The science of gene regulation and discovering the therapeutic benefits of switching genes on and off with the help of stem cells and CRISPR-Cas9
CEO: Robert Gould
Based: Cambridge, MA
Clinical focus: Two monogenic diseases: fragile X syndrome and a form of muscular dystrophy called facioscapulohumeral muscular dystrophy
The scoop: Delivering on the promise of gene regulation and creating new medicines from this approach is no easy task, but newly launched Fulcrum, led by former Epizyme CEO Robert Gould, is looking to do just that in a pair of severe monogenic diseases with limited treatment options. The big idea is gene regulation: attempting to switch on and off certain genes using patient cells and CRISPR-Cas9--some of the most recent and innovative biology and technology brought together under one roof.
What makes Fulcrum Therapeutics Fierce: In a sentence: its targets, and its science. Starting with the targets, there are currently no treatments for fragile X syndrome (FXS) and facioscapulohumeral muscular dystrophy. In FSHD, patients will end up in a wheelchair and progressively become weaker, and nothing can help slow or reverse this process. Children with FXS often become institutionalized. FXS is the most common known inherited cause of learning disabilities, affecting around 1 in 4,000 males and 1 in 8,000 females. It can cause a wide range of difficulties with learning, as well as social, language, attentional, emotional, and behavioral problems. Some of these can be helped by approved meds, but the underlying cause of the condition cannot yet be treated.
On the science side, the biotech is looking to use pluripotent stem cells (aka iPS cells), derived from skin, to mimic the cellular processes that have gone wrong in these diseases with altered gene expression. It is working on using small molecules to modulate this in its first two targets.
Gould says: “Fulcrum is founded on the tremendous breakthroughs in the last decade or so in understanding the relationship in alterations in the human genome. This is probably best known in the oncology space and the rise of so-called personalized medicine. But what’s happened over the past few years is that we realized that this incredible insight applies across a broad spectrum of biology and not just cancer.
“This has created an opportunity in my opinion to control disease progression and affect by controlling gene expression. You can think of the genome as a static thing; it can cause changes in a protein, and then this can cause a disease, but in fact, it’s much more dynamic than that. There’s around 20,000 genes in the human genome, and within this there is a tremendous amount of gene regulation.
“So you can get genetic alterations in genes and proteins themselves, and what’s become clear in the last few years is that you can get changes in these regulatory elements that also cause a disease. So the explosion in understanding around this forms much of the basis on which Fulcrum has been created. So, can we alter gene expression and help restore normal function? That’s our plan.”
So how is it looking to do this? In FXS, the underlying genetic alteration here is a lack of production of a protein called FMRP. It’s not being produced in these patients because the gene has been turned off through alterations in regulatory components that control the expression of that gene.
“So here, what we’re trying to do is turn back on this gene that has been inappropriately turned off,” Gould explains. “And this comes from the work of one of our scientific founders, Michael Green from the University of Massachusetts.”
And then there is FSHD, which in many ways is the antithesis of the approach in FXS, where the biotech is looking to turn off a protein that has been switched on. “In that case, there is a protein called DUX4 which is being produced when it shouldn’t be, as it can be toxic.”
Gould says the time is right to take advantage of this emerging scientific understanding of the biologic mechanisms in gene regulation.
The biotech is currently working on biochemical targets, but it is all preclinical. “We’re not about to go into the clinic anytime soon as we of course only launched this year. But we do have targets and lead compounds,” Gould says.
In its early-stage work, Fulcrum is modeling gene regulation in disease tissue using patient cells that are either donated through tissue biopsy or derived from skin cells using the technology of induced pluripotent stem cells.
It uses screening tools, such as CRISPR-Cas9 and chemical probe libraries, to dissect gene regulatory mechanisms in cellular models of diseases. These discoveries are then brought together with publicly available gene regulatory data to create genome-wide maps of gene regulation that enable rapid identification of drug targets for the activation or repression of disease genes.
“If you flip the lens from the science of what we’re doing to how we’ll achieve this in technical terms, we are actually going to combine advances in two areas in biology, using both stem cells and CRISPR. Using this technology, we can ask very specific questions, such as: can we eliminate the activity of Protein ‘X,’ and when that activity is eliminated, does this increase or decrease things such as DUX4. CRISPR-Cas9 technology is the best way of asking these very pointed and specific questions in our models, such as what are the targets we can attack with small molecules to elevate or decrease the proteins of interest.”
Gould concludes: “The uniqueness of Fulcrum is really this combination of iPS cell mimicking gene biology with the understanding of what human biology is trying to regulate, in terms of gene expression, and combining that with the technology of CRISPR-Cas9 and using cells from the patients that we’re trying to treat. This all together is an unprecedented approach and opportunity.”
Investor: Third Rock Ventures