Usher syndrome (USH) is a ciliopathy with an autosomal recessive inheritance pattern, characterized by sensorineural hearing impairment, retinitis pigmentosa (RP), and in some cases, vestibular dysfunction.
1 It is a primary cause of concurrent deafness and blindness, accounting for more than 50% of such cases.
2,3 The prevalence of USH ranges from 3.2 to 6.2 per 100,000 individuals,
1 and it represents 18% of all RP
3 and 5% of all congenital hearing loss cases.
4 USH is divided into four clinical types (USH1, USH2, USH3, USH4), based on the visual impairment and age of RP onset, the severity and onset of hearing loss, and the presence of vestibular dysfunction.
5–7 USH is genetically heterogeneous with 11 causative genes confirmed and two suspected.
8 Mutations in
USH1C are responsible for 6% to 7% of USH1 cases,
1 which make up one third of all USH patients and represent its most severe clinical subtype.
9 The
USH1C gene encodes various isoforms of the harmonin protein, which organize protein networks within the USH interactome.
10,11 Hearing aids and cochlear implants are the main treatments for hearing loss in USH, but there is currently no approved treatment for the USH-related vision loss.
12 Since the approval of voretigene neparvovec for biallelic RPE65-mediated inherited retinal dystrophies, there has been significant advancement in ocular gene therapy, evidenced by numerous ongoing pre-clinical and clinical trials.
13,14 In USH, several therapeutic approaches are being investigated including DNA interventions (gene augmentation, gene editing), RNA interventions (antisense oligonucleotides [ASOs], translational readthrough) and cell therapies.
15 Currently, there are no human interventional trials specifically for patients with
USH1C mutations, except for an antioxidant drug trial by Nacuity Pharmaceuticals enrolling USH patients regardless of mutation type.
16 In 2007, Lentz et al. developed a knock-in mouse model with the human 216G > A mutation (a founder mutation in North America), that exhibits severe hearing loss, balance problems, and mild vision loss.
17 Systemic treatment with an ASO targeting the 216G > A mutation rescued hearing and vestibular function in the mouse model.
18 In the same mouse model, Pan et al.
19 observed that following the delivery of wild-type
USH1C into the inner ear using an adeno-associated viral vector (AAV), there was gene and protein expression, resulting in the recovery of auditory and vestibular function. In 2022, Grotz et al.
20 developed a transgenic humanized USH1C
R31* pig model by inserting a human
USH1C gene mutation, effectively replicating key USH1 symptoms such as hearing loss, balance issues, and vision problems. This large animal model provided valuable insights into USH1C disease development and supported the establishment of a breeding herd for gene therapy trials.
20