Guidelines for the preclinical in vivo evaluation of pharmacological active drugs for ALS/MND: Report on the 142nd ENMC international workshop

Abstract

A transgenic animal model for anterior horn cell loss was established in 1994. This model is based on the insertion of a high copy number of disease-causing human Cu/Zn SOD mutations into the intact mouse genome. It serves to establish hypotheses for the pathogenesis of anterior horn cell death, but also to test potential pharmacological approaches to therapy in human ALS. Today, more than 100 -- published and unpublished -- compounds have been tested in this animal model, a large part of them being reported as successful. However, it proved to be difficult to translate these therapeutic successes in the animal model into human trials. Also, a number of disease-modifying strategies were difficult to reproduce, even by the same group. On the other hand, the step from mice to men means a huge investment for the sponsors of clinical trials and the scientific community. Therefore, establishment of standard methods for drug testing in ALS models is mandatory. In this workshop, clinical and preclinical researchers established in the field of ALS/MND met in Holland in March 2006 in order to establish guidelines for the community for drug testing in mouse models.

First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models

“…Therapeutic effects of JAK4D were also assessed in the transgenic G93A-SOD1 mouse, an established model of Amyotrophic Lateral Sclerosis (ALS) (Gurney et al, 1994;Ludolph et al, 2010Ludolph et al, , 2007, employing rotarod performance, body weight, and histological analysis of spinal cord tissue as readouts of potential therapeutic benefit from JAK4D treatment.…”

Regulation of Intracellular Copper by Induction of Endogenous Metallothioneins Improves the Disease Course in a Mouse Model of Amyotrophic Lateral Sclerosis

“…The protocol for Dex treatment was designed according to criteria suggested for preclinical studies [19,20]. The investigators were blind to the mouse genotype and treatment while performing all procedures.…”

“…Disease onset was regarded as the time when each mouse reached its peak weight before its weight began to decline. The end point was defined as the age at which a mouse was unable to right itself within 30 s after having been pushed onto its side [19]. The disease duration was regarded as the period from disease onset until the end point.…”

1st INCF Workshop on Genetic Animal Models for Brain Diseases

“…This needs to be defined before initiating comparative preclinical trials. However, for some diseases, such as ALS, guidelines for preclinical drug interventions have been established by a consortium of experts (Ludolph et al 2007). For each model it needs (1) to be discussed, which biomarker can be used to monitor treatment success, (2) to be defined which specific readouts are wanted, which are reproducible, how to reach standardization, and what scoring system should be used.…”