SPINAL MUSCULAR ATROPHY: STUDY OF THE IN VIVO AND IN VITRO EFFECT OF PHENYLBUTYRATE ON SMN2 GENE EXPRESSION

Spinal muscular atrophy (SMA) is caused by an insufficient level of the SMN protein which is produced by two genes called SMN1 and SMN2, respectively. SMA patients have no functional SMN1 gene but usually two to four SMN2 genes. Increasing the synthesis of functional SMN protein by these genes may constitute a therapeutic target for the disease. Recently, we have shown that treatment with the compound 4-phenylbutyrate (PBA) of cell cultures from SMA patients determines an at least 100% increase in SMN2 protein precursors in most of the 16 cell lines tested. The objectives of this project are to evaluate whether PBA is able to increase SMN2 gene expression in vivo and to gain insight into the mode of action of this compound. The in vivo effect of PBA will be assessed by a pilot clinical trial. TriButyrate®, a well tolerated FDA approved drug, will be administered to several SMA type II and III patients and the levels of SMN protein precursors will be determined. To investigate whether the number of SMN2 genes influences the extent of response in the PBA treated cell cultures, the number of SMN2 copies will be determined for all patients included in the study. The mode of action of PBA will be investigated by determining whether the compound activates SMN2 gene expression by changing the conformation of some proteins bound to the gene itself. Furthermore, molecular technologies will be employed to study the general effect of PBA on gene expression and to gain insight into the pathways leading to SMN2 gene activation by comparing gene expression in PBA-responding with the non responding cell cultures. This latter approach may also lead to the identification of other genes influencing SMN2 gene expression. The data obtained in this project should be useful for the design of therapeutic strategies for SMA.