Project A will build on the results achieved in the RD-CURE program by improving gene augmentation therapy using an advanced AAV-based delivery and transgene expression system to replace the defective gene and correct PDE6A expression in rod photoreceptors. 

Major improvements compared to our previous PDE6A gene therapy program in RD-CURE will include the development of novel recombinant AAV vectors with enhanced lateral spreading capabilities and altered tropism, the optimization of the transgene construct with respect to its molecular size and expression, establishment of a reliable in vitro potency assay, good-manufacturing practice (GMP) AAV production, stringent quality control of batches for clinical study medication, and testing of those in mouse and dog disease models. Project A is expected to improve drug safety and pharmacological efficacy that had been studied in the first-in-man study of the RD-CURE program.

Involved investigators:
Prof. Bernd Wissinger, Principle Investigator (Institute for Ophthalmic Research Tübingen, Molecular Genetics Laboratory)
Prof. Dr. Katarina Stingl, Co-Principal Investigator (Centre for Ophthalmology, University Eye Hospital Tübingen)
Dr. Tobias Peters, Co-Principal Investigator (Centre for Ophthalmology, Clinical Trial Unit, University Eye Hospital Tübingen)
Dr. Melanie Ziegler (Centre for Ophthalmology, Clinical Trial Unit, University Eye Hospital Tübingen)

Project B concerns the pre-clinical and clinical development of CN238, an analogue of cyclic guanosine monophosphate (cGMP) that inhibits PKG. 

CN238 and other cGMP analogues have been studied as drugs for IRD treatment for more than 15 years in the Tübingen Centre for Ophthalmology. This research was supported by major grants from the EU and the German BMBF (DRUGSFORD, transMed, TargetRD, TreatRP), and has generated a wealth of preclinical and proof-of-principle data. 

In 2017 this led to the foundation of the spin-out company Mireca Medicines GmbH (Tübingen), which aims at promoting the clinical development of CN238 and related cGMP analogues. CN238 specifically targets PKG and interferes with a degenerative pathway triggered by exceedingly high levels of cGMP in rod photoreceptors. The specific poly-lactic-glycolic-acid (PLGA)-based formulation of CN238 is referred to as MM238 and enables a sustained long-term release of the compound after injection into the vitreous body.

Involved investigators:
Prof. Francois Paquet-Durand, Principle Investigator (Institute for Ophthalmic Research Tübingen, Cell Death Mechanisms Laboratory)
Dr. Catherine Hottin (Institute for Ophthalmic Research Tübingen, Cell Death Mechanisms Laboratory) 

Project C develop the pre-clinical and clinical application of the proteostasis modulator ML240, a valosin-containing protein (VCP) inhibitor, as a treatment option for IRD. 

Mechanistically, ML240 prevents cell death of photoreceptors. Moreover, it induces a significant and long-lasting structural and functional recovery of the retina, especially when administered topically to the retina in a novel formulation. This novel formulation markedly reverts degenerative energetic patterns and the metabolic breakdown of photoreceptors, while preventing microglia activation. Project C is in an advanced preclinical development state and has been developed as a lighthouse project within the EU project OcuTher, co-funded by the US Foundation Fighting Blindness. It also received significant co-funding from the Fighting Blindness Canada foundation to explore its potential for therapeutic application in a wider range of IRDs.

Involved investigators:
Prof. Marius Ueffing, Principle Investigator (Institute for Ophthalmic Research Tübingen, Molecular Biology of Retinal Degenerations Laboratory)
Dr. Blanca Arango-Gonzales, Co-Investigator (Institute for Ophthalmic Research Tübingen, Molecular Biology of Retinal Degenerations Laboratory)
Dr. Juliane Hädicke-Jarboui, Project Coordinator (Institute for Ophthalmic Research Tübingen, Molecular Biology of Retinal Degenerations Laboratory)
Dr. Ana Almansa-Garcia (Institute for Ophthalmic Research Tübingen, Molecular Biology of Retinal Degenerations Laboratory) 
 

Project N (Natural History Study) wants to work on the identification and validation of sensitive pathophysiology-based clinical biomarkers and readouts specifically tailored to evaluate the PDE6A-, PDE6B- and RHO-linked retinal dystrophies, with the aim to identify and validate improved highly sensitive outcome measures for disease progression in a clinical setting.

Involved investigators:
Prof. Dr. Katarina Stingl, Principal Investigator (Centre for Ophthalmology, University Eye Hospital Tübingen)
Dr. Susanne Kohl, Co-Principle Investigator (Institute for Ophthalmic Research Tübingen, Molecular Genetics Laboratory)
Dr. Krunoslav Stingl (Centre for Ophthalmology, University Eye Hospital Tübingen)

Project Q is responsible for the implementation and monitoring of regulatory aspects and requirements during the preclinical phases of projects A, B and C (GLP-based toxicology, pharmacokinetics). In the clinical phase, Project Q will serve as clinical study center in the preparation and conduction of the three planned interventional phase I/II clinical trials. 

Involved investigators:
Dr. Tobias Peters, Principal Investigator (Centre for Ophthalmology, Clinical Trial Unit, University Eye Hospital Tübingen)
Dr. Melanie Ziegler, Co-Principal Investigator (Centre for Ophthalmology, Clinical Trial Unit, University Eye Hospital Tübingen)
Dr. Nadine Kahle (Centre for Ophthalmology, Clinical Trial Unit, University Eye Hospital Tübingen)