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INTERNATIONAL CONGRESS OF

PharmacoGenetics

• Pharmacogenetic study of drugs used by patients with amyotrophic lateral sclerosis (ALS)

• Delaram Hassani,^1,* Yalda Mohtaj Khorassani,² Fateme Zahra Javan,³ Sahar Ramezani Mohammadi,⁴ Amirreza Boroumand,⁵
  1. Applied Biotechnology Research Center, TeMS.C., Islamic Azad University, Tehran, Iran
  2. 6. Rayan Research Center for Neuroscience & Behavior, Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.
  3. Department of biology, Shandiz institute of higher education, Mashhad, Iran
  5. Immunology Research Center, Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
  
  
  
• Introduction: Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive and disabling neurodegenerative disorder of the nervous system that damages motor neurons (neurons that control voluntary muscle movements) in the brain and spinal cord. As these neurons die, the brain loses the ability to control muscle movements, leading to muscle weakness, paralysis, and ultimately respiratory failure. Types of this disease include Sporadic ALS, Familial ALS (FALS), Limb-onset ALS, Bulbar-onset ALS, Primary Lateral Sclerosis (PLS), and Progressive Muscular Atrophy (PMA). Known related genes include: C9ORF72, SOD1 (Superoxide Dismutase 1), TARDBP (encoding TDP-43 protein), FUS (Fused in Sarcoma).. Due to the genomics of this disease, some new treatments have been designed based on the type of genetic mutation, such as Tofersen (specific to patients with mutations in the SOD1 gene) - FDA approval in 2023 and investigational drugs for C9ORF72 and FUS. In general, ALS disease has no definitive cure. However, pharmacogenetics can help optimize treatment and reduce complications by examining genetic differences affecting metabolism and drug response. Research objectives: Identify genetic polymorphisms affecting the response to common ALS drugs such as riluzole, edaravone, design personalized algorithms based on patients' genetic profiles and reduce side effects and increase therapeutic efficacy through precision medicine.
• Methods: Materials and Methods: In this study, a list of genetic variants associated with ALS was first prepared using data from Whole Genome Sequencing (WGS) or Whole Exome Sequencing (WES). In order to investigate the effect of these variants on drug response, analysis of candidate genes carrying single nucleotide polymorphisms associated with drug metabolism was performed. Then, a more detailed interpretation of the variants was provided using bioinformatics analyses and reliable databases such as PharmGKB, ClinVar, and dbSNP. Subsequently, the effect of these variants on the metabolism of commonly used drugs in the treatment of ALS, including riluzole, edaravone, and toferon, was evaluated by pharmacogenetic modeling and the investigation of biological networks and metabolic pathways. Finally, the findings were compiled in the form of structured tables to provide a basis for detailed analysis of the relationship between genotype and drug response.
• Results: Results: Integrating genetic data into the design and selection of drugs used in patients with ALS could lead to more targeted and effective treatments. Recent advances in pharmacogenetics have opened new horizons in the development of personalized therapies and have provided the possibility of improving clinical outcomes for these patients. The findings from the design of this panel are presented in structured tables that provide a basis for more detailed analysis of the relationship between patients' genetic profiles and drug response.
• Conclusion: Discussion and Conclusion: As a result of the pharmacogenetic studies of patients and according to the results of Tables 1 and 2, a significant relationship was identified between CYP1A2 gene polymorphisms and differences in the effectiveness of the drug riluzole. Polymorphisms of the CYP1A2 gene, which encodes one of the important liver enzymes responsible for drug metabolism, play a significant role in the processing and effectiveness of the drug riluzole. Genetic differences or changes in this gene can cause changes in the speed and quality of riluzole metabolism, so that some patients may process the drug faster or slower than usual. These differences will lead to changes in the concentration of the drug in the blood and ultimately its effectiveness in ALS disease. In other words, CYP1A2 polymorphisms can affect the drug response of patients to riluzole and explain why some patients respond better to this drug and others less or face more side effects. Understanding this relationship can help optimize drug dosage and personalize treatment to increase drug efficacy and reduce side effects. The role of antioxidant genes such as SOD1 in response to treatment was also confirmed. In general, pharmacogenetics can play an effective role in the management of ALS disease; including reducing trial and error in drug administration, improving the quality of life of patients through targeted therapy, and creating a scientific basis for the development of new drugs based on molecular mechanisms. Considering the prospect of a broader pharmacogenomics study of generic drugs consumed in Iran and utilizing comprehensive domestic databases and biobanks, it will be possible to accurately prescribe drugs with personalized doses for each patient. This approach will lead to reducing side effects, selecting the optimal drug, reducing drug resistance, and ultimately increasing the effectiveness of treatment.
• Keywords: Amyotrophic lateral sclerosis, pharmacogenetics, polymorphism