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The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier).

ABSTRACT: Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials, and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared with other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional, and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease. Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw on this experience to create a road map for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.

SUBMITTER: Boxer AL

PROVIDER: S-EPMC3562382 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier).

Boxer Adam L AL Gold Michael M Huey Edward E Hu William T WT Rosen Howard H Kramer Joel J Gao Fen-Biao FB Burton Edward A EA Chow Tiffany T Kao Aimee A Leavitt Blair R BR Lamb Bruce B Grether Megan M Knopman David D Cairns Nigel J NJ Mackenzie Ian R IR Mitic Laura L Roberson Erik D ED Van Kammen Daniel D Cantillon Marc M Zahs Kathleen K Jackson George G Salloway Stephen S Morris John J Tong Gary G Feldman Howard H Fillit Howard H Dickinson Susan S Khachaturian Zaven S ZS Sutherland Margaret M Abushakra Susan S Lewcock Joseph J Farese Robert R Kenet Robert O RO Laferla Frank F Perrin Steve S Whitaker Steve S Honig Lawrence L Mesulam Marsel M MM Boeve Brad B Grossman Murray M Miller Bruce L BL Cummings Jeffrey L JL

Alzheimer's & dementia : the journal of the Alzheimer's Association 20121010 2

Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. Thi ...[more]

PMID: 23062850

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Project description:A significant portion of frontotemporal lobar degeneration (FTLD) is due to inherited gene mutations, and we are unaware of a large sequential series that includes a recently discovered inherited cause of FTLD. There is also great need to develop clinical tools and approaches that will assist clinicians in the identification and counseling of patients with FTLD and their families regarding the likelihood of an identifiable genetic cause.To ascertain the frequency of inherited FTLD and develop validated pedigree classification criteria for FTLD that provide a standardized means to evaluate pedigree information and insight into the likelihood of mutation-positive genetic test results for C9orf72, MAPT, and GRN.Information about pedigrees and DNA was collected from 306 serially assessed patients with a clinical diagnosis of FTLD. This information included gene test results for C9orf72, MAPT, and GRN. Pedigree classification criteria were developed based on a literature review of FTLD genetics and pedigree tools and then refined by reviewing mutation-positive and -negative pedigrees to determine differentiating characteristics.Academic medical center.Patients with FTLD.Familial risk.The rate of C9orf72, MAPT, or GRN mutation-positive FTLD in this series was 15.4%. Categories designating the risk level for hereditary cause were termed high, medium, low, apparent sporadic, and unknown significance. Thirty-nine pedigrees (12.7%) met criteria for high, 31 (10.1%) for medium, 46 (15.0%) for low, 91 (29.7%) for apparent sporadic, and 99 (32.4%) for unknown significance. The mutation-detection rates were as follows: high, 64.1%; medium, 29%; low, 10.9%; apparent sporadic, 1.1%; and unknown significance, 7.1%. Mutation-detection rates differed significantly between the high and other categories.Mutation rates are high in FTLD spectrum disorders, and the proposed criteria provide a validated standard for the classification of FTLD pedigrees. The combination of pedigree criteria and mutation-detection rates has important implications for genetic counseling and testing in clinical settings.

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The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier).

Publications

The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier).

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