Tacrolimus for treating tdp-43 proteinopathy
A technology of TDP-43, tacrolimus, applied in the field of tacrolimus for the treatment of TDP-43 proteinopathy, can solve the problems of no human therapeutic benefit, small survival benefit, etc.
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Embodiment 1
[0098] Example 1 - Effect of Tacrolimus in C. elegans expressing TDP-43 C-terminal fragment
[0099] Materials and methods
[0100] Caenorhabditis elegans species
[0101] The C-terminal fragment of TDP-43 is associated with pathology in ALS and FTD patients. In particular, proteolytic cleavage at Arg208 has been reported to generate a pathogenic C-terminal fragment (see, Wang et al., 2013, J. Biol. Chme. 288(13):9049- 57 and Igaz et al., 2009, "Journal of Biochemistry (J.Biol.Chem." 284 (13): 8516-24; its content is incorporated herein by reference).So, express human TDP-43 in body arm muscle Transgenic C. elegans strains of the C-terminal fragment (CTF) (aa 208-414) fused to a C-terminal GFP tag via a short linker region. Expression is under the control of the myo-3 promoter.
[0102] A control C. elegans strain was generated in the same background in which the GFP reporter was expressed only under the control of the myo-3 promoter.
[0103] These species were crossed ...
Embodiment 2
[0114] Example 2 - Effect of Tacrolimus in Mice Expressing WT and / or Q331K TDP-43
[0115] Materials and methods
[0116] mouse
[0117] Transgenic mice expressing wild-type human TDP-43 or human TDP-43 carrying a point mutation (Q331K) have been developed and developed by the Shaw laboratory (see Arnold et al., 2013, Proc. Natl. Acad.Sci.) 110(8):E736-45 and Mitchell et al., 2015, Acta Neuropathol.Commun. 3(1):36; the contents of which are incorporated herein by reference) describe. The inserted construct places the cDNA for N-terminal myc-tagged wild-type or mutant TDP-43 under the control of the mouse prion promoter, allowing expression in the CNS. Because the construct does not contain the 3'UTR of the human TDP-43 gene, TDP-43 mRNA levels are not self-regulated, and TDP-43 levels in transgenic varieties are 2 to 3-fold higher than endogenous levels.
[0118] Hemizygous lines for each construct were established (TDP-43(WT) and TDP-43(Q331K), respectively), and these ...
Embodiment 3
[0143] Example 3 - Exemplary unit dosage forms of the invention
[0144] Hard gelatin capsules are filled with the following composition:
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[0146]
[0147] One of the above capsules containing 0.3 mg tacrolimus was administered to healthy human volunteers daily for three days. Blood TNF-[alpha] levels were not significantly altered by this administration. Similarly, TNF-α levels were not altered by daily administration of 0.6 mg tacrolimus to healthy volunteers. The observed mean trough level (level 24 hours after each dose) of tacrolimus was approximately 220 pg / mL. The observed mean peak level of tacrolimus was about 3700 pg / mL and the mean area under the curve was about AUC O_t = 23500 (h*pg / mL).
[0148] The capsules described above may be used to provide the treatments previously described herein.
[0149] Simultaneous use of two such capsules providing a single dose of 0.6 mg is expected to yield a trough level of approximately 440 pg / mL.
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