The Race to Treat Genetic FTD: New Therapies Target the GRN Mutation

Heidi Hall suspected something was off when her mother, a nurse, began having language difficulties. She could no longer spell her own last name and had difficulty finding the right words to make a restaurant reservation over the phone. 

Her grandmother, at the same time, was experiencing similar problems. A year later, they learned the diagnosis for both of them: frontotemporal dementia (FTD) caused by a mutation in the GRN gene. 

Hall described the disease as being in a “prison in their own bodies,” where both her mother and grandmother could see and hear the world but couldn’t express their thoughts.

FTD, also sometimes called frontotemporal degeneration, is an umbrella term for several rare forms of dementia affecting 60,000 Americans. Unlike Alzheimer’s, where the first symptoms are often memory-related, people with FTD may experience changes in language abilities, personality, thinking, and behavior. 

Around 20 percent of FTD cases are caused by mutations in a single gene, with a half of those cases caused by the GRN gene. Inheriting one copy of that mutated gene guarantees the disease. By age 60, people with the gene have a 60 percent chance of showing symptoms. By 75, that goes up to 95 percent. 

The gene mutation lowers levels of a protein called progranulin, which is key for clearing cellular waste, including misfolded proteins like TDP-43. When aggregates of abnormal TDP-43 accumulate, neurodegeneration starts. 

“This long-term reduction of progranulin levels is exacerbating a lot of that failure of proper clearance of those damaged proteins,” Penny Dacks, chief science officer of the Association for Frontotemporal Degeneration, told Being Patient.

Many drug companies are working to develop treatments for people living with the GRN gene to slow or prevent the disease altogether. 

What makes GRN an appealing target?

With so many forms of FTD, characterized by a variety of aggregated proteins, including TDP-43, tau, and FUS, and with a lack of reliable biomarkers, researchers have set their sites on targeting GRN.

In some genetic diseases, a mutation might cause the formation of toxic or misfolded proteins. Treating them might require fixing these misfolded proteins or preventing them from wreaking havoc. People with the GRN mutation have, on average, 50 percent less progranulin. 

“That leads to a really straightforward therapeutic intervention to increase progranulin levels,” Laura Mitic, president of the Bluefield Project, a non-profit supporting the development of GRN-targeted therapies for FTD. 

Genetic testing also allows researchers to easily spot people with the GRN gene that are likely to benefit from raising progranulin levels. 

The other advantage of GRN is cross-correction. Scientists don’t need to repair every single cell so that it produces progranulin, said Mitic. The progranulin from one cell could be released and spread to other parts of the brain as well. 

To make it easier for researchers to find families like hers that carry the gene for trials, Wanda Smith formed CureGRN in March 2025. “We had this richness of investigative clinical trials, and I knew families were out there,” Smith told Being Patient. “They just weren’t connected.”

Raising progranulin levels to treat FTD

Companies are taking different approaches to treating people with the GRN gene. 

Several companies are developing therapies that boost the levels of progranulin. Denali Therapeutics and Takeda are in the early stages of testing their synthetic version of progranulin, provided intravenously, that crosses into the brain. Passage Bio, Aviadobio, and Eli Lilly are testing a gene therapy approach that delivers a healthy version of the GRN gene into the brain via a virus. 

Other companies, like Versper Bio, are developing drugs that prevent progranulin from breaking down. It will test its experimental pill in a Phase 2 trial after showing promising results early in trials. 

“I’m really excited that they are all trying different ways to boost the program and levels,” Rachael Honeyfield, who is asymptomatic but carries the GRN gene, told Being Patient.

It isn’t clear which approach will succeed. Early on, many of these drugs are effective in increasing progranulin levels in the brain and cerebrospinal fluid. Larger Phase 3 trials must show that they also slow disease progression. It also isn’t clear what type of treatment — gene therapies, monoclonal antibodies, or pills — will be first on the scene.  

“There’s some concern that if you’re ramping up progranulin too much in the periphery, you might end up having long-term side effects, and you won’t be getting enough diverted into the brain to have the benefit that you’re seeking there,” Dacks said.

Does progranulin play a role in other dementias too?

Finding treatments that target GRN could also help treat other diseases. 

“Some of those companies are also now looking at how the progranulin molecular pathways also relate to Alzheimer’s, Parkinson’s, and a lot of age-related neurodegenerative diseases,” Dacks said.

Alector and Glaxo-Kline Smith’s monoclonal antibody latozinemab, which binds to a protein called the sortilin receptor preventing progranulin degradation, failed to slow FTD in its Phase 3 trial. But because of the molecular overlap between the diseases, it is now being tested in a Phase 2 trial for Alzheimer’s, with results expected by the end of the year. 

Hall took part in the latozinemab trial as an asymptomatic participant, saying that doing so gave her “that little bit of peace of mind that I’m taking this drug and I’m not going to get what my mom and my grandmother got.”. 

Though she was disappointed when she learned the trial didn’t succeed, she said she hopes a treatment will be developed in her lifetime.