The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention

Abstract

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp -mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp -mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.

Emerging Mechanisms in the Pathogenesis of Menière’s Disease: Evidence for the Involvement of Ion Homeostatic or Blood–Labyrinthine Barrier Dysfunction in Human Temporal Bones

“…Therefore, the current study is unable to distinguish whether the differential protein expression represents the causative etiology of the disease process. Nonetheless, recent mouse model evidence of SV dysfunction resulting in subsequent delayed SGN dysfunction (72) is supportive of our observations of changes in temporal bones from patients with MD.…”

Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease

“…Immunostaining for claudin-5 (a component of endothelial cell tight junctions previously reported as a marker of the abnormal vasculature in Norrie disease; Bryant et al, 2022) showed low/absent claudin-5 in most of the Ndp-KO blood vessels of the stria vascularis and spiral ligament compared to WT (Fig 6K -P, white arrows). A few atypical vessels showed high claudin-5 (orange arrows).…”

“…Gene sets characterising barrier vasculature, BBB1 and 2, BBB endothelial transporters, CNS endothelial and CNS pericyte were significantly positively correlated (FDR < 0.25) with the WT genotype. Dot plot using scRNA seq data of the adult mouse cochlear lateral wall from GEO database: accession numbers GSM5124299, GSM5124300, GSM5124301, and GSM5124302. Gene markers used to distinguish 30 cell type clusters in the UMAP were as previously reported (Gu et al , 2020; Bryant et al , 2022). Dot plot showing expression of the 45 DEGs identified in WT versus Ndp ‐KO analysis in the 30 cell type clusters identified in the adult mouse cochlear lateral wall at the single cell level.…”

“…In the cochlea, transduction was achieved in the modiolus and lateral wall near to the blood vessels and putative targets of NDP signalling (Rehm et al, 2002;Hayashi et al, 2021;Bryant et al, 2022) (Fig 2D and E). The spiral ganglia region was transduced as well as the lateral wall and modiolus (Figs 2F-I and EV1A-E).…”

“…Previously, we identified malformation of cochlear microvasculature to be an early finding in disease development (Bryant et al, 2022). Endomucin immunostaining was used to compare the lateral wall vasculature morphology in the stria vascularis and the spiral ligament (Fig 6A -J) after treatment.…”