Many have turned their attention to frontotemporal dementia (FTD) as the family of famed action star Bruce Willis announced his diagnosis last week. While there is no cure to this neurodegenerative condition, academics and companies are pushing through with research that could help patients and their families.

Different approaches that are studied include antisense oligonucleotides (ASOs), and gene therapies, which are in early clinical trials. Other lines of research look at the genetic overlap between FTD and amyotrophic lateral sclerosis (ALS), which could be used in the development of treatments for both conditions.

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It is difficult to accurately diagnose FTD at early stages, writes Dr. Sami Barmada, associate professor of neurology at University of Michigan’s Medical School in Ann Arbor, in an email to Pharmaceutical Technology. This is one of the major challenges that slow the development of effective treatments for FTD, he adds. Efforts are also made in the study of blood marker tests that detect FTD early.

This comes nearly a year after Willis was diagnosed with aphasia, a brain disorder that affects language and speech. In their statement, Willis’s family wrote that the actor’s condition since progressed, which led to the new announcement.

According to the National Institute of Health’s (NIH) Institute on Aging, about 60% of FTD patients are aged between 45 and 64 years. There are up to 60,000 FTD patients in the US.

Different approaches for a varied condition

The lack of known mutations is one of the reasons why developing treatments for FTD is so challenging, says Barmada. While 40% of people with FTD have a family history of the condition, the majority do not have a mutation, he explains.

However, multiple companies are developing treatments that target specific mutations, which could cause the condition. This includes Denali Therapeutics whose treatment TAK-594/DNL593 is in a Phase I/II trial. The therapy is specifically aimed at treating FTD patients who have mutations in their granulin gene, which encodes for the protein progranulin (PGRN). This protein promotes lysosomal function.

Mutations here result in the loss of PGRN activity and are described as one of the most common genetic causes of FTD, based on the company’s website. TAK-594/DNL593 would serve as a PGRN replacement therapy.

In November 2022, the biopharmaceutical company shared interim data from the study’s first part in healthy volunteers. There, single doses of DNL593 were broadly well tolerated and showed dose-dependent increases in progranulin levels measured in cerebrospinal fluids (CSF). According to the biopharma, these results supported a move into trial’s second part, which will feature subjects with FTD. The company expects final data from the study’s first part in mid-2023. Denali aims to continue recruiting FTD patients for the trial’s second part this year.

Denali is not the only company that targets this mutation. In August 2022, Passage Bio dosed the first subject in a Phase I/II trial for their FTD gene therapy PBFT02.

Prevail Therapeutics, a subsidiary of the pharma giant Eli Lilly, is running a Phase I/II trial of its gene therapy PR006. The company dosed its first patient in this study in December 2020.

UK-based AviadoBio works on a potential gene therapy called AVB-001 that targets this form of FTD. The therapy received an orphan designation from both the FDA and the European Commission last year. It was previously expected to enter clinical development last year, but no announcements were made.

In addition to gene therapy, gene silencing, which can be done using ASOs, is also an interesting approach, says Barmada. However, these treatments must target a gene, which is challenging, since many FTD patients lack mutations, says Barmada. Overall, FTD is a heterogenous disorder, he adds.

Examples of the ASO approach include Wave Life Sciences’s treatment WVE-4. WVE-4 is studied in a Phase Ib/IIa trial as a potential treatment for both ALS and FTD. Specifically, WVE-4 targets transcript variants featuring hexanucleotide repeat expansions (HRE) associated with the C9orf72 gene in ALS and FTD. The trial features four cohorts.

In April 2022, the company shared a positive update where the treatment resulted in reduced levels of poly (GP) dipeptide repeat proteins in CSF. Wave expect to release data from all four cohorts in the first half of this year.

HREs in the C9orf72 gene are described as a common inherited factor behind ALS and FTD.

Proteins and biomarkers

The pathologic buildup of proteins is also a potential drug target. Here, ALS and FTD overlap. Now, companies such as AcuraStem are keen on exploring this as a potential treatment pathway. The biotech is working on an ASO that would suppress the PIKFYVE gene and target the two proteins TDP-43 and tau. Both proteins are linked to ALS and FTD.

Still, this approach comes with its own set of questions.

“A little less than half of FTD is associated with the buildup of TDP-43 in the brain. About [the] same proportion shows a different protein building up called tau. The remainder are linked with a third protein, FUS,” says Barmada. “Do we develop a single treatment for all three? Or individualised treatments for each protein?”

The development of biomarkers to detect these proteins should bring answers to this question soon, says Barmada.

Biomarker tests are also needed for the early detection of the disease. Last April, a team of researchers partly funded by the NIH’s Institute on Aging shared their findings on a potential blood marker for FTD. Aimed at the neurofilament light chain (NfL) protein, the test would be used for detecting the condition early. According to the researchers, FTD patients had higher blood levels of NfL than those with other conditions. NfL detection is also studied in conditions like Alzheimer’s disease.

Early detection of FTD is critical for any potential treatment.

“The loss of brain cells in FTD is likely to be irreversible. What this means is that it may be possible to stop the progression of disease, but not reverse any symptoms that have taken hold. In this regard, any effective therapy needs to be administered as early as possible in the disease’s course,” says Barmada.