Usher Syndrome (USH)

Usher syndrome is a less common genetic disorder characterized by the gradual loss of both hearing and vision. As a research services provider, we are committed to providing specialized Usher syndrome diagnostics and therapeutic development solutions.

Introduction to Usher Syndrome (USH)

Usher syndrome (USH) is more complex than it may seem, since it includes a combination of both genetic and phenotypical traits, for instance, the presence of sensorineural hearing loss, retinitis pigmentosa (RP), and at times vestibular dysfunctions. This condition greatly deteriorates the lifestyle and self-reliance of the concerned individuals resulting in the gradual onset of deaf-blindness.

Fig.1 Schematic representation of the structures, genes, and proteins associated with Usher syndrome. (Castiglione, A., et al., 2022)

The syndrome has an inheritance pattern of autosomal recessive and is clinically grouped into three major types: USH1, and USH2 (USH3) based on the age of onset and severity of the manifestations. So far, nine causative genes have been identified, including MYO7A, USH1C, CDH23, PCDH15, USH1G, USH2A, ADGRV1, WHRN, and CLRN1. These genes have been found to express proteins crucial for the proper activity of sensory hair cells in the inner ear and photoreceptors in the retina.

Diagnostics Development for Usher Syndrome

Genetic Testing

A key component in diagnosing Usher Syndrome is genetic testing. Advanced sequencing (NGS) panels that focus on the previously identified Usher genes have changed the way diagnosis is made. Such panels possess the capability to identify a multitude of mutations such as single nucleotide variants, small insertions or deletions, and even large genomic rearrangements. For instance, targeted exome sequencing has reported around 70-80% rates of diagnosis in Usher families.

Therapeutics Development for Usher Syndrome

• Gene Therapy
  Usher Syndrome is amenable to gene therapy. Functional copies of Usher genes are typically delivered to defective cells using adeno-associated virus (AAV) vectors. For instance, AAV subretinal injections have restored expression of the wild-type MYO7A gene in mouse models of USH1B. Delivery of large genes like MYO7A has also been tried with dual AAV vectors, which showed positive results.
• Antisense Oligonucleotides (ASOs)
  An ASO is a type of short, synthetic nucleic acid that is capable of hybridizing with the pre-mRNA and altering RNA splicing. This strategy has been employed to fix the splicing errors that are brought about by mutations in the USH2A gene. For instance, ASOs were designed to skip exon 13 and leave it out of the USH2A mRNA transcript which leads to the production of active usherin protein.
• Small Molecule Drugs
  Translational read-through-inducing drugs (TRIDs) are a type of small molecule drug that may be helpful with treating nonsense mutations in Usher Syndrome. For instance, Ataluren (PTC124) has been reported to attenuate nonsense mutations in USH1C and USH2A genes and enable the formation of full-length functional proteins.

Our Services

Protheragen provides comprehensive custom-tailored services for the Usher Syndrome diagnostics and therapeutics development. We are geared with the latest advancements in facilities, as well as the skills required for genetic testing, gene therapy, and small molecule drug discovery. Thus, solutions are catered to different researchers' needs. We offer:

Diagnostics Development

• Karyotype Analysis Service
• Omics Analysis Service
• Biomarker Development Service
• Artificial Intelligence Service
• Customized Diagnostics Development

Therapeutic Development

• Small Molecule Drug
• Cell Therapy
• Gene Therapy
• Therapeutic Antibody
• Therapeutic Peptide
• Therapeutic Protein
• Customized Therapy Development

Disease Models

• Shaker1 (mariner) Models
• Deaf Circler Models
• Waltzer (Sputnik) Models
• Ames Waltzer (Orbiter, Pcdh15a) Models
• Jackson Shaker Models
• Vlgr1/del7TM Models
• Whirler Models
• Ush2a Knockout Models

Protheragen provides a range of preclinical research services to support the development of Usher Syndrome therapeutics. Our services include:

• Biomarker Identification
  We specialize in identifying and validating biomarkers for Usher Syndrome, providing valuable insights into disease progression and therapeutic response. For example, we have identified specific retinal imaging markers and functional tests that can be used to monitor the efficacy of therapeutics.
• In Vitro and In Vivo Testing
  Our preclinical research services encompass both in vitro and in vivo testing of therapeutic candidates. We use patient-derived cells, such as fibroblasts and iPSCs, to assess the efficacy of gene editing and small molecule drugs. Additionally, we conduct in vivo studies in animal models to evaluate the safety and efficacy of gene therapy and ASO-based therapeutics.

If you are interested in our services, please feel free to contact us.

References

• Castiglione, Alessandro, and Claes Möller. "Usher syndrome." Audiology research 12.1 (2022): 42-65.
• Toms, Maria, Waheeda Pagarkar, and Mariya Moosajee. "Usher syndrome: clinical features, molecular genetics and advancing therapeutics." Therapeutic advances in ophthalmology 12 (2020): 2515841420952194.