Usher syndrome (USH) is the most common combination of deafness and blindness due to retinitis pigmentosa. USHIB, caused by mutations in the large MYO7A gene, is among the most severe and frequent forms of USH.
While deafness can be improved with cochlear implants, blindness remains untreatable. Retinal gene therapy with AAV vectors is both safe and effective in humans, however it is limited by AAV cargo capacity which would not allow transfer of the large MYO7A expression cassette.
UshTher objective is to test the safety and efficacy of a highly innovative gene therapy approach (dual AAV) in the retina of USHIB patients. The projects builds on data previously obtained by the coordinator that a single combined subretinal administration of dual AAV vectors, each packaging one of the two halves of a MYO7A expression cassette, results in MYO7A reconstitution and therapeutic efficacy in a mouse model of USHIB.
This has received the Orphan Drug Designation from the European Medicines Agency.
It would be the first time the dual AAV vector approach is tested in humans. Towards this ambitious objective, UshTher has assembled a very competitive consortium with leaders in the fields of retinal gene therapy from bench to bedside including SMEs with expertise in the development of gene therapy products. The planned activities span from manufacturing of clinical –grade dual AAV vectors to non clinical safety, biodistribution and expression studies performed under good laboratory practices up to performing a multicenter, multinational clinical trial which envisages subretinal administrations of dual AAV vectors in twelve USHIB patients.
UshTher success will set the basis for a cure for USHIB retinitis pigmentosa, and for testing dual AAV vectors in other rare and more common conditions which require delivery of large genes, thus overcoming one of the major limitations of in vivo gene therapy.


The overall objective of UshTher is to develop a phase I/II, first-in-human, clinical trial of gene therapy for USHIB retinitis pigmentosa based on dual AAV. UshTher is highly innovative as it would be the first time that dual AAV vectors are tested in humans, or that any combination of two independent gene therapy vectors are delivered in vivo to patients. This could pave the way for using a similar approach for other devastating diseases due to large genes deficiency.

UshTher objective will be achieved through the following specific aims:

  1. To produce dual AAV vectors for non-clinical studies and for the clinical trial;
  2. To assess in relevant pre-clinical species the safety, biodistribution and expression of dual AAV vectors manufactured in 1;
  3. To perform a clinical observational study on USHIB patients to better define the natural history of USHIB retinitis pigmentosa and establish baseline data on the endpoints that will be monitored in the phase I/II study;
  4. To submit and file the documents required to obtain authorizations to perform a phase I/II clinical trial;
  5. To perform a multicenter phase I/II clinical trial to investigate the safety and efficacy of subretinal administrations of dual AAV8- MYO7A vectors.