Novartis identifies new SMN2 splice-modifying drug

16 June 2015

The pharmaceutical company Novartis has published new research that identifies a novel small molecule drug that is able to increase survival motor neuron (SMN) protein levels, and therefore has the potential to treat SMA.

The compound, which is called LMI070 (or NVS-SM1 in the publication), is able to affect the splicing of the SMN2 “backup” gene, causing it to produce more of the SMN protein that is lacking in patients with SMA.

Researchers at Novartis first highlighted LMI070 by performing a large-scale drug screen searching for substances able to enhance inclusion of SMN2 exon 7 (for further information on splicing, exons, and SMN2, click here). About 1.4 million compounds were initially tested in a nerve cell model before the most promising drugs were selected for further analysis. Once identified, LMI070 was tested in mouse models of SMA and shown to result in the production of greater amounts of SMN protein, leading to improvements in the body weight and survival of the SMA mice.

The study, which was published in the scientific journal Nature Chemical Biology, then went on to show that LMI070 is able to enhance the recruitment of molecules needed to correctly read and process the SMN2 gene. By doing this, LMI070 is able to increase the amount of full-length SMN protein made by the SMN2 gene.

Critically, LMI070 does not affect how all genes are handled. The drug is able to interact with a very specific DNA sequence found within the SMN2 gene. Fortunately, this section of DNA is found in only a very limited number of other genes. This selectivity is vital to reduce the chances of the drug causing disastrous side effects in humans.

In addition to being selective, LMI070 is orally available, meaning that it can be taken in tablet form. This would allow the drug to be easily and quickly administered if proven to be safe and effective in SMA patients.

Due to these positive pre-clinical results, Novartis are now testing LMI070 in a Phase II clinical trial that is being conducted at centres across Belgium, Denmark, Germany, Italy and the Netherlands. The study is open-label, will be conducted in SMA patients aged 6 months or less, and is designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of the drug (for further information on this trial, click here).

Further Information

Novartis article on LMI070 

Abstract from the scientific publication