Antisense oligonucleotides (ASO) to increase progranulin production in frontotemporal dementia

Frontotemporal Dementia (FTD) is a debilitating disease that causes the individual to slowly lose their personalities, emotions, and control over social behaviors as disease progresses. FTD is caused due to significant neuronal loss in the frontal and temporal lobes of the brain. Though there is no treatment or cure yet for FTD, research has identified that the protein progranulin may be responsible for this neuronal loss, as a lack of progranulin has been linked to the degradation of neurons in FTD patients. Therefore, an effective treatment for FTD must aim to increase the production of progranulin in the brain. Previous research papers (Jiao J et al, 2010*) found that MicroRNA 29 (miR‐29) was responsible for regulating the translation of hPGRN (human progranulin) RNA through binding to the 3’UTR and preventing translation, suggesting that preventing miR‐29 from binding to the 3’UTR of hPGRN RNA should increase the overall production of progranulin. Antisense oligonucleotides (ASO) achieve this through binding to the hPGRN RNA and disrupting the binding site of miR‐29 and therefore preventing miR‐29 from binding. In our study, neuroblastoma cells were transfected with luciferase DNA as a surrogate measure of progranulin translation and then treated with increasing concentrations of M5 ASO and evaluated for luciferase expression. The results indicated that there was an increase in luciferase activity with the increasing concentrations of ASO, specifically concentrations of 10μM and 20μM which had a significant increase in progranulin production. Further tests were done in an attempt to confirm that the ASOs are working through binding to the 3’UTR and preventing miR‐29 from binding, however these tests came back inconclusive. These findings provide a beneficial insight into further development of these ASOs as possible treatments and therapies for FTD. *Jiao J, Herl LD, Farese RV, Gao FB. MicroRNA‐29b regulates the expression level of human progranulin, a secreted glycoprotein implicated in frontotemporal dementia. PLoS One. 2010 May 10;5(5):e10551