What is Amyotrophic Lateral Sclerosis?
 

Amyotrophic Lateral Sclerosis (ALS), commonly known as Lou Gehrig's disease, is a fatal neurodegenerative disorder characterized by the degeneration of motor neurons. The primary clinical manifestations include progressive muscle atrophy, fasciculations, bulbar palsy, and corticospinal tract signs, ultimately leading to death from respiratory failure.

ALS is classified into sporadic ALS (SALS, accounting for 90%-95%) and familial ALS (FALS, accounting for 5%-10%), with the latter predominantly following an autosomal dominant inheritance pattern. The global prevalence of ALS is approximately 5 per 100,000 individuals, with a lifetime risk of 1 in 400 to 1 in 800. The peak age of onset is between 55 and 75 years, with a median survival of about 27.5 months. In China, the average age of onset is approximately 53.7 years, relatively earlier than in some other populations.
 

Pathogenesis
 

The exact pathogenesis of ALS remains incompletely understood, involving several key aspects:

(Image: PubMed)
 

Genetic Mutations
 

● In Europe, the C9orf72 gene mutation is the most common cause of familial ALS, accounting for 30%-40% of cases. This mutation exerts neurotoxicity by producing abnormal RNA aggregates and dipeptide repeat proteins (DPRs).

(Image: Cell Press)

● In Asia, the SOD1 gene mutation is the most common causative gene, found in 20% of familial ALS and 2% of sporadic ALS cases, followed by mutations in FUS, C9orf72, and TARDBP. Mutations in the SOD1 gene lead to structural abnormalities in superoxide dismutase (SOD), resulting in misfolded aggregates that trigger oxidative stress and mitochondrial dysfunction.

● The TARDBP gene encodes the TAR DNA-binding protein 43 (TDP-43), which plays a crucial role in mRNA stability, protein translation, and nucleocytoplasmic transport. Both loss of TDP-43 function and its overexpression can lead to motor neuron dysfunction.

Proteostasis Imbalance

Mutations in ALS-associated genes can cause protein misfolding, abnormal aggregation, or impaired degradation, leading to the accumulation of toxic protein aggregates and subsequent degeneration and death of motor neurons.

Glutamate Excitotoxicity

Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS). Excessive or prolonged activation of glutamate receptors leads to degeneration and ultimately death of the associated neurons.

Oxidative Stress

SOD1 gene mutations alter antioxidant enzyme activity, disrupting the intracellular balance between oxidation and antioxidation. This results in free radical attack on neuronal cell membranes, proteins, and DNA, causing cellular damage.

Additionally, mechanisms such as mitochondrial dysfunction, impaired axonal transport, neuroinflammation, and deficiency of neurotrophic factors are also involved in the ALS disease process.
 

Gene Therapy
 

● Antisense Oligonucleotide (ASO) Technology: ASOs are short synthetic DNA molecules that bind to specific mRNA sequences, reducing target mRNA levels via RNase H-mediated degradation. In ALS, ASOs are designed to target mutant SOD1 mRNA, reducing the production of toxic protein. For example, Tofersen, an intrathecally administered ASO, is approved for treating ALS patients with SOD1 mutations. Jacifusen (targeting FUS mutations) has also shown some efficacy in clinical trials.

(Image: Cell Press)

● AAV Gene Therapy: SNUG01 (targeting TRIM72 gene) is delivered via AAV9 vectors. It employs multiple mechanisms, including membrane repair and antioxidation, and covers sporadic ALS. It has received FDA Orphan Drug designation and clinical trial approval. KLTO-202 (targeting the s-KL protein) is delivered via AAV vectors to reduce inflammation and oxidative stress, extending survival in ALS models. It has also received FDA Orphan Drug designation.

● Gene Editing Therapy: Gene editing technology can be used to target and excise mutant SOD1 genes. In vitro experiments and animal model studies indicate that this approach can effectively reduce mutant SOD1 expression with minimal impact on wild-type SOD1, showing therapeutic promise.
 

Mouse Models
 

● SOD1G93A Mice: Carry the human SOD1 gene with the G93A point mutation, modeling ALS caused by human SOD1 mutations. Symptoms typically begin at 3-4 months of age, manifesting as hindlimb weakness, tremor, and weight loss. Disease progression is rapid after onset, with an average lifespan of about 120-130 days.

● SOD1H46R/H48Q Mice: Exhibit progressive motor dysfunction, including weight loss, muscle weakness, and paralysis, with an average lifespan of approximately 189 days or less.

● TDP-43 Mice: Show motor dysfunction, neuronal loss, and abnormal TDP-43 protein aggregation, modeling key features of human ALS.

● FUS Mice: Show rapid disease progression accompanied by significant RNA metabolism abnormalities.

● C9450C Mice: Express 450 repeat sequences, used to study the relationship between autophagy defects and DPR accumulation.

● C9orf72 DPR-KI Mice: Exhibit motor neuron loss, cortical hyperexcitability, behavioral deficits (such as anxiety-like behavior), and reduced C9orf72 protein expression.
 

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target gene locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various ALS mouse models according to client needs, such as SOD1G93A mice, SOD1H46R/H48Q mice, TDP-43 mice, FUS mice, C9450C mice, and C9orf72 DPR-KI mice. We welcome inquiries!

 

References:

[1] Li Xiaoguang, Yang Lu, Liu Xudong, Jia Xinmiao, Yang Xinzhuang, Cui Liying. Research Progress on Gene Therapy Mechanisms for Amyotrophic Lateral Sclerosis. Basic and Clinical Medicine, 2023, 43(4): 674-679.

[2] Cai Qing, Li Mengya, Li Guifeng, Li Qifang. Research Progress on Immune Mechanisms of Amyotrophic Lateral Sclerosis. Modern Immunology, 2023, 43(2): 169-174. Zhao Qianqian, Li Wanzhen, Tang Beisha, et al. Research Progress on the Genetics of Amyotrophic Lateral Sclerosis. Chinese Journal of Contemporary Neurology and Neurosurgery, 2023, 23(3): 264-269. DOI: 10.3969/j.issn.1672-6731.2023.03.017.

[3] Kim G, Gautier O, Tassoni-Tsuchida E, Ma XR, Gitler AD. ALS Genetics: Gains, Losses, and Implications for Future Therapies. Neuron. 2020 Dec 9;108(5):822-842. doi: 10.1016/j.neuron.2020.08.022. PMID: 32931756; PMCID: PMC7736125.

[4] Bonafede R, Mariotti R. ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles. Front Cell Neurosci. 2017 Mar 21;11:80. doi: 10.3389/fncel.2017.00080. PMID: 28377696; PMCID: PMC5359305.

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