Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - UshTher (Clinical trial of gene therapy with dual AAV vectors for retinitis pigmentosa in patients with Usher syndrome type IB)

Teaser

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...

Summary

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. The overall goal 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. 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.

Work performed

As a preliminary step of the project, the Partners planned the production of the clinical vector under GMP conditions for use as an Investigational Medicinal Product (IMP) and provide a safety report for regulatory authorities. During the reporting period the following activities were carried out: Tech transfer from Fondazione Telethon (FTELE.IGM) to ReiThera (REI) of dual AAV8-MYO7A vectors, Production process and QC testing, Production of GMP-like plasmids, Production of GMP plasmids, Production and release of the GMP-like Drug Substance of dual AAV8-MYO7A vectors 1 and 2. We also performed a short-term and a long-term study to assess the stability of dual AAV8-MYO7A.

We proposed to conduct non-clinical safety studies for dual AAV8-MYO7A in Cynomolgus macaques given the architectural and size similarity between the human and macaque primate retina. GMP-like dual AAV8-MYO7A vectors used in non-clinical safety studies will be representative of that to be administered in the clinical study. The design of all the experiments, including sample size calculations, was carried out by FTLELE.IGM, with the support of the group of statisticians (UNIMIB). A 4-Week Single Dose Pilot Study of Dual AAV8-MYO7A in Monkeys for Analytical Sample Collection was performed at Covance (Madison, USA), the company selected for GLP non clinical safety and biodistribution studies, in order to: i) provide preliminary data on the tolerability and safety of test article; ii) define the procedure of sub-retinal administration; ii) collect tissue and fluid samples from male cynomolgus monkeys for analytical method development by Genosafe (GNS) and Genethon (GNT). Two male monkeys were injected. No mortality events were observed. No unexpected clinical observations were noted, and none were attributed to the test article. Analysis of samples for AAV8-MYO7A biodistribution/shedding and expression and characterization of immune responses will be performed by GNS and GNT.

The strategy based on ocular gene therapy for the treatment of USHIB patients received the ODD status from EMA (EU/3/14/1282). Partner 1, before the submission of project proposal, had requested the Protocol Assistance to EMA on both non-clinical and clinical development. In this first reporting period, preparation of documents has been carried out for the “pre-submission” audition with the italian Competent Regulatory Authority, to obtain technical-scientific support for the clinical trial application. The audition with the Competent regulatory Authority was held in Rome, at ISS, on June 7th, 2018. The ISS Commission gave advice on aspects regarding quality of IMP manufacturing, including the production process plans and release testing criteria. The design of non-clinical studies carried out in animals was also discussed.

Clinical sites from Italy (UNICAMP), Spain (IIS-FJD) and The Netherlands (ROI) are conducting a natural history study to further characterize the USHIB patients’ population and disease progression. Up to 30 June 2019, Partner 4 screened 23 patients; among them, 20 patients have been enrolled. As far as IIS-FJD’ patients, the total number of patients presented is 18. Of them, 14 patients have been included. Seven patients have been screned from The Netherland. We plan to complete the screening and the enrollment in the next reporting period.

In order to ensure that the clinical study will be performed according to the highest ethical standards and to organize study monitoring throughout the project, we established an Ethics Advisory Group (EAG) constituted by internationally known medical ethicists with experience in clinical trials and members of patient organizations including the Italian, Spanish, and Dutch Societies. The EAG will advise on ethical aspects of patient treatment and care and will oversee the development of guidelines for the UshTher study consent form to ensure a uniform approach in all participating centres.

The management team create

Final results

If successful, UshTher will provide the first proof-of-concept in humans that gene therapy for USHIB with dual AAV8 vectors is both safe and effective.
In terms of general impact to improve the socio-economic welfare of EU citizens, UshTher will impact specifically those connected with Usher syndrome via familial or professional (medical, educational or social) links. In addition to USHIB there are a number of other inherited retinal diseases that would benefit from the proof-of-concept provided through UshTher that subretinal administration of dual AAV vectors is safe and effective.
In addition, UshTher includes two SMEs that are new to Usher syndrome and retinal degenerations and will benefit from their novel technological approaches and already demonstrated commitment to achieve new innovative therapies for rare diseases. The resulting expansion of the contact base will foster new introductions and collaborations in rare disease. The SMEs will benefit from participation by expanding the number of diseases that they are involved in, leading to further new IP, commercial growth by an expanded project base, new jobs and increased revenues.

Website & more info

More info: http://www.ushther.eu/.