New routes in frontotemporal dementia drug discovery

ABSTRACT

Introduction: Research into the pathogenic mechanisms behind frontotemporal dementia (FTD) has yielded several new targets for therapeutic intervention; such targets include specific new pathways uncovered by mutations as well as targets involving the modulation, formation and degradation of protein aggregates.

Areas covered: Herein, the authors outline the principal molecular causes underlying FTD to date and the research that has been performed in these areas with respect to an eventual corrective strategy.

Expert opinion: While it is worthwhile targeting pathways affected by specific mutations with a causative loss of function linked to FTD, research still has to contend with issues including the remaining presence of protein aggregates or that treatments are rarely universally applicable. Aiming to recover function in a downstream target caused by the protein aggregates will likely be insufficient due to the large cascade of events affected. It is our belief that the clearance of these aggregates and the inhibition of protein misfolding are more appropriate and direct routes to an eventual therapy.

KEYWORDS:

• Aggregation
• Frontotemporal dementia
• FUS
• tau
• TDP-43
• C9orf72
• progranulin
• Antisense Oligonucleotides
• Therapeutic routes

Article highlights

• Frontotemporal dementia encompasses a clinically, pathologically and genetically diverse group of neurodegenerative disorders.

• FTD is divided into four main groups depending on the aggregates composition found in specific brain regions. Mutations in nine different genes are also found correlated to the pathology.

• Identification of the biological mechanisms affected in FTD opens the way to several areas of intervention for hypothetical disease-modifying therapy.

• Cellular and animal models of FTD are being used to test different therapeutic approaches.

• The prevention of protein misfolding and aggregation or the clearance of the aggregates are the main objectives of therapeutic approaches.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

Additional information

Funding

This manuscript has not been funded.