While the TDP‑43Q331K transgenic mouse model has been extensively characterized for progressive motor and neuromuscular deficits, published studies to date have not reported standard therapeutic efficacy experiments in this specific model. Unlike SOD1 models (where drugs like riluzole, edaravone, or Tofersen for SOD1 ALS have been used as positive controls in some studies), there is currently no universally accepted comparator molecule and/or standard-of-care therapeutic that has shown robust disease modification in the TDP‑43(Q331K) mouse model. 

However, several recently published studies have demonstrated that the TDP-43(Q331K) mouse model is pharmacologically responsive to experimental interventions. For example, a pre-print has reported that treatment with dasatinib and quercetin, a senolytic combination, improved motor performance and reduced disease-associated phenotypes in TDP-43Q331K mice (Viteri et al., 2025). In separate studies, M102, a CNS-penetrant small-molecule electrophile that activates the NRF2-ARE and heat-shock response pathways, has also been shown to ameliorate disease-related functional deficits in this mouse model of ALS and FTD (Keerie et al., 2025).  

Reach out to our team to discuss study design your therapeutic in the TDP-43Q331K mouse model. 

At InnoSer we performed validation experiments to evaluate the disease progression of the mice from 4 weeks until ∼9 months of age, confirming in line with the current literature that the model reproduces several key hallmarks of human TDP-43 proteinopathies.  

Progressive motor impairments in the TDP-43 mouse model

• Early phase (4 weeks of age): Compared to TDP-43 WT animals, TDP-43Q331K mice show mild, progressive motor deficits detectable with the inverted grid test. From 7 weeks of age until 9 months of age, mice show reduced CMAP amplitude, indicating early, progressive motor unit dysfunction. The neuronal injury biomarker plasma neurofilament light chain (NfL) is significantly increased from 2 months of age.  

• Intermediate phase (~4 months): Robust motor impairments are evident across multiple assays, including rotarod, inverted grid, and weightlifting tests, in line with previously published results (Watkins et al., 2021). 

• Late phase (~6 months): Gait abnormalities emerge, consistent with published findings (Watkins et al., 2021), highlighting the progressive nature of motor decline in this model. 

Reach out to our team to obtain the full TDP-43 mouse model validation data.  

This TDP-43 mouse model has minimal overexpression of the human TARDBP gene (Watkins et al., 2021; Mitchell et al., 2015); therefore, this single transgenic TDP-43 mouse model shows cytoplasmic TDP-43 accumulation, but no visible cytoplasmic TDP-43 aggregates and nuclear clearing of TDP-43. Consistent with this, cytoplasmic aggregation of TDP-43 into insoluble inclusions in cortical and spinal neurons has been observed in this mouse model at 24 months of age (See figure 5 of Mitchel et al., 2015), making this model more suitable for studying progressive motor deficits and early ALS/FTD-related pathophysiology. 

This is in contrast to high TDP-43 overexpression models, such as the double-transgenic TDP-43 mouse model (as described by Mitchell et al., 2015) or the TAR 4/4 TDP-43 mouse model (as described by Wils et al., 2010) where excessive TDP-43 overexpression leads to insoluble TDP-43 cytoplasmic aggregates and nuclear TDP-43 clearing, but early lethality (double transgenic TDP-43 mice live until 8-10 weeks, and similarly TAR 4/4 mice were reported to die at 3-4 weeks of age) limiting the capability to run longitudinal efficacy studies focused on motor function.  

Reach out to our team to discuss the TDP-43 model and how it can be used to evaluate your compound’s efficacy on TDP-43-associated motor function pathology.

The loss of neuromuscular junction innervation and motor neuron death are one of the 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 on the sciatic nerve, the largest nerve of the peripheral nervous system, supplying the mouse hind limb with both motoric and sensory fiber tracts, using needle electrodes. Compound muscle action potential (CMAP) measures the number and integrity of functional motor units, whereby 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 TDP-43Q331K mouse model, CMAP amplitude is significantly decreased compared to littermate TDP-43 WT animals already at 7 weeks of age before the onset of robust motor function deficits and remains significantly decreased until at least approx. 9 months of age highlighting the progressive disease phenotype.   

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 and clinical studies. Since then, many ALS clinical trials now routinely incorporate plasma and CSF NfL as a response biomarker to monitor therapeutic effects.  

Compared to littermate TDP-43 WT, TDP-43Q331K mice show elevated plasma levels of the neuronal injury biomarker from 5 weeks of age, before 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 TDP-43Q331K 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. 

Because the TDP-43Q331K model shows early and progressive pathology, compound dosing can typically begin between 2–4 months or 4–6 months of age. Studies usually end around week 8 (∼4 months of age) or week 16 (∼6 months of age), with typical dosing schedules every 2 weeks. Schedules can be adapted based on compound pharmacokinetics, mechanism of action, and study objectives.  

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.

While both SOD1-G93A and TDP-43Q331K 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 therapeutic 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 our 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.