. Author manuscript; available in PMC: 2009 Dec 1.

Published in final edited form as: Curr Opin Neurol. 2008 Dec;21(6):708–716. doi: 10.1097/WCO.0b013e328318444d

Table 2.

Summary of potential therapies for the major FTLD pathological proteins.

Protein	Biological role	Proposed pathological role	Therapeutic target	Candidate drugs	Stage of investigation
MAPT	Microtubule stabilization, signaling transduction, neural development [57*]	Toxic gain of function	Inhibit tau kinases GSK3,CDK-5, MARK [58*, 59]	Lithium [60, 61], valproic acid [62], other small molecules (reviewed by Churcher [59])	Preclinical for FTLD
MAPT		Toxic gain of function	Inhibit tau kinases GSK3,CDK-5, MARK [58*, 59]		Early clinical trials for AD [58*]

			Inhibit/reverse tau aggregation [63, 64]	Anthraquinones [65], phenylthiazolyl- hydrazides, Rember™ (TauRx Therapeutics Ltd)	Drug discovery (High- throughput screening of compounds [63])
			Inhibit/reverse tau aggregation [63, 64]		Phase III clinical trials for AD (TauRx Therapeutics Ltd)

			Reduce tau expression [66, 67]	Several FDA approved compounds identified (see [68]), siRNA	Preclinical

			Block tau cleavage	Calpain inhibitor A-705253 [69]	Preclinical for FTLD
			Block tau cleavage	Calpain inhibitor A-705253 [69]	Early clinical trials for AD

			Immuno- suppression	FK-506 [70]	Preclinical

			Alter chaperone systems to enhance tau degradation [71]	Hsp90 inhibitor [71]	Preclinical

			Interfere with splicing machinery to normalize 3R and 4R tau ratio [72]	Splicing regulators [73]	Preclinical

		Loss of normal function	Stabilize microtubules	Paclitaxel [74] NAP (NAPVSIPQ) [75, 76*]	Preclinical for FTLD
		Loss of normal function	Stabilize microtubules	Paclitaxel [74] NAP (NAPVSIPQ) [75, 76*]	NAP in phase II clinical trials for mild cognitive impairment (Allon Therapeutics Inc., Vancouver, BC, Canada)

PRGN	Growth factor mediating neural development, inflammation, [77] and survival [78*]	Loss of function (haplo- insufficiency) [46]	Ribosomal read- through of premature termination codons	PTC124 [79, 80]	Preclinical for FTLD
PRGN		Loss of function (haplo- insufficiency) [46]	Ribosomal read- through of premature termination codons	PTC124 [79, 80]	Phase II or III for other genetic deficiency syndromes

			Regulate PRGN levels	High throughput screening of compounds and RNAi libraries	Preclinical

			Block proteolytic cleavage	Elastase inhibition	Preclinical

TDP-43	Binds DNA and RNA, represses transcription, and initiates exon skipping [81]	Toxic gain of function or loss of normal function	Immune therapy, block cleavage	High throughput screening of compounds and RNAi libraries	Preclinical

Abbreviations: PRGN=progranulin