Yes, published research has shown that disease modification has been demonstrated in the transgenic SOD1-G93A mouse model in preclinical studies evaluating the efficacy of an antisense oligonucleotide (ASO), Tofersen targeting SOD1 (McCampbell et al., 2018).  

The study performed by McCampbell and colleagues has demonstrated that one of the key ALS disease-mimicking symptoms in the transgenic SOD1-G93A mouse model, namely loss in compound muscle action potential (CMAP), reflecting loss of functional peripheral nerves and an increase in the plasma serum phospho-neurofilament heavy chain levels, a biomarker of neurodegeneration, was stopped by the SOD1 ASO therapy.

In turn, this work provided the foundation for the advancement of this compound to human clinical trials and eventually its clinical indication for ALS patients with SOD1 mutation (Tofersen).

Contact our team to determine whether Tofersen can be used as a comparator or benchmark in your SOD1-G93A preclinical study. 

The loss of neuromuscular junction innervation and motor neuron death are one of key hallmarks of human ALS pathophysiology, which are quantitatively captured by nerve conduction studies (NCS). Importantly, in preclinical animal studies, NCS provide you with highly relevant translational data, as NCS are a standard diagnostic and disease monitoring tool in ALS patients.  

In mice, electrophysiological recordings are performed using needle electrodes in the gastrocnemius muscle. This muscle is innervated by the sciatic nerve, which is the largest nerve of the peripheral nervous system, supplying the mouse hind limb with both motor and sensory fiber tracts. Compound muscle action potential (CMAP) measures the number and integrity of functional motor units, whereby a lower CMAP response indicates fewer functional motor units. Nerve conduction velocity (NCV) measures the speed and nerve signal propagation, serving as a proxy marker for nerve myelination. With nerve damage, white matter is lost, which means it takes longer for the stimulus to reach the connected muscle.  

In the SOD1-G93A model, CMAP amplitude is significantly decreased compared to littermate SOD1-WT animals already at 11 weeks of age, before the onset of robust motor function deficits, confirming motor neuron degeneration and the functional decline in neuromuscular function.  

Reach out to our team to discuss the most suitable timepoint(s) to measure NCS to assess the efficacy of your novel ALS therapeutics.

Neurofilament light chain (NfL) represents a highly translationally relevant plasma biomarker of neuronal injury in many neurodegenerative diseases, including ALS.  

Importantly, the SOD1-targeting antisense oligonucleotide (ASO) Tofersen demonstrated efficacy in reducing plasma and CSF NfL levels in both preclinical (McCampbell et al., 2018) and clinical studies (Meyer et al., 2023). Since then, many ALS clinical trials now routinely incorporate plasma and CSF NfL as a response biomarker to monitor therapeutic effects.  

SOD1-G93A mice show elevated plasma levels of the neuronal injury biomarker (NfL) at 11 weeks of age, before the onset of robust motor function deficits, indicating the translational relevance of including this biomarker in your preclinical study designs. 

Reach out to our team to discuss the most suitable timepoint(s) to collect plasma NfL to assess the efficacy of your novel ALS therapeutics.

Generally, preclinical efficacy study timelines in the SOD1-G93A mouse model depend on multiple factors, including your compound’s modality (i.e., is it a small molecule therapeutics, RNA-based therapeutics such as ASOs, siRNA and gene therapy), mechanism of action (i.e., disease-modifying or symptomatic), dosing schedules, route of administration (i.e., ICV, intrathecal, IV via tail vein or retro-orbital), as well as the choice of readouts including motor function battery tests and translational readouts such as nerve conductions studies, and plasma NfL assessments.  

SOD1-G93A mice display motor function deficits starting at young ages (12 weeks of age) that are progressive up to 20 weeks of age, when animals start to reach paralysis and mortality/human endpoints, providing a relatively large window for testing of new therapeutics. Early motor unit dysfunction is evident as early as 11 weeks of age, before robust motor deficits are observed. As an example, for small molecule compounds, starting treatments around 6-8 weeks in the SOD1-G93A mice is typical.  

Reach out to our team who will help you design a preclinical study package taking into account your therapeutic’s mechanism of action, experimental goals, study timelines, and budget needs.

Previous research has shown that male and female SOD1-G93A mice do not have the same onset of symptoms (Hatizperos et al., 2015). Therefore, while possible, including both sexes in studies involving SOD1-G93A mice increases the variability, necessitating the use of more animals to reach sufficient statistical power for the detection of treatment effects.  

Reach out to our scientific experts who will be able to advise you on the details of your preclinical efficacy study design, including the inclusion of both male and female SOD1-G93A. 

While both SOD1-G93A and TDP43-Q331K models represent well-established preclinical models to study efficacy of novel ALS therapeutics, both differ in terms of target disease, onset, and progression of ALS pathophysiology.  

Briefly, the SOD1-G93A mouse carries a mutation in the superoxide dismutase 1 (SOD1) gene, which accounts for ~20% of familial ALS cases (5–10% of total ALS). This model reflects SOD1 proteinopathy, with aggregation and misfolding of mutant SOD1 leading to progressive motor neuron degeneration. The TDP-43 model expresses mutant human TDP-43 (i.e., Q331K), a pathology present in ~95% of ALS and ~50% of frontotemporal dementia (FTD) cases. This makes it highly relevant not only for ALS, but also for ALS–FTD spectrum research. 

In conclusion, if your therapy directly targets SOD1, the SOD1-G93A model is the most suitable. For therapies aiming at broader ALS mechanisms (neurodegeneration, protein aggregation, motor neuron loss, neuroinflammation), TDP-43 models are relevant to a wider patient population. 

As a preclinical ALS CRO, InnoSer has expertise in carrying out preclinical studies in both SOD1 and mutant TDP-43 mouse models. Reach out to our team to discuss whether the SOD1-G93A or TDP-43 model is most appropriate for your compound’s mechanism of action.