Moving forward in clinical trials for ALS: motor neurons lead the way please

Abstract

Amyotrophic lateral sclerosis (ALS) is one of the most complex motor neuron diseases. Even though scientific discoveries are accelerating with an unprecedented pace, to date more than 30 clinical trials have ended with failure and staggering frustration. There are too many compounds that increase life span in mice, but too little evidence that they will improve human condition. Increasing the chances of success for future clinical trials requires advancement of preclinical tests. Recent developments, which enable the visualization of diseased motor neurons, have the potential to bring novel insight. As we change our focus from mice to motor neurons, it is possible to foster a new vision that translates into effective and long-term treatment strategies in ALS and related motor neuron disorders (MND).

Induction of heat shock proteins in differentiated human neuronal cells following co-application of celastrol and arimoclomol

“…In a mouse model of ALS, arimoclomol was found to improve motor performance and extend lifespan of SOD1 G93A transgenic mice (Kieran et al 2004;Kalmar et al 2008Kalmar et al , 2014McGoldrick et al 2013;Poppe et al 2014). Interestingly, arimoclomol is now in phase IIb/III clinical trials (ClinicalTrials.gov identifier: NCT00706147) for the treatment of ALS (Genc and Ozdinler 2013).…”

“…Arimoclomol is a co-inducer of Hsps that prolongs the binding of activated HSF1 to heat shock elements (HSEs) in the promoter regions of heat shock genes (Hargitai et al 2003;Kieran et al 2004;Kalmar et al 2014). Interestingly, arimoclomol is currently in human clinical trials for ALS (ClinicalTrials.gov identifier: NCT00706147) and is well tolerated in ALS patients up to 300 mg/day (Genc and Ozdinler 2013).…”

Advances in the Development of Disease-Modifying Treatments for Amyotrophic Lateral Sclerosis

“…However, olesoxime though was tolerated well with patients, did not show a significant beneficial synergistic effect in ALS patients concomitantly treated with riluzole, with no significance in survival [56]. Dexpramipexole, noted to function as a mitochondrial membrane stabilizer showed promise in animal models of ALS by increasing the life span of human SOD1 G93A (hSOD1) mice by 7 days, and in double blinded phase II trials was safe and well tolerated in ALS patients [24], however in human phase III trials proved negative because it failed to meet its primary efficacy end point [57]. Despite the failures, there is still promise with ongoing candidates being investigated in animal models of ALS.…”

Treatment of Amyotrophic Lateral Sclerosis: Lessons Learned from Many Failures

“…7 Since both cortical and spinal motor neurons die in ALS, the main focus shifted to the health of motor neurons and motor neuron circuitry in patients, and it became important to identify compounds with that capability.…”