ALS-focused Trace Neuroscience launches with $100 million in capital

Trace Neuroscience, founded in January, has launched with $101 million raised in a series A financing round to advance its antisense oligonucleotide therapy (ASO) treatment for amyotrophic lateral sclerosis (ALS), a condition that many became aware of through the popular ice-bucket challenge.

The fundraising, led by Third Rock Ventures with participation from Atlas Venture, GV, and RA Capital Management, will help kick-start clinical trials, says Eric Green, founder and CEO of Trace Neuroscience. Its therapy aims to restore a key protein, UNC13A,which is often low or absent in ALS patients and has been linked to the progression of the disease.

Green previously cofounded Maze Therapeutics, which aims to create precision medicines based on human genetic data. When shortlisting diseases with the most significant impact on patients, Green put ALS at the top. Aaron Gitler, a professor at the Stanford School of Medicine studying neurodegenerative conditions, including ALS, became one of Maze’s scientific cofounders.

In the summer of 2020, Gitler, who was analyzing genetic data of ALS patients, had a breakthrough. According to Green, Gitler called him and said, “I think we have got it.”

Gitler had found a connection between UNC13A and another protein, TAR DNA-binding protein 43 (TDP-43). Meanwhile, Pietro Fratta of the Francis Crick Institute and University College London and Michael Ward at the National Institutes of Health made the same discovery independently. The four decided to join up, which led to the formation of Trace Neuroscience.

“The gene UNC13A was one of the first genetic associations with ALS discovered, but nobody understood how that association was working or what one could do to develop a therapy,” Green says. The link with TDP-43 was the missing piece of the puzzle.

In healthy brain cells, TDP-43 shuttles in and out of the nucleus, and when it is in the nucleus, it sits on UNC13A messenger RNA (mRNA) to ensure correct splicing. In the brains of people with ALS, TDP-43 remains stuck in the cytosol, and that leads to incorrect splicing of UNC13A mRNA. The mRNA becomes degraded, and no UNC13A is made.

“UNC13A is a critical protein for synaptic transmission and connection between neurons,” Green says. “When this protein is lost, it leads to paralysis and ultimately to respiratory failure as seen in ALS patients.” Trace’s ASO is designed to bind to UNC13A mRNA, mimicking the role of TDP-43 and restoring UNC13A protein levels.

The US Centers for Disease Control and Prevention estimates that 30,000 people in the US have the condition; an average of 5,000 cases are diagnosed each year. According to the ALS Association, the mean survival time of people with ALS is 2–5 years from the onset of the condition.

Although there is no cure for ALS, there are a handful of treatments on the market, most of which are small molecules. In 2023, the US Food and Drug Administration approved the first ASO therapy for ALS, Qalsody. It targets the mRNA of a different gene—superoxide dismutase 1 (SOD1)—which codes for an antioxidant enzyme.

Studies have shown that mutations in SOD1 result in cellular stress and the progressive development of ALS. But Green points out that SOD1 mutations are seen only in 2% of ALS patients. In contrast, low levels of UNC13A are implicated in 97% of ALS cases, making it a good target to treat a vast range of patients. “This really distinguishes us from other genetic therapy approaches out there,” he says.