Work Packages

In this work package the submission documents for the ethics committee and the Paul-Ehrlich-Institute are coordinated and compiled, on the basis of national and European regulatory requirements and preconditions for human applications of gene therapy.
The work package is also in charge for study monitoring of clinical trials in patients with CNGA3- and PDE6A-associated retinal dystrophies according to Good Clinical Practice guidelines.
STZ eyetrial will act as the CRO for both phase I/II trials in CNGA3 and PDE6A patients. Beside the development of documents and procedures related to clinical trials (patient-information, informed consent forms, procedure manuals, case report forms, trial master files, investigator site files) the STZ eyetrial also provides the coordination of patient visits (including transport and accommodation) study procedures as well as allocation, training and supervision of dedicated study personnel.
STZ eyetrial is a certified member of EVICR.net, a network for clinical sites of excellence in ophthalmology initiated by the European Vision Institute (EVI). An already implemented SOP (standard operating procedure) system regarding all issues, in ophthalmology will be applied in the two planned clinical trials.
WP 1 is responsible for coordination, logistics, administration and the Preclinical Study Monitoring including on-site participation in the NHP studies at Covance.

WP2 combines the in‐house preclinical work of the consortium. The tasks address essential steps in the process of development and translation of the therapeutic approach. WP2 has successfully generated a new model for the human PDE6a‐associated RP, the Pde6a mutant mouse. Additionally, it has established breeding colonies for other two pre‐existing Pde6a models and generated a compound heterozygous Pde6a mutant which will be used for the establishment of AAV‐mediated Pde6a gene replacement therapy and the in vivo and ex vivo characterization of treatment effects. In addition, and to pave the way for a successful translation to human patients, clinically relevant biomarkers for both rod and cone system functionality and integrity will be selected and evaluated. In preparation of the projected clinical trial, WP2 is also in charge of the testing and verification of humanized AAV vectors at different production and purity stages in vivo.

Retinitis pigmentosa (RP) is a clinically and genetically heterogenous group of hereditary retinal disorders, being one of the most common types of retinal degenerations with a prevalence of 1:4000. More than 45 genes have been associated with RP so far, whose defects cause a progressive loss of rod photoreceptor function, followed by cone photoreceptor dysfunction often leading to complete blindness. Across the world, there are 3 million patients affected by RP – in Germany approx. 30.000 to 40.000 patients are known. Achromatopsia, also known as rod monochromatism, is a rare inherited ocular disorder with a prevalence of 1:30.000, and is characterized by lack of cone photoreceptor function. Due to the complete unresponsiveness of cones, achromatopsia is considered a severe ocular disease with very poor visual acuity, severe photophobia at normal daylight conditions and complete color blindness that is accompanied mostly by a pendular nystagmus.
The modern ophthalmological functional diagnostic tools enable a precise characterisation and early recognition of such retinal diseases. The detailed results and information can help to extend our understanding of the pathological mechanisms involved in these diseases. The analysis of the genetic background of the diseases is essential not only for the clear diagnosis and proper patient counselling, but can further provide a better understanding of the nature of retinal disorders and can help in the development of new therapeutic approaches.
Our work package is responsible for the recruitment of patients with a genetically confirmed diagnosis of Retinitis pigmentosa due to PDE6A mutations or Achromatopsia due to CNGA3 mutations hereby assessing the function and structure of the retina with an extensive battery of tests.

Our consortium aims at developing an innovative gene therapy approach to cure two inherited retinal disorders. The first disorder, autosomal recessive achromatopsia (ACHM), is caused by mutations in the CNGA3 gene. These mutations result in the loss of functionality of cone photoreceptors, the cells of the human retina that are responsible for daylight vision and normal visual acuity. The second disorder, autosomal recessive retinitis pigmentosa (RP) is caused by mutations in the PDE6A gene. The loss of PDE6A function primarily affects rod photoreceptors, the cells of the human retina that confer night vision. At a later stage, cone photoreceptors, needed for daylight vision, are also affected. In both diseases, the loss of gene function results in the death of photoreceptors and, hence, in impaired eyesight. We use a recombinant adeno-associated virus (AAV) vector as a gene-carrier system to endow the diseased photoreceptors with a “healthy” copy of the mutated gene. As a proof-of-concept of this approach, we have successfully restored CNGA3 and PDE6A function in mouse models of ACHM and RP, respectively.
Work package 4 is responsible for the development, production and preclinical testing of the therapeutic AAVs. To this end, we develop specific AAVs carrying human CNGA3 and PDE6A genes including photoreceptor-specific regulatory sequences that can be applied to human patients in a clinical setting. We coordinate the virus production process according to the quality standards of the European Medicines Agency and the U.S. Food and Drug administration. Furthermore, we are involved in the preclinical efficacy and safety testing of viral vectors used for the clinical study. As part of this process, we develop a series of assays to determine the presence and correct localization of CNGA3 and PDE6A in photoreceptors after treatment.

Work package 5 is in charge of the strategic planning and conduction of the clinical trials at the University Eye Hospital Tübingen. The team consists of experienced clinicians with a proven track record in patient care and -specifically- vitreoretinal surgery for the treatment of the affected tissue, the light sensing retina. Beyond the expertise in diagnosing and advising patients with retinal degeneration, this team has an extensive research background on what causes retinal degeneration and on what can be done to treat these disorders.
Our goal is to prevent vision loss and/or restore sight in our patients.
We contribute to the pre-clinical phase of the studies with our expertise mainly in an advisory function. This is geared to ensure best possible patient safety of the resulting treatment regime and to maximise the potential for a treatment effect in our patients. At the same time, this interaction allows us to benefit from the experience our colleagues have already gathered in the preclinical development e.g. to optimise our diagnostic protocols.

Work package 6 integrates the tasks and work dedicated to the management of the project both in internal and external affairs. Due to the scale and ambition of the project as well as the tight temporal interconnection of individual tasks and deliverables, a robust and effective project management is mandatory. Hence, WP6 has developed and implemented an efficient management structure based on constituents and boards with defined tasks and responsibilities. A Central Project Office has been established to serve the coordinators in the daily scientific, administrative and financial management of the project within the partnership as well as in relation to the foundation and the advisory board. This includes scientific and financial supervision and monitoring of the project, identification and solution of problems and shortcomings, preparation and submission of scientific and financial reports, organization of project meeting and advisory board meetings, communication with patient organizations and major stakeholders, dissemination activities and public affairs.