PROTEIN KINASE D1 MODULATION THROUGH GENE THERAPY AS A NEW THERAPEUTICAL APPROACH AGAINST AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic Lateral Sclerosis (ALS) is the most common form of motoneuron (MN) disease estimated to affect ~3-4 new cases per 100,000 people every year in Europe. ALS is a devastating adult-onset neurodegenerative disease characterized by the degeneration of upper and lower MNs leading to weakness, muscle atrophy, progressive paralysis and finally patient death 2-5 years after diagnosis. Familiar ALS consists in heritable mutations in determined genes, representing 10% of cases, while the other 90% are known as sporadic ALS. Protein kinase D (PKD) is a serine/threonine kinase family conformed by three main isoforms, PKD1, PKD2 and PKD3. Extensive progress has been made to understand PKD structure, regulation, function and downstream signaling pathways. However, the role of PKD1 in MN diseases such as ALS remains unexplored. Despite the need for further research on PKD1 in neuronal tissue, some emerging evidence suggests that it could play a neuroprotective role in neurodegenerative diseases. Our results demonstrate that activation of PKD1 through phosphorylation is dysregulated in lumbar spinal cord of SOD1G93A mouse model and in human iPSCs-derived MNs (hiMNs) carrying ALS causing mutations. We hypothesize that maintaining high levels of activated PKD1 in spinal MNs may exerts a neuroprotective effect in ALS disease course. To test this hypothesis, we have designed a viral vector (AAV9-hSyn1-caPKD1) to overexpress active PKD1. First, we have tested the efficacy of AAV9-hSyn1-caPKD1 in rat SCOCs. Finally, our goal is to evaluate the therapeutic efficacy of this treatment in the SOD1G93A mouse model and in hiMNs carrying ALS causing mutations.