Design and development of SINEUP non-coding RNA targeting human and murine alpha-amylase, to increase endogenous protein synthesis and degrade Lafora bodies in vitro.

Lafora disease (LD) is a severe genetic form of progressive myoclonus epilepsy, which affects children or adolescents and has a rapid and fatal evolution. LD is caused by homozygous or compound heterozygous alterations in either EPM2A or EPM2B genes. To date, there is no specific treatments available for LD, but a lot of progress have been made on the understanding of its pathological mechanism, also thanks to the development of disease-specific animal models. Loss of function alterations in these genes result in chemically-abnormal glycogen accumulation (polyglucan), called Lafora bodies (LB), in different tissues, such as brain, muscle, liver and skin. The clinical manifestations of LD are primarily due to pathologic neuronal storage of polyglucan. Since the unsolved issue is to find a way to either hinder polyglucan accumulation or to degrade LB, we aimed to ideate an innovative approach directed to foster the translation of the pancreatic alpha-amylase. This approach is based on the use of SINEUPs, synthetic small molecules potentially able to remove polyglucan accumulation. SINEUPs targeting both murine and human alpha-amylase has already been designed. We plan to validate alpha-amylase up-regulation in known low-expressing cell-line models. Moreover, LB degradation will be assessed in polyglucan accumulation-affected cell-line models. These data will pave the way to develop this methodology in vivo, using an adeno-associated virus as a delivery vector in a mouse model of the Lafora disease (already possessed by the PI).