Body weight was assessed weekly and as can be seen in Figure 1C,D, the maximum body weights of all three mutant genotypes were lighter than their wildtype littermates and male mice were generally 20% heavier than their female counterparts, on the genetic backgrounds studied.
Both combination doses were well tolerated with maximum body weight loss of 4.5 and 4.7%, respectively.
Pracinostat was very well tolerated in both studies (maximum body weight losses of 7 and 4.7%, respectively, in the MV4-11 and HEL92.1.7 model).
Rats that received adjuvant HIPEC had a maximum body weight loss of 12.3 ± 1.7%, which was significantly higher than that after CS alone (P <.001) or CS + RIT (P <.001).
Experiments were performed blind to genotype and lifespan was defined as a loss of 20% of maximum body weight or the presence of piloerection.
As already described [ 16], the body weight of the G93A SOD1 mutant rats is reduced by up to 10% of their maximum body weight when the first signs of paralysis become detectable (disease onset: 129 +/- 17.3 days of age; Figure 1B, T0), on average 6 days after the measurement of the maximum body weight.
During the experimental periods, both wild-type and Als2−/− mice showed a constant increase in their body weight (Figure S2A and S2B), while mice carrying the SOD1H46R transgene reached their maximum body weight at 12 14 weeks of age, and terminally decreased as disease symptoms progressed (Figure 1A and 1B).
The resistant mice, however, had no evident gross pathology at the time of maximum body weight loss and no alteration in the appearance of the liver (Fig. 1D).
Clinical disease onset manifested primarily as perceived body muscle-mass reduction and gradual weight loss, which reached ≥20% of maximum body weight over 2 to 8 months.
Progression to the final stage of the disease (defined as weight reduction of 25% from maximum body weight), was very rapid and it was complete in approximately 7 days from disease onset (disease end-stage: 139 +/- 17 days of age; Figure 1B).
