Can a wealthy family change the course of a deadly brain disease?

Robin Richards Donohoe, a venture capitalist in Silicon Valley, remembers 2005 as the year her charming, outgoing mother, Alice, “just went mute.”

Alice Richards was a born communicator, a journalism major, and mother of seven who, as her husband’s company helped bring electricity to the rural South, threw her energies into countless civic and philanthropic causes. She could give a stirring speech, her family members recall. But as Alice entered her 70s, her words began to slip away.

Like her father and sister before her, Alice had been struck with frontotemporal dementia (FTD). Fast-progressing and fatal, this deterioration in the frontal and temporal lobes of the brain is the second most common form of dementia after Alzheimer’s disease in people younger than 65. About 40% of cases are caused by known inherited genetic mutations. In 2006, mutations in GRN, a gene that codes for a protein called progranulin, were found to be a major cause of familial FTD. Alice and her relatives, it turned out, had one of them.

After Alice’s death in 2007, her children decided to commit some of the family fortune to supporting progranulin research, as a “gift to our family and the world,” Richards Donohoe says. With her brother-in-law Bob Farese Jr., then an endocrinology researcher at the Gladstone Institutes, she founded a nonprofit research consortium, later named the Bluefield Project after Alice’s hometown in Virginia. The organization would go on to pour tens of millions of dollars into science that helped establish progranulin as essential for quelling inflammation and recycling waste in the brain—as well as a potential key to treating FTD and other neurodegenerative diseases.

“Bluefield has been transfor­mative—truly—for FTD research over the past 10 to 15 years,” says neuro­logist and dementia researcher Bradley Boeve of the Mayo Clinic, who has not been part of the consortium.

Bluefield investigators, and eventually drug companies, saw something compelling about FTD-GRN, the form of the condition Alice had. In other genetic neurodegenerative disorders, such as familial Alzheimer’s and Huntington disease, mutations spark the production of toxic proteins, generating complex cascades of pathology. But the culprit mutations driving FTD-GRN block progranulin production, leaving carriers with less than half as much of the protein as noncarriers. Many dementia researchers came to describe FTD-GRN as a “low-hanging fruit” among neuro­degenerative diseases, using words such as “intuitive” and “tractable” to characterize its biology. The solution seemed obvious: A treatment just needed to raise progranulin levels in the brain.

Fueled in part by that confidence, six clinical trials have been launched to test progranulin-boosting therapies in FTD-GRN. Companies also hope the anti-inflammatory properties of a progranulin-boosting agent could help in Parkinson’s disease, Alzheimer’s, amyotrophic lateral sclerosis (ALS), and FTD caused by other mutations or without a known genetic cause.

All has not gone according to plan, however. In October 2025, a landmark phase 3 clinical trial of a progranulin-boosting drug in people with FTD-GRN did not keep their disease from progressing. In February, a small trial of a gene therapy delivering a healthy copy of GRN to the brain was halted, also for lack of effect.

Most scientists affiliated with Bluefield still think a therapy could work, as long as progranulin gets into brain cells in patients whose disease is not yet too advanced. Still, the trial failures have cast a pall over what had been, until recently, an unusually optimistic corner of neurodegeneration research. And they have raised a pointed question for the field: Can any neurodegenerative disease truly be called a low-hanging fruit?

“Progranulin is a good target to bet on, and we’re all very hopeful,” says Farese, now at Memorial Sloan Kettering Cancer Center. “But it may or may not work. The history in the last 30 years or so is pretty humbling. Neurodegenerative diseases are hard.”

The first Bluefield meetings often felt like family gatherings. Farese and Richards Donohoe, intent on forming a trusting, close-knit research community, recruited heavily from Gladstone and the University of California San Francisco (UCSF). They hosted the scientists in their Bay Area homes, with pets and kids running freely as data were presented. Richards Donohoe says she aimed to foster “a unique culture of warmth and gratitude” that made scientists want to collaborate rather than compete.

Rosa Rademakers, a geneticist at the University of Antwerp who was among the first researchers funded by Bluefield, recalls feeling inspired by the coziness and camaraderie. “We didn’t have to get a million dollars,” she says. “It was OK to get maybe a smaller grant. We wanted to come twice a year to be part of this community.”

Always present at these gatherings was the threat of FTD-GRN to the consortium’s funders and their loved ones. (Richards Donohoe says she and three siblings have been tested for GRN mutations as part of studies, but most have not opted to learn whether they are carriers.) “If you work in the field with these families, you develop a relationship, a sense of responsibility,” says neurologist Bruce Miller of UCSF, who, along with fellow neuroscientists Lennart Mucke of Gladstone and Joachim Herz of the University of Texas Southwestern, helped Farese set the group’s research priorities. “Here was this beautiful family that really wanted to find a cure. And none of us scientists wanted to let them down.”

Unlike Alice, not all FTD patients lose their speech. More often, they show stark and bewildering personality changes. Some “may have completely lost the ability to care about people,” says physician and neuroscientist Adam Boxer of UCSF, who, like Miller, has treated generations of FTD families. And in inherited cases—linked to mutations in one of three major genes, including GRN—the illness tends to strike a family again and again. “It’s a terrible neurodegenerative disease, horrible,” Boxer says. “Much worse than Alzheimer’s.”

For the nascent Bluefield team, the first step in fighting FTD-GRN was to get a handle on progranulin’s function. A handful of papers suggested the protein was active in wound healing and possibly a promoter of tumor growth. Its role in the central nervous system, where it is expressed by neurons and brain immune cells called microglia, had yet to be explored.

In a lab at UCSF, working closely with neuropathologist Eric Huang, Farese created lines of mice that produced little or no progranulin. They found that at 1 year old, the mouse equivalent of middle age, the animals developed inflammation in the thalamus, the sensory hub of the brain. (A parallel pattern was later observed in brain scans of people with FTD-GRN.)

As they aged further, the mice developed problems with balance and coordination and began to groom themselves compulsively, causing fur loss and skin sores. By 19 months, “They’re just very, very miserable and have to be euthanized,” Huang says. Although the animals’ symptoms didn’t exactly match those seen in humans, the experiments established a link between abnormal behavior and progranulin deficiency in mice.

When Huang injected mice lacking progranulin with a toxin used in experiments to induce neurodegeneration, they showed much more severe inflammation in their brains and more neuron loss than control mice. Microglia, which normally help maintain neurons by trimming the fine projections that connect them to other cells, began to aggressively overprune these synapses. “It was the first evidence that progranulin plays an important role in microglia,” says Huang, who is now at Washington University in St. Louis. Li Gan, a neuroscientist then at Gladstone, found that removing progranulin from microglia alone was enough to induce severe disease in mice.

Another major breakthrough came with the 2012 discovery of a rare condition in two siblings whose parents hailed from northern Italy—a region that had been identified as a hot spot of FTD-GRN. As young adults, both siblings had developed a fatal neurodegenerative disorder called neuronal ceroid lipofuscinosis. Lysosomes, organelles that handle lipid recycling, malfunction in the disease, leading lipid waste to accumulate in the brain and retinal cells. It turned out that both siblings had inherited a mutation in both their copies of GRN. That startling finding suggested lysosomes and brain lipids might play a central role in FTD-GRN.

Progranulin research, some of it funded by Bluefield and some occurring independently, began to take off. Researchers identified an abnormal buildup of lipid wastes in the brain and retinal cells of people with just one GRN mutation. Rademakers and others documented how a protein called sortilin carried progranulin to lysosomes, where, once inside, it was cleaved into smaller peptides called granulins that did the work of lipid recycling. Farese, an expert in lipid metabolism, got to work understanding the lysosomal wastes that accumulated with progranulin deficiency, and eventually found one type, called gangliosides, to be prominent.

Some 10 years after Bluefield’s founding, a hypothesis had emerged about what went wrong in FTD-GRN: Lysosomes naturally weakened by age malfunctioned, filling neurons with lipid wastes. Progranulin-deficient microglia, instead of coming to the stressed neurons’ aid, made matters worse, attacking synapses and shooting out inflammatory proteins. TDP-43, a protein normally restricted to the cell nucleus, aggregated and spread, doing more damage to neurons (see graphic, above).

The Bluefield-funded effort “opened the door to understanding this really interesting protein,” Miller says. “And it led in directions that I never, ever would have imagined.”

Beginning around 2013, as the biology of FTD-GRN was still being untangled, the consortium set out to put the disease on drug companies’ radar. Over 5 years the group’s director, veteran biotech researcher Rodney Pearlman, and Laura Mitic, its scientific director, met with 40 teams—from established giants to biotech startups so new they were still ­unnamed—to pitch them on progranulin.

They argued FTD-GRN was a tractable problem, and that as a treatment strategy, “elevating progranulin makes a lot of sense,” says Mitic, now the group’s director. One advantage of progranulin was that the protein could be made by one type of cell and taken up by another, meaning a therapeutic approach did not have to target a single cell type. Adding further enticement, Bluefield offered the companies free use of its data. “That was the best decision we made,” Pearlman says. “To give everything away.”

By the early 2020s, several companies had progranulin therapies in the pipeline. But they faced a problem: a dearth of patients to study. Many people are unaware that they carry GRN mutations, and by the time they are diagnosed with FTD-GRN, they often have advanced disease, making them poor candidates for trials.

Bluefield had always planned to exit the scene once progranulin research was established. The founders’ resources were not infinite, and Richards Donohoe believed strongly in deadlines. But “we realized that in order ultimately to be successful, Bluefield needed also to engage and support clinical trials,” Mitic says.

Bluefield’s board voted to wind down basic science in favor of funding the kind of ancillary studies that might help trials succeed. The group launched brain imaging and blood marker studies to gauge how fast the disease progressed and when treatments might work best. It also backed efforts to find families affected by GRN mutations, set up free genetic testing, and supported campaigns to improve awareness of genetic FTD.

The decision to pivot from basic research left Farese uneasy. He felt that the field still needed to learn more about how FTD-causing mutations trigger disease. And he wanted to explore ways to promote neuronal recovery and repair—not just restore missing progranulin. With his brother-in-law Roy Richards, a longtime Bluefield board member, he would eventually form a new nonprofit to pursue those goals.

The split was amicable, all parties say. But it reflects important differences in opinion that have emerged of late about progranulin as an exclusive disease target.

“It could take 100 targets to find [a drug] that works,” Farese says, “and right now we’re only working on one.”

Pearlman sees it differently. “Academics like to fill in the whole jigsaw puzzle,” he says. “And when you work in industry, you’ve got to say, ‘Well, I can sort of see it’s a picture of a fishing boat. I’m going to move.’”

Moving ahead meant certain key questions—which cell type and disease stage to target, which part of the brain offers the best spot to deliver a gene, and whether boosting progranulin levels might produce unintended effects in the body—would have to be answered by trials.

Three trials launched to test gene therapies, which use an adeno-associated virus (AAV) vector to deliver a healthy copy of GRN either to the fluid-filled space at the base of the brain called the cisterna magna or to the thalamus, deep in the center of the brain. “We chose the thalamus because it is connected to every single part of the brain,” says neurologist Chris Shaw of the U.K. company AviadoBio. “Our question is, can we ask the [neurons of the] thalamus to be the factory to make progranulin? Will it be trafficked up the axons into the cortex, secreted at synapses, and taken up by other cells?”

The trial is small because “nobody would have brain surgery without good reason,” as Shaw acknowledges, and because all gene therapies come with significant risks, including toxicity. (Some therapies delivered to the bloodstream face concerns about tumor-promoting effects, but those concerns aren’t thought to apply to the brain.)

Denali Therapeutics, a company in San Francisco, is testing an intravenous infusion that delivers lab-grown human progranulin, attached to an antibody fragment designed to shuttle it across the blood-brain barrier and into the brain. Neurologist Richard Tsai, a former UCSF researcher now at Denali, notes that the antibody fragment targets receptors present on both neurons and microglia. The trial, Tsai says, will “directly [answer] the question: If you get enough progranulin into cells all over the brain for a consistent period of time, does that help?”

A third strategy is to block the receptor sortilin, which takes up and degrades progranulin, so that more of the protein is available in the fluid surrounding cells. A sortilin-targeting antibody developed by San Francisco–based Alector raised progranulin in the cerebrospinal fluid of people with FTD-GRN. But as the company reported in October 2025, this didn’t slow disease progression.

The failure of that trial—the first phase 3 trial in genetic FTD—came as a blow but not necessarily a shock: Several scientists had predicted that an antibody degrading sortilin, which transports other essential proteins in the neuron, could backfire. (A Danish company continues to test a small molecule that blocks sortilin’s binding to progranulin without compromising its other functions.)

Then last month came another blow: Prevail Therapeutics and Eli Lilly halted a trial of a GRN-carrying AAV vector and abandoned the therapy, citing a lack of efficacy.

Boxer, who is a principal investigator on several FTD studies, notes that the gene-therapy trial was small, making anything less than a dramatic improvement hard to detect. “It remains possible that the therapy could have worked if it were delivered earlier, or in a population that was selected differently,” he says.

Some are enthused about an emerging approach—yet to be tested in people—consisting of stem cells that differentiate into progranulin-overexpressing microglia once inside the brain. Microglia naturally make more progranulin than any other cell type, including neurons—plus they’re mobile in the brain, and unlike neurons, can multiply, says Gan, now at Weill Cornell Medicine. The goal is a therapy that would “harness progranulin’s superpower and microglia’s superpower and combine them.”

Sponsoring company	Strategy	Route of administration	Planned participants
Denali Therapeutics/Takeda Pharmaceuticals	Progranulin ferried to brain by an antibody fragment	Intravenous	85
Vesper Bio	Small molecule that blocks sortilin	Oral	6
AviadoBio	Adeno-associated virus (AAV) delivering functional GRN	Injection to the thalamus	9
Passage Bio	AAV delivering functional GRN	Injection to base of brain	30
Prevail Therapeutics/Eli Lilly*	AAV delivering functional GRN	Injection to base of brain	35
Alector*	Antibody that blocks sortilin	Intravenous	119

In mouse experiments, Gan and her colleagues have depleted natural microglia with a chemotherapy drug and then injected engineered microglial precursor cells into the brain, where they rapidly colonize it. The intervention “works like a charm” to alleviate FTD-GRN pathology, Gan says, and a single treatment lasts for the life span of the mouse.

In northern Italy, stem cell researcher Alessandra Biffi is working with a company called Orchard Therapeutics on a similar approach, testing two different modes of delivery: infusing the cells into the bloodstream or injecting them into the brain. In January, Biffi and her colleagues at the University of Padua reported that both methods restored defective lysosomes and reversed pathological behavior in mice lacking progranulin.

The Bluefield project has always been laser focused on curing FTD-GRN, but its researchers have long suspected progranulin could treat other disorders marked by neuroinflammation and lysosomal dysfunction—including Alzheimer’s.

Back in 2014, Gan and Farese showed that depleting progranulin in microglia worsened symptoms and biomarkers in a mouse model of Alzheimer’s—and that raising the levels alleviated the symptoms. Epidemiological data echo those findings. Rademakers and others found that people with genetic variants that reduce progranulin are at higher risk for a wide range of neuro­degenerative diseases. Similarly, Miller says, “We see a lot of people who get Alzheimer’s disease on top of the fronto­temporal dementia.”

Gan and her colleagues are now testing their progranulin-overexpressing microglia in models of other diseases. Sarah Naguib, a postdoctoral researcher in Gan’s lab, reported at the Society for Neuroscience meeting in San Diego in November 2025 that in mouse models of Parkinson’s, the transplants relieve motor symptoms associated with alpha-synuclein, the signature protein in Parkinson’s, and protect against neuronal death. “In the field of neurodegeneration, the ideal scenario is that we can find things that would be broadly applied to multiple diseases,” Naguib says. Alector, which shelved its FTD-GRN program after the trial failure, continues to test a progranulin therapy in people with Alzheimer’s.

Shaw says that although he agrees progranulin therapy could eventually have a range of indications, FTD-GRN remains the right place to start. “If we can do it safely and effectively in this context, definitely there’s an opportunity in other disorders. But we need to get there first.”

As the four remaining clinical trial programs press ahead, Bluefield is still advancing studies of biomarkers and seeking eligible patients to funnel into trials. Despite the two failures, Richards Donohoe is optimistic a progranulin-boosting therapy will pan out. “You have to have a lot of shots on goal,” she says.

The nonprofit Farese and Richards founded this year, called Kestrel ­Neuroscience, has just begun to award its first grants on basic research into alternative targets for FTD-GRN.

Gone are the cozy gatherings where scientists swapped basic research findings and shooed the household cats off their chairs. But Bluefield alumni say the family that bolstered their science still inspires them to keep investigating FTD-GRN. Rademakers, who no longer receives funding from the group, keeps—Richards Donohoe’s Christmas cards on the wall of her lab in Belgium to remind her students and postdocs why they’re working long hours. “These are real people,” she tells them. “And they need treatments.”