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

Abstract

Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X‐linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model (Ndptm1Wbrg), which recapitulates abnormal retinal vascularisation and progressive hearing loss. We delivered human NDP cDNA by intravenous injection of adeno‐associated viral vector (AAV)9 at neonatal, juvenile and young adult pathological stages and investigated its therapeutic effects on the retina and cochlea. Neonatal treatment prevented the death of the sensory cochlear hair cells and rescued cochlear disease biomarkers as demonstrated by RNAseq and physiological measurements of auditory function. Retinal vascularisation and electroretinograms were restored to normal by neonatal treatment. Delivery of NDP gene therapy after the onset of the degenerative inner ear disease also ameliorated the cochlear pathology, supporting the feasibility of a clinical treatment for progressive hearing loss in people with Norrie disease.

Mechanisms Underlying Rare Inherited Pediatric Retinal Vascular Diseases: FEVR, Norrie Disease, Persistent Fetal Vascular Syndrome

“…Our research group has demonstrated that a single intra-vitreal injection of Norrin protein can accelerate vascular regrowth and reduce inner-retina neuronal cell loss in the mouse oxygen-induced retinopathy model [6,45]. More recently, Pauzuolyte et al (2023) have shown that intravenous treatment of Ndp knockout mice with an adeno-associated viral vector 9 (AAV9) could rescue the failed development of the microvasculature in the neural retina and cochlea [46].…”

“…nopathy model [6,45]. More recently, Pauzuolyte et al ( 2023) have shown that intravenous treatment of Ndp knockout mice with an adeno-associated viral vector 9 (AAV9) could rescue the failed development of the microvasculature in the neural retina and cochlea [46].…”

Molecular differences between neonatal and adult stria vascularis from organotypic explants and transcriptomics

“…Wang et al, 2012) and Frizzled-4 knockout mice experience vascular degeneration in these tissues as well as the inner ear (Xu et al, 2004). In fact, dysregulation of the canonical Wnt/β-catenin pathway is the cause of Norrie disease, a progressive vascular disorder that results in hearing loss (Bryant et al, 2022; Pauzuolyte et al, 2023; Rehm et al, 2002). Since we dissect the whole SV including all the components of the BLB for our in vitro cultures, it would be pertinent in future work to gain a molecular perspective on the vascular cells of the SV.…”

A patient with 18p11.32-p11.21 deletion have monaural deafness caused by an inadequate haplodose of THOC1: A case report

“…Inherited forms of deafness are highly prevalent and severe conditions that significantly affect 5% of the world’s population, the lack of therapeutic options for these conditions poses a major socioeconomic burden. [ 1 , 2 ] So far, many genetic factors have been found to cause deafness. However, there is a lack of treatments to prevent hearing loss due to genetic causes.…”

“…However, there is a lack of treatments to prevent hearing loss due to genetic causes. [ 2 ] The discovery of new genetic pathogenic genes is particularly important for the prevention and treatment of deafness. A recent study found that THOC1 deficiency leads to late-onset nonsyndromic hearing loss in zebrafish, [ 3 ] but no case of deletion in THOC1 has been reported.…”