International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 42-53 http://medscipublisher.com/index.php/ijmms 47 6.2 Drug development targeting mutations The identification of specific genetic mutations in FHH opens avenues for targeted drug development. For example, in silico screening has identified several potential drugs targeting the TPM1 mutation, which could be further investigated for therapeutic use (Carlus et al., 2020). Additionally, understanding the molecular mechanisms underlying these mutations can lead to the development of drugs that specifically address the altered pathways. For instance, the discovery of PCSK9 inhibitors has significantly advanced the treatment of Familial Hypercholesterolemia (FH), a condition with genetic similarities to FHH, by targeting the PCSK9 gene mutations. PCSK9-targeted therapy is a quintessential example of translating genetic research into clinical applications. This pathway, through identifying the role of PCSK9 in regulating Low-Density Lipoprotein Cholesterol (LDL-C) levels, has driven the development of various innovative therapies (Figure 2) (Abifadel and Boileau, 2022). These therapies, ranging from antibody drugs to genetic interventions, demonstrate diverse potential applications. These advancements highlight the potential of developing mutation-specific therapies, which can more effectively manage and treat FHH. Figure 2 PCSK9 timeline-from discovery to targeted therapies (Adopted from Abifadel and Boileau, 2022) 6.3 Prospects for gene therapy Gene therapy holds promising prospects for treating FHH by directly addressing the underlying genetic causes. Advances in gene editing technologies, such as CRISPR-Cas9, offer the potential to correct pathogenic mutations at the DNA level. For instance, correcting mutations in the MYH7 or TPM1 genes could potentially restore normal cardiac function and prevent the progression of hypertrophic cardiomyopathy and related conditions (Carlus et al., 2020). Additionally, the success of gene therapy in other genetic disorders, such as the use of viral vectors to deliver functional copies of defective genes, provides a framework for developing similar approaches for FHH. Ongoing research and clinical trials will be crucial in determining the safety and efficacy of these gene therapy strategies for FHH. 7 Case Studies 7.1 Family case studies Several studies have documented the association of MYH7 mutations with familial hypertrophic cardiomyopathy (HCM). For instance, a study reported a family with a MYH7 mutation (Arg663His) that caused predominant cardiac morphology changes and atrial fibrillation. Longitudinal clinical evaluations in this family revealed that 47% of affected adults developed atrial fibrillation, significantly higher than in ungenotyped HCM populations. Another case involved a 23-year-old male with obstructive HCM due to double heterozygosity for MYH7 mutations (403Arg→Trp and 453Arg→His), with the latter being a de novo mutation (Haluza et al., 2001).
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