Table 1:
Clinical trials conducted to evaluate safety and efficacy of therapies to improve cognitive deficits in Down syndrome
| Treatment | Trial Id# | Phase | Participants | Ages | Use/MOA | Pre–clinical Data | Results | References |
|---|---|---|---|---|---|---|---|---|
| Rivastigmine |
i II |
N/A 1, 2 |
14 42 |
8+, 10–17 yrs. | AD/ Cholinesterase inhibitor | Derivative or Physostigmine/Galantamine–Ts65Dn improve 4–arm maze, olfactory test | No significant improvement in aspects of cognition, language, or overall function | [101-103] |
| Donepezil/ E2020 |
III IV V VI VII |
2 3 3 2 2 |
128 8 9 36 150 |
6–10, 11–17, 15–39 yrs. | AD/ Cholinesterase inhibitor | Ts65Dn– no change in MWM, Altered cholinergic system in DS | Terminated due to lack of efficacy | [104] |
| Memantine |
VIII IX X |
4 N/A 2 |
42 180 200 |
18–32, 15–32, 40+ yrs. | AD/ NMDA uncompetitive antagonist | Evidence of cognitive improvement/ partial improvement in Ts65Dn–Contextual fear conditioning, MWM, WRAM, NOR | No improvement in primary measures, p<0.10 improved CVLT–II scores, PAL Stages, DAS–II Recall of Digits | [22, 105] |
| ELND005/scyllo–inositol | XI | 2 | 23 | 18–45 yrs. | AD/Prevent/reduce amyloid aggregation, increase amyloid–β clearance and myo–inositol regulation to improve cognitive function | Amyloid anti–aggregation effects in vitro, protective effects on oligomer–induced neuronal toxicity, and positive effects on learning in animal models of AD | No differences in cognitive or behavioral measures, and there were no SAEs or deaths in the study, high dose groups discontinued | [23] |
| ACI–24 | XII | 1 | 24 | 25–46 yrs. | AD/ liposomal vaccine– induce anti–Aβ antibodies | Ts65Dn non–significant reduction in brain Aβ levels, improved NOR and CFC, reduction of cholinergic neuron atrophy | Ongoing | [24] |
| Nicotine–transdermal | XIII | 1, 2 | 15 | 25+ yrs. | Nicotinic Cholinergic | No studies performed | Ongoing | |
| Basmisanil/ RO5186582/ RG1662 |
XIV XV XVI XVII |
2 1 1 2 |
173 35 13 45 |
6–11, 12–30, 18–30, 18–40 yrs. | Inverse agonist/negative allosteric modulator of GABAAR | Antagonism of GABA in Ts65Dn–improvement in NOR, MWM, Y–maze | Terminated due to lack of efficacy. | [29, 104] |
| BTD–001/pentylenetetrazole/PTZ | ACTRN12612000652875XXIV | 1 | 88 | 13–35 yrs. | Non–competitive GABAAR antagonist | Chronic treatment improved NOR, MWM, persisted after cessation of treatment | Ongoing | [21, 104] |
| Bumetanide | 2015–005780–16XXV | 2 | 24 | 10–16 yrs. | Autism & Seizure trials/ Sulfamyl loop diuretic for heart failure/ blocks the NKCC1 cation–chloride co–transporter, decreases neuronal intracellular Cl– | Rescue of LTP, NOR, OL in Ts65Dn | Ongoing | [32, 106] |
| EGCG |
XX XXI |
2 2 |
31 87 |
14–29, 14–39 yrs. | DYRK1A inhibitor, lipid lowering properties, antioxidant | Inhibition by EGCG– showed improved MWM, NOR, Y–maze, | Some improvement in cognitive performance with EGCG and training | [10, 107] |
| Folic Acid/ Folic Acid + Thyroid hormone |
XXII XXIII |
2, 3 3 |
120 175 |
3–30 mos., 6–18 mos. | Vitamin– does not require dihydrofolate reductase for its conversion | Genes related to folate metabolism are located on chromosome 21–leading to abnormal metabolism & low folate levels | Some low–level positive impact on developmental age | [13] |
| Vitamin E |
XXIV XXV |
3 3 |
350 349 |
50+ yrs. | α–tocopherol, a lipophilic chain–breaking antioxidant, acts as an inhibitor of lipid peroxidation | Ts65Dn improvement in EP–maze, MWM, R–maze | Did not slow cognitive deterioration in older individuals with DS | [108] |
AD: Alzheimer disease, GABAAR-GABA-A receptor, NKCC1-Na-K-Cl-Cotransporter, MWM: Morris water maze, WRAM: water radial arm maze, NOR: novel object recognition, CFC: conditioned fear conditioning. LTP: long-term potentiation of synaptic activity, CVLT-II: California Verbal Learning Test 2nd ed., PAL: Paired Associates Learning task, DAS-II: Differential Ability Scales-II, SAE: Significant Adverse Effect