Modulation of SMN2, the ‘Back-Up’ Gene: Through Small Molecules
Modulation of SMN2, the ‘Back-Up’ Gene: Through Small Molecules
Page last checked: 20th March 2023
Last updated: 23rd February 2023
For our lower motor neurons to function and remain healthy, our cells need to produce the survival motor neuron (SMN) protein. The ability to do this is mainly controlled by the survival motor neuron 1 (SMN1) gene.
The SMN2 gene also contributes to the production of SMN protein, though it only makes approximately 10% of that produced by SMN1. For this reason, SMA is caused only by mutations in the SMN1 gene and not SMN2, and also why SMN2 is often called the SMN ‘back-up’ gene.
Anyone who has SMA has at least one copy of the SMN2 gene. Individuals can have multiple copies of SMN2, and, in general, it seems that those with more copies have a less severe form of SMA.
Most of the SMN protein made by SMN2 (about 90%) is missing an important piece called exon 7. The remaining 10% of the protein produced by SMN2 includes exon 7 and is the same as that made by SMN1. A number of treatment strategies that target SMN2 to make more functional SMN protein are being explored; they aim to do this in one of three main ways:
- Correct SMN2 splicing, allowing SMN2 to more efficiently produce functional SMN protein.
- Increase the protein production from SMN2 leading to more functional SMN protein.
- Stabilise the functional SMN protein made by SMN2 and therefore make it last longer.
Small molecules are chemicals or compounds that are capable of treating or even curing a disease. These potential drugs may be used to increase the amount of SMN protein made by SMN2.
A multi-step process is used to convert small molecules into drugs:
- Researchers screen hundreds of thousands of chemicals through a process called ‘high-throughput screening’ in their search for a chemical that that might work for SMA, i.e. one that increases SMN protein levels.
- Using medicinal chemistry, scientists then modify the chemical numerous times trying to optimise its structure to make a safe and useable drug.
- These ‘optimised candidate drugs’ are then tested in animal studies for their efficacy and safety before they are trialled on humans.
- Successful optimised candidate drugs are then redefined as an ‘Investigational New Drug’ (IND) and an application is submitted for it to be approved for human clinical trials.
A number of companies and academic laboratories have small molecule programmes that are attempting to identify and develop compounds that target the SMN2 gene.
For an up to date view of progress see:
During this time, there have been phenomenal developments using this treatment approach – notably with risdiplam. You can follow this link for for further updates about this drug. Other new drugs with this treatment approach is tracked below.
23rd February: An interim analysis of data from the JEWELFISH Trial was published in the scientific journal, Neurology and Therapy.
17th March: The latest risdiplam (Evrysdi) data updates were presented virtually at the 2022 MDA Clinical and Scientific Conference on 13th – 16th March. These were for the SUNFISH and RAINBOWFISH trials.
To date, more than 5,000 people had been treated with Evrysdi in clinical trials, compassionate use or real-world settings. Roche leads the clinical development of Evrysdi as part of a collaboration with the SMA Foundation and PTC Therapeutics.
21st July: Novartis discontinues the development of branaplam (also known as LMI070) for the treatment of SMA. They explain that their decision was "made as the result of rapid advancements in the SMA treatment landscape in recent years."
As the decision was not driven by any safety or efficacy issues, Novartis encouraged patients currently receiving branaplam through trials to continue their treatment until an alternate solution is arranged for ongoing care.
14th June: Preliminary results from the RAINBOWFISH and JEWELFISH trials were presented at the Cure SMA 2021 Virtual SMA Research & Clinical Care Meeting, which took place from 9th to 11th June 2021.
19th April: Roche presented new two-year data from part 2 of its FIREFISH study at the 73rd American Academy of Neurology (ANN) Annual Meeting held virtually 17th – 22nd April 2021.
17th March: Roche shared new, 2-year, longer-term data from part 2 of the SUNFISH trial at the 2021 Muscular Dystrophy Association Virtual Clinical & Scientific Conference.
February: Data from part 1 of FIREFISH, a dose-determining study, were published in the New England Journal of Medicine.
October: Data on Part 1 of the FIREFISH trial presented at the virtual 25th Annual Congress of the World Muscle Society showed that infants treated with the therapeutic dose of risdiplam continued to improve and achieve motor milestones.
16th June: Roche presented two-year data on Part 1 of the SUNFISH trial, at the virtual Cure SMA Annual Conference.
6th February: Roche presented 1-year data from the pivotal Part 2 of their SUNFISH trial at the 2nd International Scientific and Clinical Congress on SMA in Evry, France.
15th January: Novartis reported that their study of branaplam (LMI070) was progressing well with 29 infants receiving the treatment. Infants who were enrolled into Part 1 of the study had been receiving branaplam for between approximately 4 and 5 years. Participants in Part 2 have been on study treatment for between 7 and 19 months. Part 3 of the study to assess the long-term safety, tolerability and effectiveness of extended treatment with branaplam was planned.
12th November: Roche announced positive data from part 2 of the SUNFISH trial.
May: At the 2019 American Academy of Neurology Annual Conference, Roche presented positive data from its SUNFISH study and reported that enrollment for the FIREFISH study was now complete with preliminary results expected in early 2020.
14th June: Roche announced all available screening slots in SUNFISH had been allocated by the active study centres, which meant that no new sites and countries would be activated for SUNFISH. This included the UK
June: PTC Therapeutics presented preliminary data at the 2018 Cure SMA conference in Dallas indicating that risdiplam appears to be well tolerated at all doses tested and to date has not caused any drug-related adverse events causing patient withdrawal from the trial.
August: Roche had begun to enrol SMA patients in the FIREFISH Phase II trials of their splice-modifying drug, RG7916 (also known as RO7034067) in the US, Belgium, Italy, Switzerland, and Turkey
11th July: PTC Therapeutics presented an update on their SUNFISH trial of their splice-modifying drug, RG7916, at the 2017 Cure SMA Conference in Orlando, USA.
27th September: Roche have announced that they were to begin recruiting SMA patients to the FIREFISH and SUNFISH.
18th August: In May 2016, safety concerns with the treatment LM1070 caused Novartis to pause enrolment in the trial. Animals treated with LMI070 every day for a year (as a safety precaution) showed unexpected complications with their blood vessels, kidneys, spinal cord and peripheral nerves, such as the motor neurons (click here for more information). In addition to pausing enrolment, as an added precaution Novartis have lowered the dose of LMI070 for patients already enrolled in the study.
16th June: Novartis published new research identifying LMI070 (or NVS-SM1 in the publication) as a candidate for development by performing a large-scale drug screen searching for substances able to enhance inclusion of SMN2 exon 7. 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. The study was published in the scientific journal Nature Chemical Biology.
15th May: Roche, PTC Therapeutics, and the SMA Foundation announced that due to safety concerns, administration of RG7800 in the trial named Moonfish had been immediately suspended as a precautionary measure. In long-term experiments in mice, unexpected side-effects had been reported in the eyes of treated animals.
26th November: PTC Therapeutics announced that its SMN2 splice-modifying drug, RG7800, had entered a Phase Ib/IIa clinical trial in adults and children with SMA.
13th August: Researchers in the US identified three new, orally available compounds named SMN-C1, SMN-C2, and SMN-C3 – read more.
30th January: PTC Therapeutics announced a Phase I clinical trial of its selected drug in healthy adult volunteers The PTC compound was at this stage the fifth drug in clinical development for SMA.
19th August: PTC Therapeutics announced that it had selected and would continue to develop a candidate drug that has the potential to treat SMA.
Drugs using this treatment approach being investigated in 2013:
- Novartis (pre-clinical)
- Paratek (pre-clinical trials of tetracycline)
- CALIBR (pre-clinical focusing on optimising chemical properties of small molecule enhancers of SMN protein, led by Peter G Schultz)
- Rubin lab at Harvard University (pre-clinical focusing on small molecule drug screening in motor neurons, led by Dr Lee Rubin)
- Androphy lab at Indiana University (pre-clinical)
- Pfizer (Phase 1 trials of RG3039, a.k.a. Quinazoline)
27th September: Repligen Corporation initiated a Phase Ib clinical trial of RG3039 which had US Orphan Drug and Fast Track status. Researchers at the Jasper Clinic in Kalamazoo, Michigan aimed to study further the safety and pharmacokinetics of the drug. RG3039 was licensed by Repligen in 2009 from Cure SMA.