| Popis: |
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease with a mean age of onset of 55 years and mean survival time is 3.5 years. There are two approved drugs: Riluzole and edaravone. ALS patients show high plasma norepinephrine levels, indicative of a sympathetic overactivity, which has been described in ALS. Sympathetic hyper-activation is common in chronic illness and contributes significantly to disease progression and muscle atrophy. However, sympathetic activation can effectively be treated with beta-blockers. We have previously shown that treating B6SJL-Tg(SOD1*G93A)1Gur/J ALS mice with s-oxprenolol attenuated disease progression and improved survival compared to r-oxprenolol, riluzole or racemic oxprenolol. When mice were euthanized 41 days after first ALS symptoms, a higher number of motoneurons was seen in spinal cord of s-oxprenolol-treated mice compared to placebo. Muscle fiber diameter was higher due to an inhibition of catabolic signaling. In the proposed project we aim to replicate these findings in a multicenter approach using B6SJL-Tg(SOD1*G93A)1Gur/J and Thy1-TARDBP*G298S)S97Pcw mouse models in a randomized, parallel, blinded preclinical study. Mice will be treated with s-oxprenolol, riluzole, edaravone, a combination of s-oxprenolol with riluzole or edaravone vs placebo. Survival (=reaching ethical endpoint) will be the primary endpoint and secondary endpoints will be disease progression and a composite endpoint of muscle function and coordination. Mice will also be randomized to be euthanized for histological and biochemical assays. |
