Research group Molecular therapies for otogenetic disorders

Aims

1. Developing RNA therapies for otogenetic disorders
2. Developing personalized ‘n-of-1’ treatments for ultra-rare variants
3. Improving delivery of therapeutic molecules to the inner ear
4. Generation and characterization of innovative models for otogenetic disorders
5. Unraveling regeneration pathways in zebrafish

Achievements

• RNA based therapies for Usher syndrome and non-syndromic hearing loss

  We have developed and valorised RNA based therapies for Usher syndrome and non-syndromic hearing loss. Usher syndrome and non-syndromic hearing loss are severely debilitating disorders affecting quality of life of patients, that are currently still untreatable.

  We have developed and characterized suitable in vitro (2D/3D organoids, cellular splice assays) and in vivo models (zebrafish and humanized mouse models) for different types of Usher syndrome (USH2A, USH2C) and non-syndromic hereditary hearing loss (DFNA9 and DFNA21), designed and (pre)clinically validated antisense oligonucleotides, resulting in the filing of seven patents.

  A license agreement with ProQR (and later on Thea Laboratoires – SepulBio) was signed, after which in collaboration ultevursen was developed, a splice-switching antisense oligonucleotide targeting USH2A exon13, which is currently being assessed in a phase 2b clinical trial. In addition, an exclusive license agreement was signed between Radboudumc and the the Radboudumc spin-off company Astherna BV for five additional patents related to antisense oligonucleotides targeting USH2A

• Sleep deficiency as symptom of Usher syndrome

  We have recognized sleep deficiency as a hallmark symptom of Usher syndrome. A major complaint of Usher syndrome patients is poor sleep quality and fatigue. These problems significantly affect the quality of life of patients, although they are most often neglected in our current healthcare system.

  We started investigating the presence and origin of sleep deficiencies in genetically confirmed Usher syndrome patients. A large questionnaire study indeed confirmed the presence of impaired sleep quality, that was unrelated to the progression of the disease. Actigraphy recordings confirmed that the interdaily variation in sleep behavior was significantly higher in patients as compared to controls. These data were corroborated in functional sleep assays in zebrafish Usher syndrome mutants.

  Finally, expression and localization assays have revealed the presence of the Usher syndrome-assoicated proteins in the sleep-regulating organ in the brain (pineal gland) of zebrafish and other species (including human). Current research focuses on understanding the role of these proteins in regulating sleep. As a result, the carepath of Usher syndrome has been adapted in which patients are now also being referred to a somnologist and that sleep problems are recognized as a hallmark symptom of the disease (Orphanet).

• Generated functional models

  We have generated functional models for Usher syndrome and nonsyndromic hearing loss, including 3D organoids, (humanized) zebrafish, porcine and mouse models.

Alumni

• Hannie Kremer
• Margo Dona
• Ralph Slijkerman
• Renske Schellens
• Janine Reurink
• Lisette Hetterschijt
• Ferry Kersten
• Fien Aben
• Heleen te Brinke