A new drug candidate for SMA therapy

A new paper published in Human Molecular Genetics from the Laboratory of Dr. Brunhilde Wirth at the Institute of Human Genetics of the University of Cologne, Germany, entitled “LBH589 induces up to 10-fold SMN protein levels by several independent mechanisms and is effective even in cells from SMA patients non-responsive to valproate”, investigate the novel histone deacetylase inhibitor LBH589 as a putative drug for SMA therapy.
Histone deacetylase inhibitors (HDI) are potential candidates for therapeutic approaches in cancer and neurodegenerative diseases such as spinal muscular atrophy (SMA). Among the compounds which have been evaluated for SMA therapy within the past years HDI turned out to efficiently activate SMN2 expression thereby compensating for the loss of SMN1. Well investigated HDIs are valproate (VPA) and phenylbutyrate. However, clinical trials demonstrated effectiveness of the valproate and phenylbutyrate only in <50% of patients, therefore the identification of new drugs is of vital importance.

The research reports on hydroxyamic acid LBH589, a novel HDI (panobinostat), which has received orphan drug status for the treatment of cutaneous T-cell lymphoma by the FDA in 2007. Nowadays, further phase I and II clinical trials are ongoing to assess the anti neoplastic efficacy of LBH589 in diverse types of cancer.
In order to evaluate the potential of LBH589 in SMA therapy, the researchers treated skin cells (fibroblasts) from SMA patients with LBH589 and were able to detect 6 to 10-fold increased SMN protein amounts after treatment with LBH589. It is noteworthy that this is the highest increase in SMN protein reported so far and that it is achieved at comparable low doses. Most importantly, LBH589, which was well tolerated in all experiments, also induced SMN2 expression in fibroblast cell lines from SMA patients inert to valproate.
In conclusion, the novel HDI LBH589 is a highly promising candidate for SMA therapy which induces high SMN amounts by several different mechanisms.

(source: Human Molecular Genetics)