Development of disease-modifying drugs for frontotemporal dementia spectrum disorders

Abstract

Frontotemporal dementia (FTD) encompasses a spectrum of clinical syndromes characterized by progressive executive, behavioural and language dysfunction. The various FTD spectrum disorders are associated with brain accumulation of different proteins: tau, the transactive response DNA binding protein of 43 kDa (TDP43), or fused in sarcoma (FUS) protein, Ewing sarcoma protein and TATA-binding protein-associated factor 15 (TAF15) (collectively known as FET proteins). Approximately 60% of patients with FTD have autosomal dominant mutations in C9orf72, GRN or MAPT genes. Currently available treatments are symptomatic and provide limited benefit. However, the increased understanding of FTD pathogenesis is driving the development of potential disease-modifying therapies. Most of these drugs target pathological tau — this category includes tau phosphorylation inhibitors, tau aggregation inhibitors, active and passive anti-tau immunotherapies, and MAPT-targeted antisense oligonucleotides. Some of these therapeutic approaches are being tested in phase II clinical trials. Pharmacological approaches that target the effects of GRN and C9orf72 mutations are also in development. Key results of large clinical trials will be available in a few years. However, clinical trials in FTD pose several challenges, and the development of specific brain imaging and molecular biomarkers could facilitate the recruitment of clinically homogenous groups to improve the chances of positive clinical trial results.

Key points

  • Frontotemporal dementia (FTD) refers to a group of progressive neurodegenerative syndromes with different clinical presentations, the most common of which is behavioural variant FTD.

  • FTD is caused by an accumulation of pathological tau, transactive response DNA binding protein of 43 kDa (TDP43), or fused in sarcoma protein, Ewing sarcoma protein and TATA-binding protein-associated factor 15 (FET proteins).

  • Symptomatic treatments have limited benefits and can exacerbate symptoms.

  • An increased understanding of FTD pathogenesis is helping the development of disease-modifying therapies.

  • Disease-modifying drugs for FTD mainly target tau, but therapies for genetic forms of FTD (caused by mutations in GRN, C9orf72 and MAPT) are also being pursued.

  • Several potential disease-modifying therapies have been or are being tested in phase II clinical trials.

  • Several challenges must be overcome to recruit homogeneous patient cohorts and ensure that appropriate biomarkers and clinical end points are used so that clinical trials produce meaningful results.

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Fig. 1: Associations of molecular, genetic and neuropathological subtypes of FTLD with different clinical FTD phenotypes.
Fig. 2: Potential therapeutic interventions for FTLD.

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F.P., M.L., D.S., A.D. and B.P.I. researched data for the manuscript. F.P., M.L., M.W. and B.P.I. wrote the manuscript. F.P., M.L., G.G. and B.P.I. contributed substantially to discussions of the article content and review and/or editing of the manuscript before submission.

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Correspondence to Francesco Panza.

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B.P.I. is an employee at Chiesi Farmaceutici and has developed and is co-inventor of patents on anti-Alzheimer disease drugs; he does not hold stock options. All other authors declare no competing interests.

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A post-translational modification that involves the addition of a single N-acetyl-glucosamine residue (GlcNAc) to specific serine or threonine residues in proteins.

Taxane diterpenoid

A class of diterpenes, some of which are widely used as chemotherapy agents.

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Panza, F., Lozupone, M., Seripa, D. et al. Development of disease-modifying drugs for frontotemporal dementia spectrum disorders. Nat Rev Neurol 16, 213–228 (2020). https://doi.org/10.1038/s41582-020-0330-x

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