A groundbreaking development in the fight against frontotemporal dementia (FTD) is opening up new avenues for drug discovery. Recent clinical trials suggest that boosting progranulin levels in the brain could slow disease progression, potentially transforming treatment strategies for this rare but devastating neurodegenerative condition.
Understanding frontotemporal dementia and the role of progranulin
FTD is the most common form of dementia in individuals under 60, with symptoms typically emerging between the ages of 45 and 65. This condition leads to the deterioration of the frontal and temporal lobes of the brain, causing personality changes, speech difficulties, and a decline in cognitive function. Up to 40% of cases have a genetic basis, often linked to mutations in the GRN gene, which encodes progranulin—a crucial protein for brain health. Individuals carrying the R493X mutation in GRN, in which an arginine codon is replaced with a termination signal, experience a significant drop in progranulin levels, leading to neuroinflammation and neurodegeneration. Although the onset age and progression of the disease can differ significantly, individuals who inherit a mutation will inevitably develop FTD, establishing GRN as a definitive causal gene for a subset of frontotemporal dementia (FTD-GRN).
The push for progranulin-boosting therapies
Several biotech companies are exploring diverse approaches to restore progranulin levels. For instance, Aviado Bio, Passage Bio, and Prevail partnered with Eli Lilly are using AAV-based gene therapy to deliver functional copies of the GRN gene directly into the brain. In another strategy, Alector, in collaboration with GSK, is developing the monoclonal antibody latozinemab (AL001), which works by blocking progranulin degradation to boost its availability. Meanwhile, Vesper Bio is testing an oral small-molecule inhibitor aimed at preventing progranulin breakdown for a more convenient treatment option. Additionally, Denali Therapeutics, partnering with Takeda, has engineered DNL593, a recombinant form of progranulin designed to efficiently cross the blood–brain barrier and reach the central nervous system.
Encouraging clinical results
Early clinical trials have shown promising results. Alector’s phase 2 study demonstrated that patients receiving AL001 had tripled progranulin levels in plasma and more than doubled cerebrospinal fluid levels. Additionally, disease progression slowed by 54%, and brain shrinkage was reduced by 48%, offering strong evidence that progranulin restoration could alter the disease trajectory. Denali’s approach is leveraging innovative transport mechanisms to deliver recombinant progranulin, showing potential in early trials. Similarly, gene therapy trials from Passage Bio and Prevail report high levels of sustained progranulin expression, raising hopes for long-term solutions.
If successful, these therapies may not only help FTD-GRN patients but also pave the way for tackling other neurodegenerative disorders.
By Ramona Stringhi, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan
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