Frontotemporal degeneration, the next therapeutic frontier: molecules and animal models for frontotemporal degeneration drug development

Abstract

Frontotemporal degeneration (FTD) is a common cause of dementia for which there are currently no approved therapies. Over the past decade, there has been an explosion of knowledge about the biology and clinical features of FTD that has identified a number of promising therapeutic targets as well as animal models in which to develop drugs. The close association of some forms of FTD with neuropathological accumulation of tau protein or increased neuroinflammation due to progranulin protein deficiency suggests that a drug's success in treating FTD may predict efficacy in more common diseases such as Alzheimer's disease. A variety of regulatory incentives, clinical features of FTD such as rapid disease progression, and relatively pure molecular pathology suggest that there are advantages to developing drugs for FTD as compared with other more common neurodegenerative diseases such as Alzheimer's disease. In March 2011, the Frontotemporal Degeneration Treatment Study Group sponsored a conference entitled "FTD, the Next Therapeutic Frontier," which focused on preclinical aspects of FTD drug development. The goal of the meeting was to promote collaborations between academic researchers and biotechnology and pharmaceutical researchers to accelerate the development of new treatments for FTD. Here we report the key findings from the conference, including the rationale for FTD drug development; epidemiological, genetic, and neuropathological features of FTD; FTD animal models and how best to use them; and examples of successful drug development collaborations in other neurodegenerative diseases.

Figure 1. Neuropathological classification of FTD subtypes

Frontotemporal lobar degeneration (FTLD) encompasses three distinct neuropathologic categories which are identified by the molecular pathology of the misfolded protein within the inclusion: FTLD-Tau, FTLD-TDP, and FTLD-FUS; the molecular pathology of a fourth category, FTLD with epitopes of the ubiquitin-proteasome system (FTLD-UPS), remains indeterminate. 3R, 4R, 3R/4R the predominant tau isoform within the inclusion; PICK, Pick disease; FTLD with microtubule-associated protein tau (MAPT) mutation with inclusions of 3R, 4R, or 3R and 4R tau protein; CBD, corticobasal degeneration; PSP, _ progressive supranuclear palsy; WMT-GGI, white matter tauopathy with globular glial inclusions; AGD _ argyrophilic grain disease; NFT Dementia, neurofibrillary tangle-predominant dementia; FTLD-U, FTLD with ubiquitin-immunoreactive inclusions, now called FTLD-TDP; FTLD with progranulin (GRN) mutation; FTLD with TAR DNA-binding protein of 43 kDa (TARDBP) mutation; FTLD with valosin-containing protein (VCP) mutation; FTLD with C9ORF72 expansion; NIFID, neuronal intermediate filament inclusion disease; aFTLD-U, atypical FTLD with ubiquitin inclusions; BIBD, basophilic inclusion body disease; FTLD with fused in sarcoma (FUS) mutation; FTLD with charged multivesicular body protein 2B (CHMP2B) mutation. Within each molecular pathology there may be unclassified entities.