A newly identified small molecule able to cross into the brain — named TEC-1 — significantly eased disease severity and prolonged survival in a mouse model of spinal muscular atrophy (SMA), a study from Japan reported.
But TEC-1 showed signs of better selectivity than Evrysdi, which might allow for higher doses to be given, increasing its therapeutic benefits without raising unwanted safety concerns, its researchers wrote.
More work is needed before similarities or superiority might be confirmed, as this molecule’s oral bioavailability — which determines dosing — was inferior to that reported for risdiplam in mouse model studies.
The study, “Discovery of a CNS penetrant small molecule SMN2 splicing modulator with improved tolerability for spinal muscular atrophy,” was published in the journal Scientific Reports.
While the gene therapy Zolgensma delivers to cells a healthy copy of SMN1, the mutated gene in SMA, both Spinraza and Evrysdi treat the disease by targeting SMN2, a gene that can partly compensate for the loss of SMN1-derived SMN protein.
SMN is found in virtually every cell in the body, but motor neurons — specialized nerve cells that control voluntary movement — appear to be highly SMN-dependent, dying without this protein. SMN deficiency and subsequent motor neuron loss lead to the progressive muscle weakness and atrophy that characterizes SMA.
Spinraza and Evrysdi increase SMN levels by correcting SMN2‘s “alternative splicing” — an event that limits to 10–15% the amount of working SMN produced through the gene. But each therapy does so through distinct mechanisms.
Alternative splicing allows for a single gene to give rise to many different proteins. Much like in a recipe, adding or removing certain key ingredients — in this case, pieces of genetic information — can change the resulting protein.
Unlike Spinraza, Evrysdi is an orally available, small molecule that can reach peripheral tissues through the bloodstream, and the cells of the brain and spinal cord by crossing the blood-brain barrier.
This barrier is a specialized membrane protecting the brain and spinal cord from viruses or other blood-borne insults by preventing larger molecules and harmful microorganisms circulating in the blood from entering.
Evrysdi has a high specificity to SMN2, affecting the splicing of only a few other genes. FOXM1, a gene involved in regulating cell division, was a main safety concern for Genentech, as risdiplam at high levels did affect FOXM1 splicing, resulting in the production of a protein that halted cell division and affected chromosome stability.
The company responded by putting in place a strict monitoring program to ensure that Evrysdi at ideal doses would be below that threshold to not affect cell division. Clinical evidence to date strongly supports its favorable safety profile.
However, an oral SMN2 splicing modifier with fewer off-target effects could potentially allow for higher doses to be given to patients, carrying greater benefits without worrisome side effects.
The team began by screening more than 300 potential compounds in lab-grown cells, collected from an SMA type 2 patient, to identify SMN2 splicing modifiers with higher selectivity. They named the small molecule spotted through this work TEC-1.
TEC-1 was found to correct SMN2 splicing at levels similar to those achieved with Evrysdi, or with a risdiplam-like molecule referred to as SMN-C3.
The researchers then evaluated TEC-1’s effects in the splicing of three genes previously identified as off-targets of risdiplam and similar molecules — the FOXM1, GALC, and HTT genes — in the patient-derived cells. (Of note, GALC is involved in the breakdown of certain fat molecules, while HTT is thought to be key for nerve cell survival.)
TEC-1 promoted no or weaker changes in the genes’ splicing, compared with risdiplam and SMN-C3, showing “improved selectivity toward SMN2 splicing over three representative secondary splice targets,” the researchers wrote.
Further analysis showed that the molecule weakly affected the activity of a separate gene, ACHE, but at doses much higher than those needed to correct SMN2 splicing. It also effectively crossed the blood-brain barrier and showed favorable pharmacokinetics (movement into, through, and out of the body).
“Our findings demonstrate that TEC-1 is a key member of a class of compounds with a low risk of acute and chronic side effects for SMA treatment,” the researchers wrote.
TEC-1 was also found to effectively correct SMN2 splicing and increase SMN levels in motor neurons generated from induced pluripotent stem cells (iPSCs) derived from the same SMA patient. (iPSCs are derived from fully matured cells that are reprogrammed back to a stem cell-like state, where they can give rise to almost every type of human cell.)
Mice in a model of severe SMA treated with TEC-1 also showed significantly improved motor function and survival. However, the researchers noted, the molecule appeared to have lower oral bioavailability than did risdiplam in similar mouse models.
These findings suggest that TEC-1 is a disease-modifying therapy with a “potentially higher therapeutic window” than Evrysdi and similar molecules, the researchers wrote.
“TEC-1 may have promising therapeutic potential for SMA, and our study demonstrates the feasibility of RNA-targeting small-molecule [therapy] development with an improved tolerability profile,” they added.
These researchers now plan to improve TEC-1’s oral bioavailability, and assess whether optimized formulations will result in greater therapeutic effects than did risdiplam in preclinical studies. Further work is also needed to characterize the molecular mechanism of TEC-1.