Amyotrophic lateral sclerosis (ALS), commonly known as “Lou Gehrig’s disease,” is a rare neurodegenerative condition and one of the world’s five major incurable diseases. It is characterized by the gradual loss of neurons in the brain, brainstem, and spinal cord that communicate with muscles, leading to muscle weakness, difficulty in speaking and swallowing, respiratory function decline, and eventually paralysis. Patients ultimately die from complications such as infections or respiratory failure.

The incidence of ALS is generally 1.5-2.4 per 100,000 people, with most cases occurring between the ages of 40 and 70, and an average onset age of 55. Most ALS patients die within 3-5 years of diagnosis. Although rare, ALS has affected notable individuals such as astrophysicist Stephen Hawking, former vice president of JD.com Cai Lei, and former director of Wuhan’s Jinyintan Hospital Zhang Dingyu.

 

Unclear Mechanisms and Limited FDA-Approved Drugs

The mechanisms behind ALS are not fully understood, with multiple potential causes including genetic and environmental factors. Only 5%-10% of cases have a clear genetic component, while 90%-95% are sporadic. Environmental factors such as air pollution, consumption of mercury-contaminated seafood, and pesticide-laden agricultural products can increase the risk of ALS.

Currently, ALS is incurable, and treatment focuses on symptom relief and quality of life improvement through medication and good care. To date, only four drugs have been approved by the FDA for ALS treatment: riluzole, edaravone, Relyvrio, and the gene therapy drug Tofersen. Tofersen is used to treat ALS patients with superoxide dismutase 1 (SOD1) mutations, approved based on reduced plasma neurofilament light chain (NfL) levels in treated patients. It is administered intrathecally, costing $14,230 per injection (approximately 102,000 RMB per injection), with 14 injections required in the first year (about 1.43 million RMB/year), and 13 injections annually thereafter for maintenance (about 1.33 million RMB/year).

 

Gene Therapy Brings New Hope

Recent advances in basic research have made gene therapy an exciting prospect. Several companies, both domestically and internationally, have made strides in this field. In November 2023, Shenjing Changhua’s ALS gene therapy drug SNUG01, developed by Professor Dongsheng Fan’s team at Peking University Third Hospital, completed its first domestic patient administration in an investigator-initiated trial (IIT), marking a breakthrough in China’s ALS gene therapy.

Gene therapy strategies for ALS mainly include:
(i) Using microRNA or antisense oligonucleotides (ASOs) to eliminate or inhibit abnormal transcription at the RNA level,
(ii) Using RNA interference (RNAi) to degrade abnormal mRNA,
(iii) Using CRISPR/Cas and other methods for DNA genome editing. The marketed ALS gene therapy drug Tofersen employs the first strategy, and other strategies are in clinical trials.

Searches of Clinicaltrials and the Chinese Clinical Trial Register show an increasing number of ALS gene therapy clinical trials in recent years, focusing primarily on microRNA or ASO approaches targeting SOD1, C9ORF72, and FUS. Most of these trials are in early stages. Clinical research results indicate that ALS gene therapy drugs have good safety and some efficacy, but further clinical trials and research are needed to optimize and achieve the best therapeutic effect.

 

Summary and Outlook

While treatment for ALS has made steady progress, there is still an urgent need for more effective therapies to prevent neurodegeneration and alleviate the disease. The expectations for ALS gene therapy drugs remain high. The development of these drugs hinges on understanding the pathogenic, susceptibility, and modifier genes of ALS. Since ALS is a rare disease, the small patient population and limited clinical samples impede research progress. Additionally, challenges such as constructing disease models, recruiting clinical trial subjects, and high development costs slow down ALS gene therapy drug development. Fortunately, widespread attention and collaborative efforts in recent years have accelerated the development of ALS gene therapy drugs in China.

In the future, PackGene will continue to uphold its mission of making gene therapy affordable for everyone. With a customer-oriented approach, we will deepen the development of vector processes and platform technologies, stay updated on ALS gene therapy drug development, and provide comprehensive CMC solutions for cell and gene therapy clients. These services range from druggability assessment to process development, analytical method development, pilot production, testing, regulatory submission in the US and China, and commercial production, thereby facilitating the research and clinical translation of cell and gene therapy drugs.

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Reference
[1] Wang, H., L. Guan and M. Deng, Recent progress of the genetics of amyotrophic lateral sclerosis and challenges of gene therapy. Front Neurosci, 2023. 17: p. 1170996.
[2] Fang, T., et al., Gene Therapy in Amyotrophic Lateral Sclerosis. Cells, 2022. 11(13).
[3] Seelen, M., et al., Long-Term Air Pollution Exposure and Amyotrophic Lateral Sclerosis in Netherlands: A Population-based Case-control Study. Environ Health Perspect, 2017. 125(9): p. 097023.
[4] https://clinicaltrials.gov
[6] https://www.epainassist.com/
About PackGene

PackGene Biotech is a world-leading CRO and CDMO, excelling in AAV vectors, mRNA, plasmid DNA, and lentiviral vector solutions. Our comprehensive offerings span from vector design and construction to AAV, lentivirus, and mRNA services. With a sharp focus on early-stage drug discovery, preclinical development, and cell and gene therapy trials, we deliver cost-effective, dependable, and scalable production solutions. Leveraging our groundbreaking π-alpha 293 AAV high-yield platform, we amplify AAV production by up to 10-fold, yielding up to 1e+17vg per batch to meet diverse commercial and clinical project needs. Moreover, our tailored mRNA and LNP products and services cater to every stage of drug and vaccine development, from research to GMP production, providing a seamless, end-to-end solution.

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