Annual Newsletter no. 4
GDNF mimetics 1.11.2013-31.10.2017

What is it all about?

Four years ago we started this collaborative project between University of Helsinki (UoH) and Estonia based SME Molcode Ltd (MC). We had two goals for the upcoming years. The scientific goal was to develop small molecules mimicking a neurotrophic factor called GDNF. GDNF protects and repairs dopamine neurons, the population of the cells that progressively degenerates and dye in the brains of Parkinson’s disease (PD) patients, causing diagnostic motor symptoms of the disease. However, GDNF’s pharmacological properties makes its clinical use complicated in contrast to small molecules with biological activity similar to GDNF. Our other goal – combining the skills and knowledge, and sharing partners’ available methodology – has been pursued at the same time in a determined way by putting the scientists’ heads together in UoH and MC. Equally important to combining the know-how of the two partners was the goal of training scientists at the early stage of their career by giving them an opportunity to be part of a drug development process, and see the aspects of it from biological, pharmacological and computer based molecules’ design points of view.

Outcomes

During these four years we have been working and collaborating with many enthusiastic and skilled scientists with different backgrounds. Dr. Gunnar Karelson (MC) visited UoH and learned the basic principles of immortalized cell culturing and became familiar with biological assays for selection and validation of GDNF mimetics. After his returning back to MC, he executed the technology transfer from UoH to MC by setting up a laboratory with appropriate equipment to carry out experiments with cell cultures in Tartu. MSc. Hans Priks (MC) started learning cell culturing already in MC’s new laboratory space, and while his 12-month split stay in UoH, he got to learn the biological methods utilized in UoH and screened a number of potential GDNF mimetics (developed in MC) in in vitro assays and analyzed the mode of action of active compounds. Neuroscientist Dr. Yulia Sidorova (UoH) spent 14 months in total in MC, learning the basic principles of QSAR models, the use of different softwares for computer based predictive testing, acquired understanding on the effect of molecules’ structure on their properties, and gained experience on the modus operandi of the business world.

The Marie Curie IAPP funding made it possible for us to recruit 4 scientists, all with expertise on their fields, for a duration of 12-15 months. They all did their part in helping us trying to achieve the goal of developing a new type of drug against PD. The first recruited computational chemist Dr. Girinath Pillai was working on lead optimization and small molecules design in MC. Material scientist Dr. Wei Li, recruited to UoH, was concentrating on improving the solubility and delivery of the compounds developed within the project by porous silicon nanoparticles. Medicinal chemist Dr. Lauri Sikk was recruited to MC to continue the work of developing GDNF mimetics with good pharmacological properties. Dr. Tanel Visnapuu, with expertise on behavioral neurosciences, was focused on analysis of biological activity of GDNF mimetics in vivo in UoH.

All of the newly recruited researchers participated actively in training a number of scientists working under the project, whether they were at home or abroad on a secondment. In addition to the seconded fellows Dr. Sidorova, Dr. Karelson and MSc. Priks, UoH based fellows MSc. Ilida Suleymanova (mathematician), MSc. Karmen Kapp (pharmacologist), MSc. Arun Mahato (neuroscientist), MSc. Mikael Jumppanen (medicinal chemist) and Dr. Jaakko Kopra (pharmacologist) spent 4-6 months in MC as secondees. They all learned new skills in the field of computational chemistry and got valuable experience on working in a company, hopefully being able to make use of the experience in their future careers!

Last, but not least, Dr. Mehis Pilv from MC was acting as innovation officer while on his 2-month secondment in UoH. His task was to familiarize himself with the research methods used in UoH, and focus on IPR and patenting related questions, as well as meeting with companies with potential common interest.

As you see, a lot of people have been trained within this project, but how about the scientific outcomes? Did we manage to establish GDNF mimetics that could lead to the development of treatment or cure for Parkinson’s disease?

During these four years, we obtained in vivo proof-of-concept and showed that GDNF mimetics are able to alleviate motor symptoms in animals with experimental PD. We are now in the process of the analysis of the brains of experimental animals to see if GDNF mimetics were able to influence the degeneration of dopamine neurons in vivo. Because of the rather long duration of animal experiment and limited financing of research in this project we could only test GDNF mimetics from the first and second generation in animal model of PD. These GDNF mimetics required further improvement of biological activity and other properties. In the course of the project we also developed 3rd and 4th generation of GDNF mimetics. In in vitro experiments these later compounds showed superior activity in comparison to the 1st and 2nd generation GDNF mimetics. Although improved to some degree, the solubility of these compounds still remained poor. Therefore we examined the use of porous nanoparticles-based drug delivery system with promising results. We also found several new chemical scaffolds with GDNF-like activity. Overall, the general understanding of the relations of small molecule structure and GDNF-mimetic properties was achieved, which opens the possibility of developing further generations of the mimetics as well as studying other chemical domains for GDNF mimetic scaffolds.

Future steps

In the future we plan to evaluate the biological activity of 3rd and 4th generation of GDNF mimetics in animal models of PD and to optimize them further as needed. We expect 1-2 additional rounds of compound optimization and pre-clinical testing before they can progress to any clinical trials. We will also follow the biological activity of new chemical structures more closely and refine the predictive models for the construction of optimized structures. At the moment we are looking for partners and financing to continue the development.

We will continue publishing updates on the project on our Facebook page

GDNF mimetics team
team@gdnf.mimetics.eu