Developing a safe 'designer drug' to correct the genetic faults behind inherited eye disorders

Research details

  • Type of funding: Project Grant
  • Grant Holder: Dr Mariya Moosajee
  • Institute: UCL Institute of Ophthalmology
  • Region: London
  • Start date: December 2013
  • End Date: December 2016
  • Priority: Treatment
  • Eye Category:


DNA is the set of instructions for how to build the proteins our bodies need to keep working. A ‘nonsense mutation’ is the name for a change to these instructions that means the last part is never read. This stops production of the protein before it is completed. About 12% of genetic faults are nonsense mutations. Key examples of inherited eye disorders caused by nonsense mutations include some types of retinitis pigmentosa, choroideremia, ocular coloboma and Leber congenital amaurosis.

In previous research with zebrafish, the team found that a group of antibiotics called aminoglycosides can override the nonsense mutation stop sign. They had some success at treating the eye, but the drugs are toxic and cause harmful side effects in the ear and kidney. But they worked out what makes aminoglycosides toxic and found that it’s not connected to their ability to override nonsense mutations. So the team has now produced an aminoglycoside ‘designer drug’ that they hope will be safer to use.

In this project they’re testing out the designer aminoglycosides in zebrafish and in human tissue from the light-sensitive part of the eye (the retina) that has been grown in a lab dish. They want to know whether the new version of the drug can still override the stop signs so that the cells make healthy proteins. They also want to know whether there are any side effects and what’s a safe dose. At the end of the project the team hopes to be in a position to start early clinical trials.

  • Scientific summary

    Designer aminoglycosides to treat nonsense-mediated inherited retinal disease

    An estimated 12% of all genetic mutations are nonsense, resulting in premature termination codons, and this can be extrapolated to inherited retinal disorders. Key examples include nonsense mutations in the CHM gene accounting for over one-third of patients with choroideraemia, and the most prevalent single disease-allele causing autosomal dominant retinitis pigmentosa (RP) being the p.R667X nonsense mutation in RP1.

    Previously, the team successfully demonstrated that traditional aminoglycoside drugs could suppress nonsense mutations and partially restore full-length, functional protein in zebrafish models of choroideraemia and ocular coloboma leading to phenotypic and functional rescue. However, clinical application was restricted due to significant drug-related oto- and nephro-toxicity. Further research has determined three distinct mechanisms that underlie aminoglycoside toxicity, and importantly, these are unrelated to nonsense suppression during cytoplasmic translation. Hence, using systematic structure–function analyses, next generation designer aminoglycosides have been developed with greater nonsense suppression and safer drug profiles.

    The aim of this study is to determine the safety and efficacy of designer aminoglycosides, as a treatment for inherited retinal disorders using disease prototypes choroideraemia and CRB1-related Leber’s congenital amaurosis. The drugs will be tested on (i) in vitro human-derived pathogenic RPE and photoreceptor cells from patients carrying nonsense mutations via induced pluripotent stem (iPS) cell technology and (ii) in vivo nonsense-mediated zebrafish disease models. If successful, the team aims to progress to clinical trials. A molecular therapy that safely targets nonsense mutations has the potential to treat sight-threatening genetic eye disease in a disease- and gene-independent manner, making the approach practical and economical.
  • Research update

    In the first year of the project the team tested a range of doses for each drug to assess any toxic side effects in cells grown in a lab dish and in live healthy zebrafish. They have also found the safest and most effective dose for treatment. The team has started testing the drugs on zebrafish versions of choroideremia, and started the process of turning human skin cells from patients into retinal cells, for future drug testing.