Gains in early-onset dementia with progranulin open new paths for drug discovery – Nature Biotechnology

A genetic medicine that delivers progranulin into the brains of patients with a rare form of dementia has shown promise in an early safety trial, a paper in Nature Medicine reported last year. At least six companies are pursuing the progranulin pathway to treat frontotemporal dementia (Table 1). What they find not only may prove transformational for this rare disease but also could represent a gateway to treating other types of dementias. “The fact that there are several companies in this one space is really exciting, and it’s exciting for patients with FTD and neurodegenerative disease in general,” says William Chou, president and CEO of Passage Bio, a biotech running a program in FTD.

FTD is the most common form of dementia in people under 60. Symptoms generally present between ages 45 and 65, but sometimes appear as early as 30. Because the disease ravages the frontal and temporal lobes of the brain, causing cortical neuronal loss, the first signs manifest in erratic behavior, inability to control emotions, difficulty in using words and a swift decline in the ability to perform everyday tasks.

Up to 40% of all cases of FTD are hereditary, mostly with one of three genes implicated: MAPT (microtubule-associated protein tau), coding for tau; the open reading frame C9ORF72, whose protein product is not fully characterized; and the granulin gene (GRN), encoding progranulin.

In people who inherit the GRN R493X mutation, in which an arginine codon is replaced with a termination signal, less progranulin is produced from the affected gene. Several other FTD-associated mutations have the same effect, but R493X is the most frequent in human populations. These mutations directly affect progranulin production: healthy people have an average of 96–125 ng/ml of blood progranulin, but it drops by more than half, to below 50 ng/ml, in those carrying FTD-related mutations. Altered amounts of progranulin in blood can serve as both a diagnostic biomarker and a predictor of the disease’s severity and progression.

The age of onset and the disease’s progression can vary widely, but people who inherit a mutation will invariably develop FTD, making GRN a causal gene for a subset of frontotemporal dementia (FTD-GRN). Mutations that reduce progranulin production by neurons have also been identified in Alzheimer’s disease, and conversely, progranulin appears to have protective effects in animal models of ALS, Parkinson’s disease, stroke, arthritis and atherosclerosis.

Progranulin is a secreted glycoprotein structured like ‘beads on a string’, with individual granulins connected by short linkers. The protein is secreted and expressed in the central nervous system, and it is also internalized inside the cell: inside lysosomes, it is processed into individual proteases that are dedicated to the destruction and digestion of biomolecules and pathogens. When progranulin production is insufficient, as in patients with FTD-GRN, this results in neuroinflammation as well as systemic inflammation. This is probably due to defective lysosome biology and specifically lipid metabolism, which alters macrophage activity and results in a build-up of toxic proteins, neuro-inflammation and neurodegeneration.

Given that progranulin deficiency is tightly linked to neuropathology, many have proposed ramping up progranulin production or restoring its levels to stop the changes that hurtle towards FTD-GRN. “This is a loss-of-function disease,” says Laura Mitic, acting president and CSO of the Bluefield Project, a San Francisco–based nonprofit consortium founded to accelerate treatments for FTD. “Most individuals have a heterozygous loss of function, a bad copy that produces no progranulin.” To have therapeutic effect, progranulin can be delivered though the bloodstream and cerebral spinal fluid to the areas it’s needed. “Neurons need it, microglia need it, astrocytes need it,” she says.

Companies are deploying a constellation of strategies to restore progranulin, including introducing a corrected progranulin gene in gene therapies using adeno-associated virus (AAV)-mediated GRN gene delivery, dosing people with progranulin engineered to cross the blood–brain barrier, and blocking progranulin degradation with monoclonal antibodies that target its transport receptor.

Of the six companies with clinical trials underway, some are attempting to boost progranulin in people who have already developed FTD-GRN symptoms. Others are availing themselves of genetic testing to start treatment soon after an initial diagnosis, to check whether such agents might block symptoms from developing in the first place.

The most advanced therapy belongs to Alector Therapeutics, in collaboration with GSK. The company’s human monoclonal antibody latozinemab AL001 binds the sortilin receptor and increases progranulin levels by blocking its transport into the lysosome, thereby preventing its destruction. “The idea is that if we can find a way to restore the protein back to normal levels, we could find a treatment,” says Arnon Rosenthal, Alector’s co-founder and CEO.

During the phase 2 trial, individuals with FTD-GRN received intravenous infusions of AL001 every four weeks. Within two weeks of the first dose, progranulin increased to three times baseline amounts in plasma and more than doubled in the cerebrospinal fluid, remaining so for the duration of the 12-month study. Alector also compared cognitive, behavioral, language and functional measurements from patients treated with FTD-GRN to those from historical controls over a similar time frame and found that progression slowed by 54%. Brain shrinkage measured by MRI also slowed by 48% in treated people compared with historical controls. “This is, we think, a very profound effect.”

The company has already closed enrollment for its phase 3 trial to assess AL001 both in symptomatic patients and in 16 pre-symptomatic people who are positive for GRN mutations. “Ultimately, the ideal situation is to treat patients who have the genetic mutations with prevention therapy before they develop symptoms—that’s our long-term goal,” Rosenthal says. But given the unpredictability of onset, it’s difficult to know when people will begin to develop signs of disease. So far, none of the non-symptomatic patients in the study have shown symptoms of FTD. ”But we don’t know if that’s the drug or the disease,” he says.

Vesper Bio is also taking aim at sortilin, but with an orally available small molecule. Vesper’s sortilin inhibitor VS001 can regulate plasma progranulin in the brain of animal models and humans. “Vesper is coming up fast, hoping that Alector’s drug is approved,” Mitic says. “Then they can follow right along using the same pathway with an oral. I think patients probably appreciate that.”

It’s still unclear which mechanism to rebalance progranulin levels would yield the best results. Potentially, different approaches used in combination could boost the efficacy of progranulin-enhancing gene therapies. In studies that are still unpublished, progranulin-deficient mice, when treated with gene therapy and agents to block sortilin, showed greater beneficial effects on neurodegeneration than similar mice treated with either approach alone.

Denali Therapeutics is attempting to restore progranulin levels in its phase 1/2 trial in patients with FTD-GRN using systemic injections of recombinant progranulin. Because progranulin is a large protein, to ensure that it moves across the blood–brain barrier and into the CNS, Denali has engineered what it calls a ‘transport vehicle’ that takes advantage of the transferrin (TfR1) receptor. These transferrin receptors on the blood–brain barrier’s endothelial cells normally move iron from blood into the brain. Denali’s DNL593 fuses progranulin to an antibody Fc fragment that binds to the transferrin receptors. This ensures that the recombinant progranulin contained in DNL593 is ferried into the brain.

“So not only are we able to cross the blood–brain barrier, but we’re able to go up to the cell surface and get brought into the lysosome,” says Richard Tsai, a senior medical director at Denali, of the company’s brain shuttle technology.

So far, Denali has dosed healthy volunteers with DNL593, a full-length modified progranulin administered intravenously. As the trial progresses, in collaboration with Takeda, Tsai say, they intend to keep close tabs on biomarkers of neurodegeneration such as neurofilament light chains in order to determine their drug’s optimal dose.

Others are betting on gene therapy: AviadoBio, Passage Bio, and Prevail partnered with Eli Lilly. Although their methods vary slightly, they all aim to boost progranulin by introducing a corrected progranulin gene into neurons in the brain with an adenovirus. Because adenoviruses don’t cross the blood–brain barrier particularly well, however, the therapy must be delivered via CT-guided injections. AviadoBio delivers the therapy directly by injection into the thalamus region of the brain, whereas Passage and Prevail inject into the cisterna magna, a space filled with cerebrospinal fluid (CSF) located behind the cerebellum, and rely on the CSF to transport the AAV–progranulin gene construct into the brain. Once incorporated into cells, the construct enables them to churn out progranulin.

Passage Bio’s therapy differentiates itself in its choice of adenovirus. “All adenoviruses have different capsids. Ours is AAV-1, which has a particular tropism for certain types of cells in the CNS,” says Chou. “What we’ve seen in the first five patients we’ve dosed is very high progranulin levels—higher than anything else in the clinic.” And those levels remained high for at least a year. Although the amounts are up to ten times higher than normal, Chou doesn’t see this as concerning. “There’s no known toxicity for progranulin,” he says. Without toxicity as a potential concern, he says, aiming for higher progranulin levels means they have a higher chance of seeing a measurable response.

AviadoBio uses AAV9 and delivers it directly to the thalamus, deep in the brain. It’s a rare strategy, and their patients are the first adults to receive therapy delivered intrathalamically. “The thalamus is a sensory relay hub,” says Lisa Deschamps, CEO of AviadoBio, a biotech collaborating with Astellas Pharma. “By delivering directly into the thalamus, you let it do the work for you.”

Alector’s phase 3 trial is expected to read out by the end of the year, and the entire field is watching. Whoever succeeds will smooth the path to approval for everyone else working on FTD, Mitic says. With an established infrastructure for symptom assessment, testing and more, development will accelerate. It could also allow people with a family history of GRN-FTD to get tested for the disease and, if positive, begin treatment for progranulin deficiency before they become symptomatic.

CNS diseases are starting to see an explosion of therapeutic approaches and targeted therapies. “That’s the beauty of having competing companies: you get to an answer faster about what matters for delivery, for dose, for when to intervene,” Mitic says. “It’s fantastic that there’s such interest in the field because it will translate into knowledge faster, to the benefit of patients.”