Jaan-Olle Andressoo

Gene knock-up via 3’UTR targeting to treat Parkinson’s disease

Parkinson’s s disease (PD) affects 1% of elderly persons and is currently incurable. PD pathogenesis is driven, at least in part, by defects in proteostasis and mitochondrial function, leading to degeneration of dopaminergic axons and neuronal death. Neurotrophic factors (NTFs) can protect and restore dopaminergic axons. However, attempts to deploy NTFs ectopically in therapy models, or to increase proteostasis and mitochondrial function, have met with only limited success.

The project hypothesised that instead of ectopic application, over-expression of relevant pathways restricted to physiologically appropriate cells provides a potent therapeutic approach to treat PD. Prior to the project, Andressoo had already shown that elevation of endogenous GDNF levels protects mice from experimentally induced PD. The project focused on the use of 3’UTR targeting to study the therapeutic potential of overexpressing endogenous genes using transgenics and CRISPR-Cas9-mediated 3’UTR editing in adult mice.

Results

The central yet unresolved question is how to link genome-wide association study (GWAS) data to phenotypes/diseases. It is clear that in most cases, it must come from fine-tuning the levels of certain proteins; however, we currently lack the tools to do that for most of the 20,000 proteins. This study focused on analysing and editing regions before and after protein-coding regions in genes called untranslated regions (UTRs) of the genes. After five years of work, it became clear that the chosen approach, as well as the available knowledge about UTRs, is not complete. The team was able to engineer one UTR but not all UTRs successfully, as was predicted prior to the start of the project. Much more work is needed before control is gained over protein expression levels. The suggested approach for PD did not work. However, it led to understanding how a subgroup of schizophrenia patients may develop the disease, as well as pointed the way to the treatment target.

Impact

We need to learn to control the levels of all proteins in our bodies to understand and treat diseases. Since we are built of about 20,000 proteins, it is not hard to see how vital this knowledge is to us. The project revealed that the individual level of one of those 20,000 proteins, called GDNF, regulates many diseases during development and adulthood. These include, but are not limited to, kidney malfunction, a schizophrenia subtype, and gut function. The results of the project illustrate how basic studies of gene regulation can lead to insights into diseases and thereby to new knowledge important for developing novel treatments.

The efforts are ongoing as Andressoo continues his study on gaining control over protein expression levels. He currently has a Business Finland Research to Business grant, as well as several others, including a precision medicine drug development project to devise treatment for a sub-group of schizophrenia patients, which Andressoo team pushes forward in collaboration with a number of expert teams. The ERC grant as seed funding made the expansion of this research possible.