascular health. Around half of affected children die within the first six months of life, and surviving patients often suffer from skeletal abnormalities, growth impairment, and hearing loss—seen in up to 75% of cases. American researchers have now demonstrated that hearing loss caused by ENPP1 deficiency can be prevented or reversed in mice using enzyme replacement therapy (ERT).
Impaired Ossicle Mineralization as a Cause of Hearing Loss
ENPP1 regulates mineralization processes in the body. Its deficiency disrupts normal bone development and causes calcium deposits in arteries. Conditions associated with ENPP1 deficiency include generalized arterial calcification of infancy (GACI) and autosomal recessive hypophosphatemic rickets type 2 (ARHR2).
Hearing loss in these conditions is likely due to conductive deficits caused by abnormal mineralization of the auditory ossicles. The researchers behind the study set out to evaluate whether ERT could restore hearing in ENPP1-deficient mice and whether the effect was linked to changes in bone structure within the ossicles.
Bone-Targeted ERT
The tested enzyme therapy was originally developed in 2015 by Professor Demetrios Braddock at Yale School of Medicine. It had previously shown promise in correcting skeletal abnormalities in ENPP1 deficiency and is currently under human clinical investigation. However, its effect on hearing loss had not been explored. For this study, the researchers modified the therapy to specifically target bone tissue.
Mice with ENPP1 deficiency received either a soluble or bone-targeted version of the ERT, starting at 5 weeks of age (analogous to adolescence in humans, when hearing loss typically begins in patients). Injections were administered once weekly. Results from both treatment groups were compared to untreated ENPP1-deficient mice and to healthy controls. Hearing was assessed at 17 weeks of age.
Hearing Function Improved
Untreated ENPP1-deficient mice showed elevated hearing thresholds across test frequencies (8, 16, and 32 kHz), indicating generalized hearing loss. In contrast, treated mice demonstrated normal or near-normal hearing thresholds as measured by auditory brainstem responses (ABRs).
Both forms of ERT were effective, with bone-targeted therapy yielding stronger results and showing a dose-response effect. Researchers also observed improvements in plasma mineral metabolism markers, bone mineralization in the ossicles, and normalized osteocyte function within the malleus bone. Remarkably, bone-targeted ERT corrected the presence of mineralized osteocytic lacunae—newly documented in ENPP1-deficient mice.
Promising Outlook
This study suggests that hearing loss due to ENPP1 deficiency may be preventable or reversible through targeted improvement of ossicle mineralization. According to Prof. Braddock, the findings may even hold potential for broader application—such as in age-related hearing loss, where aberrant mineralization can also play a role.
Editorial Team, Medscope.pro
Sources:
1. Ocokoljic A. et al. Improvements in hearing loss with bone-targeted enzyme replacement therapy are associated with corrected hypomineralization and osteocyte properties of auditory ossicles in Enpp1-deficient mice. Journal of Bone and Mineral Research, 2025 Jun 11. doi: 10.1093/jbmr/zjaf082.
2. Backman I. Novel enzyme therapy restores hearing in mice with rare genetic bone disorder. Yale University, 2025 Jul 18. Available at: medicalxpress.com
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