C01 TRACK-TGHD MINIPIG—introduction of a longitudinal tgHD minipig phenotyping study using MRI, motor and cognitive endpoints

Abstract

<h3>Background</h3> In 2009 a tgHD Minipig was created, driven by a human huntintin promoter carrying a truncated human N-terminal part of htt (548aa) with 124 Q. This model was especially designed to fit the needs of future pre-clinical translational studies in Huntington9s disease. Meanwhile, it is known that the F0, F1 and F2 generations express uniform genetic characteristics (copy number of insert, localisation of transgene, length of polyQ stretch) and expression levels of mutant human htt. <h3>Aim</h3> Our aim is to assess the potential of this model for pre-clinical translational studies by investigating the development of a phenotype and identifying the most suitable and reliable endpoints for proof-of-concept studies. <h3>Methods and Techniques</h3> A battery of tests has been developed with five control animals (male, castrated). Based on the human UHDRS-TMS a “Large Animal UHDRS-TMS” was created. It explores a wide range of motor and cognitive functions. For example, physically and mentally challenging tasks performed in an obstacle course. Quantitative motor assessments will deliver objective measurements of motor dysfunction, for example, using automated gait analysis (GAITRite). A colour differentiation test is applied to assess cognition. Furthermore a protocol for MR Imaging has been developed and tested. <h3>Outcome</h3> Preliminary data of the GAITRite carpet has been collected in n=25 Libechov Minipigs (m-wt=5, m-tg=10, f-wt=5, f-tg=5) at a baseline and a 6 months follow-up assessment showing feasibility to perform the tests. In order to verify these results and further investigate feasibility the same group of animals will be assessed under the same conditions at future 6 months intervals. So far 16 MRI scans have been performed in 10 different animals. 5 wt Minipigs have been scanned once (age: 5, 6, 8, 12 and 25 months), 1 wt has been scanned twice (age: 12 and 24 m.), 1 wt has been scanned four times (age: 5, 18, 28 and 28 m.), 1 tg has been scanned once (age: 25 m.) and 2 tgs have been scanned twice (both age: 12 and 24 m.). All animals survived the procedure which lasted up to 4 h. VBM Volumetry, DTI/Fiber tracking and NMR Spectroscopy were applied. <h3>Conclusions</h3> Feasibility to repeatedly perform all assessments with the Libechov Minipig and to obtain reproducible data were shown. Future investigations of an increased number of Minipigs will be performed.