Amyotrophic Lateral Sclerosis (ALS) Modeling & Pharmacodynamics Service
Introduction
Amyotrophic Lateral Sclerosis (ALS) is a devastating and currently incurable neurodegenerative disease characterized by the progressive loss of both upper and lower motor neurons, typically leading to respiratory failure and death within 3 to 5 years of onset. While approximately 10% of cases are familial (fALS), with mutations in SOD1 accounting for up to 20% of these instances, the disease's complex pathophysiology involves protein misfolding, mitochondrial dysfunction, and neuroinflammation across both familial and sporadic forms. Given this intricate nature and the typically rapid disease progression, effective drug development necessitates highly specialized preclinical models. Creative Biolabs' platform addresses this need by providing a comprehensive suite of ALS services, integrating genetically relevant animal models with precise electrophysiological and pathological readouts to bridge the gap between discovery and clinical success.
Fig. 1 An overview of biomarker development in frontotemporal dementia and amyotrophic lateral sclerosis.1,3
Available ALS Models
We offer a diverse portfolio of ALS models tailored to different therapeutic strategies, ranging from acute neurotoxic models to chronic proteinopathy simulations. While the SOD1-G93A Transgenic Mouse remains the most widely utilized preclinical model for Amyotrophic Lateral Sclerosis (ALS), the landscape is rapidly expanding to reflect the disease's genetic diversity. Currently, the SOD1-G93A Transgenic Rat model is gaining traction for its larger size, which facilitates complex surgical interventions and longitudinal CSF sampling. Furthermore, models targeting TDP-43 Proteinopathy, FUS mutations, and C9orf72 hexanucleotide repeats are under active development and refinement. These models are essential for dissecting ALS pathogenic pathways and validating therapeutic modalities, including antisense oligonucleotides (ASOs), protein clearance agents, and gene therapies.
| ALS Models | Modeling Method | Application Values | Animal Species |
| SOD1-G93A Transgenic Mouse ALS Model | Overexpression of the human mutant SOD1 gene (G93A mutation), leading to progressive motor neuron loss and muscle atrophy. | Gold Standard: Mimics clinical paralysis, weight loss, and shortened lifespan. Primarily used for screening neuroprotective agents and antioxidants, such as Riluzole and Edaravone. | SOD1-G93A Transgenic Mouse |
Platform
Our multi-dimensional platform captures the full trajectory of motor neuron decline and therapeutic rescue:
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Functional & Motor Assessment:
- Grip Strength & Rotarod: Quantifying muscle weakness and motor coordination.
- Fine Motor Kinematics: Automated gait analysis to detect early-stage walking abnormalities.
- Lifespan Analysis: Monitoring survival extension as a primary efficacy endpoint.
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Electrophysiology:
- Compound Muscle Action Potential (CMAP): Non-invasive measurement of motor unit integrity and neuromuscular junction (NMJ) function.
- Motor Unit Number Estimation (MUNE): Tracking the progressive loss of functional motor units.
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Histopathology & Molecular Analysis:
- Motor Neuron Counting: Stereological quantification of Alpha-motor neurons in the spinal cord ventral horn.
- NMJ Innervation: Visualizing the colocalization of pre-synaptic (Synaptophysin) and post-synaptic (AChR) markers to assess denervation.
- Neuroinflammation: Profiling microglial (Iba1) and astrocytic (GFAP) activation via IHC/IF.
- Biomarkers: Measuring Neurofilament Light Chain (NfL) in plasma/CSF as a sensitive indicator of axonal damage.
Applications
- ASO & Gene Therapy: Validated for quantifying the silencing of mutant human SOD1 mRNA and protein aggregates. Key applications include assessing the drug's ability to delay symptom onset and extend survival in a genetically precise ALS environment.
- Lead Optimization: Utilized to evaluate CNS drug penetration by leveraging the model's progressive Blood-Spinal Cord Barrier (BSCB) leakage. This application is critical for determining the ED50 and optimizing delivery routes (e.g., Intrathecal vs. Systemic).
- Mechanism: Applied to investigate the rescue of mitochondrial vacuolization and axonal transport deficits. It allows for the study of misfolded SOD1 protein clearance and the modulation of microglial/astrocytic neuroinflammation.
- Translational Modeling: Used to bridge the gap to clinical trials by measuring NfL as a neuronal damage biomarker and CMAP to track neuromuscular integrity. These metrics directly align preclinical data with human clinical endpoints.
- Safety & Neurotoxicity Screening: Employed to screen for off-target risks, such as DRG toxicity, within a vulnerable neural landscape. Automated gait analysis ensures that motor improvements are therapeutic rather than drug-induced behavioral artifacts.
Our Advantages
- High-Fidelity Modeling: Access to well-characterized colonies with predictable disease onset and progression.
- Specialized Surgery: Expert stereotaxic and intrathecal (IT) delivery for CNS-targeted therapeutics.
- Longitudinal Tracking: Capability for repeated non-invasive measurements (e.g., CMAP, blood biomarkers) in the same cohort.
- Rigorous Data Interpretation: Studies led by neuroscientists specializing in spinal cord circuitry and neuromuscular diseases.
Work with Us
- Summarize the project requirements and fill in the information collection form.
- Sign a CDA from both parties to further communicate information, such as targets.
- Select an animal model, discuss experimental design, and determine assay parameters.
- Project costing and project schedule forecasting.
- We provide a detailed project plan, including the required sample quantities, methods, and protocols.
- Both parties confirm the project details and start the project.
- Confirm the timeline of the project.
- We provide periodic results and information on the animal's condition.
- We will work together to make project adjustments as necessary.
- We provide a comprehensive project report promptly.
- We arrange transportation for the produced samples.
- We provide a discussion of the project results and help to arrange the next steps.
- Data storage and archiving.
FAQs
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Q: When should treatment begin in the SOD1-G93A model?
A: Depending on the goal, we offer pre-symptomatic dosing (to test prevention) or dosing at disease onset (to test therapeutic rescue), typically around day 60-70.
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Q: Can you evaluate respiratory function?
A: Yes, we can perform plethysmography to measure respiratory rate and tidal volume, which are critical terminal markers in ALS models.
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Q: Is NfL a reliable biomarker in your models?
A: Absolutely. NfL levels in SOD1 and TDP-43 models correlate strongly with motor neuron loss and serve as a robust translational bridge.
Published Data
Oral administration of RD2RD2 significantly improves motor function in SOD1-G93A transgenic mice, as evidenced by enhanced performance in the pole test, hind-limb grip strength, and hind-limb extension reflex. Furthermore, treatment effectively delays the average age of disease onset by 11 days.
Fig. 2 RD2RD2 administration prevented deficits in motor performance and delayed onset of disease in SOD1G93A mice.2,3
References
- Katzeff, Jared S et al. "Biomarker discovery and development for frontotemporal dementia and amyotrophic lateral sclerosis." Brain: a Journal of Neurology vol. 145,5 (2022): 1598-1609. https://doi.org/10.1093/brain/awac077
- Post, Julia et al. "Oral Treatment with RD2RD2 Impedes Development of Motoric Phenotype and Delays Symptom Onset in SOD1G93A Transgenic Mice." International Journal of Molecular Sciences vol. 22,13 7066. https://doi.org/10.3390/ijms22137066
- Distributed under Open Access license CC BY 4.0, without modification.
For Research Use Only.