More than a decade ago, studies began showing that people who don’t make the usual amount of a protein called progranulin are at higher risk of developing certain neurodegenerative diseases, including frontotemporal dementia. “Scientists knew about this but didn’t really know what to do with the information,” said Arnon Rosenthal, Ph.D., CEO of the biopharmaceutical company Alector.
Rosenthal co-founded Alector in 2013 to study innovative ways to treat neurodegenerative diseases. The company’s scientists soon had a new idea for a drug target: a protein that interacts with progranulin. But studying progranulin was just one of several projects the company was working on, and no one knew which was the most promising. “We considered shutting down the project because we just didn’t have enough resources,” Rosenthal said.
Instead, in 2015, Rosenthal applied for and received an NIA Fast-Track Small Business Innovation Research (SBIR) grant. With that support, the company performed basic research that led to a new investigational monoclonal antibody treatment known as AL001 or latozinemab.
Latozinemab is currently being tested in a phase 3 clinical trial with people who have frontotemporal dementia due to mutations in GRN, the gene associated with making progranulin. Alector, now a public company, is partnering with the larger pharmaceutical company GSK for this study, with hopes of applying for U.S. Food and Drug Administration (FDA) review of latozinemab in late 2025.
Investigating the role of progranulin
The instructions for cells to make the protein progranulin are in a gene called GRN. If a person has a mutation in GRN that blocks production of progranulin, they may develop frontotemporal dementia (FTD-GRN), with symptoms usually starting in the person’s 50s or 60s. If they have two bad copies of the gene, the person may develop an even more serious disease, called neuronal ceroid lipofuscinosis, when they are even younger.
At the time that Rosenthal co-founded Alector, studies suggested that increasing the amount of progranulin in the body might help prevent or treat neurodegeneration, which happens when the cells of the central nervous system stop working properly. But progranulin is difficult to make outside the body, and it doesn’t last in the bloodstream long enough to get to where it is needed for frontotemporal dementia treatment.
Instead of trying to make progranulin, the Alector team identified another protein, sortilin, that is involved in breaking down progranulin. The team hypothesized that blocking sortilin could help increase levels of progranulin in the brain, similar to the way that certain drugs treat depression by blocking the absorption of serotonin in the brain.
The Alector team now had a goal: blocking sortilin. “At the time, we weren’t sure that we could develop a drug that
could do it,” Rosenthal said. Even if they could block sortilin, the team would need to test for the effects they hoped to see: increasing levels of progranulin and slowing neurodegeneration. Doing all the tests to determine answers to these and other questions would be expensive. “We didn’t have the resources to test all of the uncertainties.”
Funding the basics to bridge research gaps
NIA’s SBIR support enabled Alector to develop a test to show the relationship between levels of progranulin and sortilin in cells. Then the team used that test to find antibodies that decreased sortilin and increased progranulin. Next, they tested those candidates in mouse models and observed how the antibodies changed the level of progranulin in the brain. Latozinemab looked the most promising.
“These findings really, internally, convinced us that there is a way forward — that we may have a drug,” Rosenthal said. With these data, Alector also attracted new investors to fund the next phase of research: clinical trials for latozinemab. Investors wanted to see data before they invested, Rosenthal said, but without funding, it was impossible to generate data. The data made possible by NIA’s small business funding “helped us convince investors that it’s worth investing in this drug,” Rosenthal said.
In 2018, Alector obtained additional funding from investors and began a phase 1 clinical study of latozinemab with healthy volunteers to test it for safety and optimal dosage. Findings from that study and preliminary results of a subsequent phase 2 study showed promise, indicating that latozinemab may increase levels of progranulin, including in people with FTD-GRN. As a phase 3 clinical trial got underway, these initial results also attracted the attention of GSK, which partnered with Alector to advance the research toward FDA approval.
Multiplying opportunities with SBIR funding
Alector already had venture capital funding when the company turned to NIA for support. “Even companies that have already attracted investment, as Alector had, can benefit from applying for NIA’s SBIR funding,” said Todd Haim, Ph.D., director of the NIA Office of Strategic Extramural Programs. “This funding provides unique opportunities to pursue potential avenues of drug development that, although containing a degree of risk, could bring big rewards.”
By funding basic research at its earliest stage, NIA is accelerating progress on drug targets that may help treat Alzheimer’s disease and related dementias. For successful applicants, “NIH funding gives you the opportunity to develop enough certainty to make either large pharma or private investors interested,” Rosenthal said. “It’s a great opportunity to convert a hypothetical idea to reality.”
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