Table 3 Summary of the efficacy of P42 in cellular, Drosophila, and mouse R6/2 HD models
From: The P42 peptide and Peptide-based therapies for Huntington’s disease
Peptide | Model | Population | Way of administration | End point | Method of evaluation | Results |
|---|---|---|---|---|---|---|
P42 (Arribat et al., 2013) [55] | Cell culture | HeLa cells (hHtt171aa-136Q) | Co-transfection: polyQHtt + P42 or empty vector | Htt aggregation | Immunostaining; filter retardation assays | Rescue = 80 % |
P42TAT (Arribat et al., 2014) [61] | Cell culture | HeLa cells (hHtt171aa-136Q) | Co-transfection: polyQHtt + P42TAT or empty vector | Htt aggregation | Immunostaining; filter retardation assays | Rescue = 80 % |
P42TAT-TAMRA provided in culture cell medium | Htt aggregation | Immunostaining; filter retardation assays | Rescue = 90 % (P42TAT concentration dependent) | |||
P42 (Arribat et al., 2013) [55] | HD Drosophila | MS-1096-Gal4; UAS-HA-hHtt171aa-138Q | Genetic cross: UAS-P42 vs UAS-LacZ (neutral control) | Htt aggregation | Immunostaining; filter retardation assays (L3 larval salivary glands) | Rescue = 80 % |
GMR-Gal4; UAS- hHttex1-93Q | Genetic cross: UAS-P42 vs UAS- GFP (neutral control) | Eye toxicity | Phenotypical comparative analysis (eyes of adult flies) | Rescue = 100 % | ||
OK6-Gal4/UAS-NPY-GFP; UAS-hHtt548aa-128Q | Genetic cross: UAS-P42 vs UAS-LacZ (neutral control) | Larval locomotion | Locomotion (mm/min) | Rescue close to 100 % | ||
OK6-Gal4/UAS-NPY-GFP; UAS-hHtt548aa-128Q | Genetic cross: UAS-P42 vs UAS-LacZ (neutral control) | Axonal transport | Immunostaining and live imaging to quantify different parameters of Neuropeptide Y vesicles trafficking in larval motoneurons. | Recovery of the different parameters: Number of vesicles: 28 %; % of pausing: 21 %; velocity: 31 % | ||
ELAV-Gal4; UAS-hHtt548aa-128Q | Genetic cross: UAS-P42 vs UAS-LacZ (neutral control) | Adult survival | Mean, median, and maximal survival (days) | Increased median survival (day 18 to 26); no effect on mean and maximal survival | ||
P42TAT (Arribat et al., 2014) [61] | R6/2 mice | hHttex1-140Q | Transmucosal daily administration of P42TAT with Aonys® water-in-oil microemulsion (600 μg/ml/kg) vs empty microemulsion at pre-symptomatic (wk2 to wk11) R6/2 and Wt mice. | Motor performance | Latency to fall from accelerating rotarod (weeks 6, 8, and 10) | Significant amelioration compared to placebo-treated R6/2 mice |
Clasping test | Frequency and duration of the foot-clasping posture (twice a week at wk 7, 9, and 11) | Complete rescue vs placebo-treated R6/2 and to wt mice | ||||
Weight loss | Weight measure between wk8 and wk10 | Significant reversion of body weight loss curve vs placebo-treated mice | ||||
Intranuclear brain aggregates; astrogliosis | Immunostaining: number and size of cortical and striatal intranuclear aggregates; cortical and striatal astrocyte number | Significant 50 % reduction of cortical and striatal aggregates; non significant reduction of the astrogliosis | ||||
Cerebral atrophy | Lateral ventricle enlargement | Rescue = 30 % |