Table 1 Summary of the efficacy of the different peptides against HD
From: The P42 peptide and Peptide-based therapies for Huntington’s disease
Peptide | Target of the peptide | Model | Population | Way of administration | End point | Method of evaluation | Results |
|---|---|---|---|---|---|---|---|
Bivalent Htt-binding peptide (Kazantsev et al., 2002) [31] | PolyQ stretches | Cell culture | COS-1 cells | Co-transfection of hHtt17aa-103Q ± bivalent Htt-binding peptide | Aggregation | % of aggregate-positive transfected cells | Delayed aggregate formation: 37.6 % reduction at 48 h; no reduction at 96 h |
Drosophila HD | ELAV-Gal4; UAS- 48/108Q | Genetic cross: bivalent Htt-binding peptide vs placebo | Survival | Survival rate | Significant increased survival | ||
Aggregation (CNS) | Immunostaining on L3 larvae | Significant aggregate reduction | |||||
GMR-Gal4; UAS- 48/108Q | Genetic cross: bivalent Htt-binding peptide vs placebo | Photoreceptor neurodegeneration | Quantification of the number of rhabdomeres/ommatidium | Significant rescue of eye neurodegeneration | |||
Polyglutamine-binding peptide 1 (QBP1) (Nagai et al., 2000) [32] | Expanded polyQ stretch | Cell culture | COS-7 cells | Co-transfection of 45Q-/57Q-/81Q-YFP ± QBP1-CFP | Aggregation | % of aggregate-positive transfected cells | Significant aggregate reduction, more important with shorter polyQ |
(QBP1)2 (Nagai et al., 2003) [33] | Expanded polyQ stretch | Drosophila polyQ models | GMR-92Q | Genetic cross: Eyeless-Gal4; UAS-(QBP1)2 or GMR-Gal4; UAS-(QBP1)2 | Photoreceptor neurodegeneration | Phenotypical comparative analysis (adult flies) | Significant suppression of eye degeneration |
GMR-Gal4; UAS-MJDtr-78Q | Genetic cross: UAS-(QBP1)2 | Photoreceptor neurodegeneration | Phenotypical comparative analysis (adult flies) | Significant suppression of eye degeneration | |||
GMR-92Q | Genetic cross: Eyeless-Gal4; UAS-(QBP1)2 | Aggregation in the eye imaginal disc | Immunostaining (third instar larvae) | Significant inclusion bodies reduction | |||
ELAV-Gal4; UAS-MJDtr-78Q | Genetic cross: UAS-(QBP1)2 or UAS-(scrambled)2 | Survival | Life span (adult flies) | Significant increase in survival (median life span from 5.5 to 52 days) | |||
PTD-QBP1 | Expanded polyQ stretch | Cell culture (Popiel et al., 2007) [39] | COS-7 cells | Co-transfection of 81Q-GFP ± Antp-QBP1 provided in the cell medium | Aggregation | % of transfected cells forming inclusion bodies | Significant reduction (from 42 % to 30 %) |
COS-7 cells | Co-transfection of 57Q-GFP ± TAT-QBP1 provided in the cell medium | Cell survival | Quantification of cell death | Significant reduction of cell death (from 11.8 % to 7.4 %) | |||
Drosophila polyQ model (Popiel et al., 2007) [39] | ELAV-Gal4; UAS-MJDtr-78Q | Oral administration of Antp-QBP1 | Survival | Survival rate (5,10, and 15 days) | Significant increase | ||
Aggregation in the eye imaginal disc | Immunostaining (third instar larvae) | Significant reduction of inclusion bodies | |||||
Mouse model (Popiel et al., 2009) [40] | R6/2 mice | Long-term continuous intraperitoneal administration of either Antp-QBP1 (2 mg/week) or saline from wk2 | Motor performances | Latency to fall with accelerating rotarod (from wk5 to death) | No significant difference | ||
Body weight | Weight measure (from wk5 to death) | Significant weight increased compared to saline-treated mice from wk5 to 10 | |||||
Survival | Life span | No significant difference | |||||
Long-term continuous intraperitoneal administration of either Antp-QBP1 (2 mg/week) or saline from wk2 | Aggregation | Brain section immunostaining with anti-htt antibody | No significant difference | ||||
ED11 (Aharony et al., 2015) [41] | Inhibitor of caspase-6 | Cell culture | PC12 cells | Inducible mHtt- 145Q ± TAT-ED11 provided in the cell medium | Survival | Cell viability and cell death assessment | Significant increased cell viability and decreased cell death |
Mouse model | Full-length hHtt-97Q BACHD | Pre-symptomatic treatment (from wk5); continuous infusion (4 mg/kg/day; subcutaneously implanted mini-pump) of ED11 peptide vs vehicle in BACHD mice and of vehicle in wt mice | Body weight (excessive weight) | Weight measure | Attenuation of weight gain | ||
Motor performances | Latency to fall with accelerating rotarod (monthly from wk9) | Preserved motor performance compared to wt mice. | |||||
Depressive-like behaviour | Immobility evaluation during the forced swim test (FST) (5 months of age) | Prevention of increased immobility | |||||
Basal locomotor activity, exploratory activity, anxiety-related behaviour | Open field test (wk22): total travelled distance; time spent in the centre and number of transitions to the centre | Unchanged basal locomotor activity; lower anxiety levels and improved exploratory behaviour in treated vs untreated mice | |||||
Inhibition of caspase-6 activity | Quantification of mHtt586aa fragments (6-month-old mice) | Not evaluable (no detectable mHtt586aa fragments in untreated mice) | |||||
Aggregation | Immunostaining (6-month-old mice) | Not evaluable (no detectable aggregates in untreated mice) | |||||
Post-symptomatic treatment (from w36); continuous infusion (4 mg/kg/day; subcutaneously implanted mini-pump) of ED11 peptide vs vehicle in BACHD mice and of vehicle in wt mice | Motor performances | Latency to fall with accelerating rotarod (monthly, wk30 to 44) | Increased motor performance compared to untreated mice | ||||
Depressive-like behaviour | Immobility evaluation during the forced swim test (FST) (11 months of age) | Rescue at the level of wt littermates | |||||
Cognitive deficits | Swimming T-maze test; shifting abilities (time to reach the re-located hidden platform) | Rescue at the level of wt littermates | |||||
Brain atrophy | MRI volumetric measurements (12 months of age) | Not evaluable (no significant atrophy in untreated BACHD mice) |