Study Finds How Branaplam May Work to Help Treat Huntington’s

Potential therapy reduces mutant huntingtin by interfering with mRNA splicing

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Branaplam (LMI070), an experimental oral therapy for Huntington’s disease that’s currently in early clinical trials, reduces levels of the mutant huntingtin protein by interfering with a process called mRNA splicing, a new study reveals.

“Here, we delineated the mechanism of action of Branaplam,” researchers wrote.

The study, “An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington’s disease patient neurons,” was published in Nature Communications.

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Branaplam originally developed for spinal muscular atrophy

Huntington’s is caused by mutations in the gene HTT, which provides instructions to make the huntingtin protein. Disease-causing mutations result in the production of an abnormally long version of this protein, which forms toxic clumps in nerve cells. Reducing levels of this toxic protein is widely seen as a potential treatment strategy.

Novartis’ branaplam is an orally-available small molecule originally developed for a genetic neuromuscular disease called spinal muscular atrophy. Its testing in SMA was based on branaplam’s ability to alter the alternative splicing activity of a gene called SMN2. However, Novartis announced in July 2021 that it’s stopping the clinical testing of branaplam for SMA.

Alternative splicing is a natural process that 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 called exons — can change the resulting messenger RNA (mRNA) and final protein. Of note, mRNA is the molecule derived from DNA that guides protein production.

During early testing in SMA, researchers found that the oral therapy also reduced levels of HTT’s mRNA. In subsequent studies, branaplam was shown also to decrease levels of mutant huntingtin protein in animal models.

Novartis is currently testing the therapy in a Phase 2 clinical trial called VIBRANT-HD (NCT05111249), though dosing was paused a few months ago due to possible neurological side effects.

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However, details of the therapy’s mechanism of action in Huntington’s remain unclear. To learn more, a team led by scientists in Germany conducted a battery of experiments in lab-grown cells derived from four Huntington’s patients and four healthy people.

Neurons and connective tissue cells were generated from induced pluripotent stem cells or iPSCs. iPSCs are derived from fully matured cells, such as those in the skin or blood, that are reprogrammed back to a stem cell-like state, where they can give rise to almost every type of human cell.

The team found that branaplam treatment led to the inclusion of an extra exon in the HTT mRNA in cells derived from both patients and healthy people. This extra exon makes the mRNA molecule unstable, and it ends up getting rapidly destroyed through a cellular waste-disposal system known as nonsense-mediated RNA decay.

This ultimately results in a reduction in the levels of HTT mRNA molecules, consequently lowering the production of huntingtin protein.

The researchers also found that lab-grown, patient-derived neurons showed widespread alterations in mRNA alternative splicing — more than 1,400 abnormally spliced exons — recapitulating the abnormal splicing events seen in the brains of Huntington’s patients.

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Branaplam helped restore alternative splicing in neurons

In addition to modulating HTT’s alternative splicing, branaplam treatment helped to restore alternative splicing: in treated neurons, about half of splicing events became comparable to those of neurons derived from healthy people.

“This suggests that Branaplam ameliorates a prominent molecular signature” of Huntington’s in patient-derived neurons, the researchers wrote.

Further investigation showed that these alterations were not a direct effect of the medication itself, suggesting that the induced reduction in mutant HTT mRNA and protein levels is what helps lessen abnormal alternative splicing in other genes.

“We show that aberrant AS [alternative splicing] is ameliorated following Branaplam treatment,” the researchers wrote.

“Our findings give only a glimpse into AS in HD, but show that iPSC … neurons may be a powerful model to study this distinct [Huntington’s disease]-associated [feature],” they added.

However, “there is an urgent need for future studies thoroughly dissecting the origin of aberrant AS” in Huntington’s disease, the team concluded.