Developing microRNA based therapy for Amyotrophic lateral sclerosis

The IMiDiaTALS project is to identify novel treatment strategy to treat Amyotrophic lateral sclerosis (ALS). The ambitious goal of the project will be attainable through the public-private partnership between UMCU and InteRNA. Both partners bring complementary background knowledge such as neurodegenerative diseases and stem cell research (UMCU) and preclinical animal models and market knowhow (InteRNA) that combined, enable maximum scientific, societal and economic impact of the project.

ALS is a chronic neurological disease without any cure. Life expectancy is short as patients die of respiratory failure within 3-5 years after symptom onset. Current therapies for ALS involve usage of small molecules targeting dysregulated pathways among the various cell types that only slow the progression of disease. Most people who develop ALS are between the ages of 40 and 70. It goes without saying, ALS has a huge impact not only on these patients but equally on the beloved ones of patients and caregivers. The direct economic burden is significant as this devastating disease comes with a high loss of productive years. The results from this project will potentially lead towards development of a new treatment paradigm that will provide clinicians with an additional source of therapy.

Our approach relies on cell-type specific targeting of a microRNAs (miRNA) deregulated in motor neurons (MNs) and microglia cells carrying ATAXIN2 and C9ORF72 patient mutations. To re-establish cellular homeostasis we will antagonise the expression of miRNA in individual cell types by generating adeno-associated virus (AAV)-based gene therapy tools. For our investigations, we will use patient-derived human induced pluripotent stem cells (iPSC) to generate human MNs in 2D and human microglia cells from cerebral organoids in 3D. In addition we will investigate the mode-of-action (MoA), biomarker potential and effect on rescuing disease phenotypes of the anti-miRNA sponge treatment.