BYLINE: Ian Demsky
Newswise — In everyday life, when things turn out the opposite of what you expect, it’s usually a cause for frustration. In science, it is often the starting point of a discovery.
That’s what happened to a team of researchers at Memorial Sloan Kettering Cancer Center (MSK) and their collaborators at the Icahn School of Medicine at Mount Sinai. Their unexpected laboratory findings point to an opportunity to improve therapies using small RNAs to silence disease-causing genes, potentially including those involved in cancer.
‘Sometimes you do an experiment,’ says developmental biologist Eric Lai, PhD. “You think you’re testing an idea, but when it doesn’t turn out the way you planned, it can lead you to come up with something else, much more interesting.”
In this case, the researchers — led by Seungjae Lee, Ph.D.postdoctoral researcher at MSK’s Lai Lab Sloan Kettering Institute – were testing how a protein called ALAS1 helps make small regulatory RNAs called microRNAs. When they removed the protein from the cells, they expected to see microRNA levels drop.
“But instead, we were surprised to see them increase,” says Dr. Lai.
This counterintuitive result led to the discovery of a previously unknown role for ALAS1 beyond its well-known role in heme production. (Heme is an important player in many biological processes, including the transport of oxygen – hence the name hemoglobin – in energy production and in the manufacture of microRNAs.)
The team the results were published in Scienceone of the most prestigious scientific journals in the world.
How few RNA snippets silence genes
MicroRNAs and the related class of small interfering RNAs (siRNAs) are small snippets of RNA – just 21 or 22 nucleotides long – that bind to and repress specific messenger RNAs (mRNAs).
There are a multitude of players that together convert longer RNA molecules into tiny active products, and one of the key takeaways is that scientists have harnessed this knowledge to turn small RNAs into drugs capable of silence genes responsible for specific diseases.
The first siRNA drug, patisiran, was approved by the US Food and Drug Administration (FDA) in 2018 to treat a debilitating genetic disease called hhereditary transthyretin amyloidosis. A handful of additional siRNA-based drugs have since been approved, and more are in clinical trials. Doctors see great potential develop siRNA drugs against rare diseases and more common diseases (siRNA drugs are sometimes called RNAi drugs, meaning they work by interfering with the accumulation of messenger RNA).
An enzyme in the dark
Back at the Lai Lab, Dr. Lee had discovered that by removing ALAS1 from cells, they produced more microRNAs. And further experiments showed that removing the other enzymes in the heme biosynthesis pathway did not affect microRNA levels.
“This showed us that ALAS1 had another role besides helping to make heme, which no one had realized,” says Dr. Lee.
“We can think of this as a function of ‘moonlighting’,” adds Dr Lai. “And here we discovered that ALAS1 has this secret role in regulating microRNAs that is not related to its normal role in heme synthesis.”
Potential to improve the effectiveness of siRNA drugs
The discovery led MSK researchers to team up with colleagues at the Icahn School of Medicine at Mount Sinai, who specialize in heme regulation and ALAS genes – Makiko Yasuda, MD, PhD, Robert Desnick, MD, PhDand postdoctoral fellow Sangmi Lee, PhD. This allowed MSK researchers to extend their findings from cell culture to custom animal models developed by the Mount Sinai group.
And in mice, again, deletion of ALAS (particularly in liver cells) led to an overall increase in microRNAs.
“The emerging situation is that ALAS acts as a brake on microRNA production,” explains Dr. Lai. “So we thought, now that we know how to remove this brake, maybe we could use it to improve the effectiveness of siRNA drugs and their ability to silence their target genes.”
In theory, this knowledge could help boost the activity of siRNA drugs against any problematic overactive genes in the disease, Dr. Lai says. Potentially, this could include oncogenes known to cause cancer.
“But we’re not there yet,” he says. “Therapeutic siRNA drugs do not work well enough against all targets and are currently limited in where they can be used in the body.” In fact, all six siRNA drugs approved by the FDA target hepatocytes in the liver.
“It’s easy to get drugs into the liver, which serves as a filter for the body,” explains Dr. Lai.
So, as a proof of concept, the team showed that not only could they deplete mouse liver cells of ALAS, leading to an increase in microRNAs, but this also improved the silencing activity of another siRNA model compound delivered to mice.
Coincidentally, one of six approved siRNA drugs deactivates ALAS1 to treat acute hepatic porphyrias. Dr. Yasuda and Dr. Desnick worked on the preclinical and clinical trials of the drug, known as givosiran. Since an siRNA against ALAS1 works effectively and safely in humans, this raises the possibility of combining such an agent to improve other siRNA drugs. Dr. Lai notes that this strategy could be generally applicable to any siRNA.
And if siRNA drugs could be improved, it could improve their cost-effectiveness, reduce side effects by making them effective at lower doses, and perhaps help target additional cell types beyond liver cells , he adds.
Why Discovery Science Matters
In December 2024, Gary Ruvkun, PhD, a geneticist at Harvard, was received the Nobel Prize with Victor Ambros, PhD, for their joint discovery of microRNA and its role in gene regulation in the early 1990s. At that time, Dr. Lai was doing his undergraduate thesis in Dr. Ruvkun’s laboratory (on another class of genetic regulators) and he credits it with launching his own career.
“I had my first real exposure to how science was actually done and developed a lifelong interest in developmental biology and small RNAs,” says Dr. Lai, adding that his mentor’s recent honor highlights the importance of curiosity-driven research.
“Dr. Ruvkun didn’t start out looking for microRNAs,” says Dr. Lai. “Like Dr. Ambros, he studied the development of nematodes, these tiny worms that live in the soil. And not only did it unveil a whole new paradigm for how genes are controlled, but the field they pioneered ultimately led to a new class of human therapies.
“When people ask why we don’t spend all of our research dollars directly studying diseases like cancer, why we fund research on the cells and processes of model organisms like fruit flies, yeast and bacteria , it’s a great example of how discovery science fuels the greatest advances,” he continues. “And I think it’s especially critical to keep this conversation active, given the uncertainty and. disagreements that exist within society and from government on how much public funding for scientific research should be provided and in what areas. Hopefully there will be continued support to keep the fundamental research engine strong.
Funding and disclosures
Research funding includes grants from the National Institutes of Health (R01DK134783, R01-GM083300, P30-CA008748); a pilot grant for Cooperative Centers of Excellence in Hematology (10040500-05S1); and a NYSTEM training grant (C32559GG).
The researchers have filed a patent application on their methods to improve the effectiveness of RNAi therapy by targeting ALAS1/ALAS2 (WO2024148236A1).
Drs. Yasuda and Desnick are also co-inventors on a patent for RNAi therapy for acute hepatic porphyrias. They also report on pharmacy consultancy work. Please see the study for more details.
Read the study: “Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA-mediated silencing“, Science. DOI: 10.1126/science.adp9388.