MND Awareness Day 2026: Overcoming ALS Drug Development Bottlenecks with Predictive In Vivo Tools
As June 21, 2026 approaches, the global community prepares to mark MND Awareness Day, a day that symbolizes light, strength, and the resilience of people living with motor neurone disease[1]. Also known as amyotrophic lateral sclerosis (ALS) in many countries, this progressive neurodegenerative condition destroys the motor neurons that control voluntary movement, leading to muscle weakness, paralysis, and typically death from respiratory failure within two to five years of symptom onset. Worldwide, approximately 140,000 new cases are diagnosed each year, with a prevalence of around six per 100,000 people[2]. While about 90 percent of cases arise sporadically, the remaining 10 percent are familial and have revealed key genetic drivers that continue to guide research[3]. Unlocking effective treatments for this complex disease depends on high-quality experimental models that faithfully capture its pathology in both living systems and controlled cellular environments. Cyagen provides specialized gene-edited and humanized mouse models, together with complementary CRO platforms, to help accelerate ALS research and the development of new therapies.
Figure 1. Distribution of amyotrophic lateral sclerosis (ALS) cases and genetic causes underlying familial ALS[3].
1. SOD1 Mutations in ALS: Accelerating Gene-Silencing Therapies with G93A Mouse Models
Among the genes linked to familial ALS, SOD1 stands out as one of the most critical due to its foundational role in disease research and therapeutic development. The SOD1 gene encodes copper-zinc superoxide dismutase, an enzyme that protects cells against oxidative damage by converting superoxide radicals into less harmful molecules. Since the identification of SOD1 mutations as the first genetic cause of ALS in 1993, more than 180 variants have been documented, with the G93A mutationserving as a particularly influential example [4]. These mutations do not simply eliminate enzyme activity; instead, they produce a toxic gain of function that triggers protein misfolding and aggregation, mitochondrial dysfunction, glutamate-mediated excitotoxicity, and sustained neuroinflammation. The resulting selective death of motor neurons in the spinal cord and brainstem closely mirrors key aspects of human pathology. Decades of study using SOD1 models have revealed core mechanisms shared across ALS forms and have directly supported the advancement of targeted therapies, including antisense oligonucleotides and gene-silencing strategies now progressing through clinical evaluation [5].
![Figure 2. Proposed pathogenic mechanisms in ALS <sup>[5]</sup>.](https://web.cdn.cyagen.com/cyagen-en-v2/pictures/c1e34f8d0c2a1ae70cd8a344a72f27e4.png)
Figure 2. Proposed pathogenic mechanisms in ALS [5].
2. FUS Mutations in Familial ALS: Targeting RNA Metabolism and Aggressive Neurodegeneration
FUS mutations represent another important genetic driver of ALS, frequently associated with earlier disease onset and faster progression compared with other familial forms. The FUS protein normally functions in RNA transcription, splicing, and transport, as well as in the formation of stress granules during cellular stress responses. Disease-causing mutations disrupt nuclear localization signals, leading to cytoplasmic mislocalization, aggregation, and loss of normal RNA-processing functions [6]. These alterations impair neuronal homeostasis and contribute to synaptic dysfunction and motor neuron vulnerability. FUS-related ALS often overlaps clinically with frontotemporal dementia, and the gene's role in RNA granule dynamics has opened new avenues for investigating how RNA metabolism defects converge with other ALS pathways to drive neurodegeneration.
![Figure 3. Mutant FUS impairs DNA nick ligation and oxidative damage repair in familial ALS <sup>[7]</sup>.](https://web.cdn.cyagen.com/cyagen-en-v2/pictures/7c7e8bf83ae68ec3e2f8972ec893aceb.png)
Figure 3. Mutant FUS impairs DNA nick ligation and oxidative damage repair in familial ALS [7].
3. TDP-43 Pathology and Proteinopathy: A Universal Target for Sporadic and Familial ALS
Mutations in TARDBP, the gene encoding TDP-43, account for a modest share of familial ALS yet carry broad significance because TDP-43 aggregates appear in nearly all ALS cases, including sporadic forms [8]. Disease-associated changes cause TDP-43 to mislocalize to the cytoplasm, where it forms toxic aggregates that disrupt RNA processing, stress granule assembly, and axonal transport. This convergent proteinopathy links genetic and non-genetic disease mechanisms and represents a high-priority target for therapies seeking to restore nuclear TDP-43 function or promote aggregate clearance [9]. Humanized TDP-43 mouse models have proven valuable for exploring these processes and evaluating candidate interventions.
![Figure 4. A variety of approaches have been used in animal and in vitro models to target TDP-43 <sup>[7]</sup>.](https://web.cdn.cyagen.com/cyagen-en-v2/pictures/eb229e7dfdc02469e83b673596e3da8a.png)
Figure 4. A variety of approaches have been used in animal and in vitro models to target TDP-43 [7].
4. Precision Humanized Mouse Models for ALS Gene Research and Therapy Testing
To empower researchers in dissecting the complex mechanisms of ALS Cyagen has developed a specialized portfolio of precision mouse models targeting the disease's primary genetic drivers. Our humanized SOD1 models carrying the G93A mutation provide a highly reliable platform for evaluating SOD1-targeted therapeutics. For researchers focused on proteinopathies and RNA dysregulation, our custom TARDBP and FUS strains enable precise in vivo tracking of TDP-43 mislocalization and aggregate pathology. To address hexanucleotide repeat expansions in C9orf72, which represent the most frequent genetic cause of familial ALS, we offer robust knockout and conditional models [10]. These tools are specifically engineered to help researchers investigate mechanisms such as haploinsufficiency, autophagy impairment, and the efficacy of novel repeat-expansion interventions.
These models deliver key advantages, including faithful reproduction of human-like pathology on consistent genetic backgrounds that enhance experimental reproducibility, options for customization to introduce additional modifications or combine alleles, and full integration with Cyagen’s CRO services for comprehensive phenotyping, behavioral analysis, and efficacy studies.
| Product Name | Product Number | Full Strain Name |
|---|---|---|
| hFUS Mice | C001965 | C57BL/6JCya-Fustm2(hFUS)/Cya |
| huFUS-R521C Mice | C001647 | C57BL/6JCya-Fusem3(hFUS*R521C)/Cya |
| RCL-huSOD1-G94A Mice | C002001 | C57BL/6JCya-Gt(ROSA)26Sorem1(hSOD1*G94A)/Cya |
| huTARDBP | C001418 | C57BL/6JCya-Tardbptm1(hTARDBP)/Cya |
| huTARDBP-Q331K/M337V/A382T | C001963 | C57BL/6JCya-Tardbptm2(hTARDBP*Q331K*M337V*A382T)/Cya |
| C9orf72-KO | S-KO-14101 | C57BL/6JCya-C9orf72em1/Cya |
| C9orf72-flox | S-CKO-15649 | C57BL/6JCya-C9orf72em1flox/Cya |
● Featured Case Study: Tracking Motor Deficits in the huFUS and huFUS-R521C Model
A robust preclinical ALS model should display successful humanization with appropriate gene expression together with the development of progressive motor and cognitive impairments. In our comprehensive validation of the huFUS strain, we confirmed high human FUS expression in brain and spleen with no detectable mouse Fus, alongside comparable FUS protein levels in the cerebral cortex of huFUS and wild-type mice. Phenotypic tracking of huFUS-R521C mice against wild-type and huFUS controls over 16 weeks revealed that while early grip strength and rotarod performance remained largely intact at 8 weeks, significant and progressive motor coordination deficits emerged on the rotarod from 12 weeks of age, accompanied by grip strength reductions in females at 12 weeks and clear deficits in novel object recognition by 16 weeks, thereby providing an ideal therapeutic window for evaluating candidate compounds targeting FUS pathology.
● Growth Curve
Figure 5. Growth curve of wild-type (WT), huFUS, and huFUS-R521C mice.
● Results of Behavioral Tests on 8-week-old, 12-week-old and 16-week-old Mice
● Grip strength force of WT, huFUS, and huFUS-R521C mice.
8-week-old
12-week-old
16-week-old
No significant alterations in force across all models, indicating similar muscle activity.
● The latency to fall for WT, huFUS and huFUS-R521C mice in rotarod test.
8-week-old
12-week-old
16-week-old
huFUS-R521C mice exhibited a significant reduction in latency to fall compared to both WT and huFUS mice from 12 weeks of age, across both male and female cohorts, indicating impaired motor activity and coordination.
5. Preclinical CRO Solutions for ALS: Integrated Neuroinflammation and Evaluation Platforms
Robust animal models represent only the first step. To truly accelerate your ALS therapeutic pipeline Cyagen provides integrated preclinical contract research services tailored to neurodegenerative diseases. Neuroinflammation plays a critical role in driving ALS progression. Our established immunology and neuroinflammation profiling platforms make use of advanced flow cytometry together with multiplex cytokine assays. These tools enable you to precisely measure microglial activation and immune responses.
These capabilities integrate with our comprehensive neurobehavioral phenotyping and AAV gene therapy evaluation services to provide the data necessary to advance your candidate from early validation to IND submission.
Partner with Cyagen to Accelerate Your ALS Drug Discovery and IND-Enabling Studies.
On MND Awareness Day we reaffirm our commitment to providing the global scientific community with precision SOD1, FUS, TARDBP, and C9orf72 mouse models alongside comprehensive efficacy studies.
6. Reference
[1] MND Association. Global MND Awareness Day 2026 [Internet]. Northampton (UK): MND Association; 2026 [cited 2026 Jun 17]. Available from: https://www.mndassociation.org/about-us/who-we-are/global-mnd-awareness-day
[2] Wolfson C, Gauvin DE, Ishola F, Oskoui M. Global Prevalence and Incidence of Amyotrophic Lateral Sclerosis: A Systematic Review. Neurology. 2023 Aug 8;101(6):e613-e623. doi: 10.1212/WNL.0000000000207474. Epub 2023 Jun 12. PMID: 37308302; PMCID: PMC10424837.
[3] Maharjan N, Saxena S. Models of Neurodegenerative Diseases. In: Egger B, editor. Neurogenetics. Cham: Springer; 2023. p. 179-209. doi: 10.1007/978-3-031-07793-7_10
[4] Pansarasa O, Bordoni M, Diamanti L, Sproviero D, Gagliardi S, Cereda C. SOD1 in Amyotrophic Lateral Sclerosis: "Ambivalent" Behavior Connected to the Disease. Int J Mol Sci. 2018 May 3;19(5):1345. doi: 10.3390/ijms19051345. PMID: 29751510; PMCID: PMC5983710.
[5] Hu Y, Chen W, Wei C, Jiang S, Li S, Wang X, Xu R. Pathological mechanisms of amyotrophic lateral Sclerosis. Neural Regen Res. 2024 May;19(5):1036-1044. doi: 10.4103/1673-5374.382985. PMID: 37862206; PMCID: PMC10749610.
[6] Almalki S, Salama M, Taylor MJ, Ahmed Z, Tuxworth RI. FUS-related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review. Front Mol Neurosci. 2025 Oct 31;18:1671910. doi: 10.3389/fnmol.2025.1671910. PMID: 41245603; PMCID: PMC12615431.
[7] Wang H, Guo W, Mitra J, Hegde PM, Vandoorne T, Eckelmann BJ, Mitra S, Tomkinson AE, Van Den Bosch L, Hegde ML. Mutant FUS causes DNA ligation defects to inhibit oxidative damage repair in Amyotrophic Lateral Sclerosis. Nat Commun. 2018 Sep 11;9(1):3683. doi: 10.1038/s41467-018-06111-6. PMID: 30206235; PMCID: PMC6134028.
[8] Balendra R, Sreedharan J, Hallegger M, Luisier R, Lashuel HA, Gregory JM, Patani R. Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy. Lancet Neurol. 2025 May;24(5):456-470. doi: 10.1016/S1474-4422(25)00109-7. PMID: 40252666; PMCID: PMC7617675.
[9] Yan X, Kuster D, Mohanty P, Nijssen J, Pombo-García K, Garcia Morato J, Rizuan A, Franzmann TM, Sergeeva A, Ly AM, Liu F, Passos PM, George L, Wang SH, Shenoy J, Danielson HL, Ozguney B, Honigmann A, Ayala YM, Fawzi NL, Dickson DW, Rossoll W, Mittal J, Alberti S, Hyman AA. Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates. Cell. 2025 Jul 24;188(15):4123-4140.e18. doi: 10.1016/j.cell.2025.04.039. Epub 2025 May 23. PMID: 40412392; PMCID: PMC12303766.
[10] Mizielinska S, Hautbergue GM, Gendron TF, van Blitterswijk M, Hardiman O, Ravits J, Isaacs AM, Rademakers R. Amyotrophic lateral sclerosis caused by hexanucleotide repeat expansions in C9orf72: from genetics to therapeutics. Lancet Neurol. 2025 Mar;24(3):261-274. doi: 10.1016/S1474-4422(25)00026-2. PMID: 39986312; PMCID: PMC12010636.
