HD is a hereditary neurodegenerative disease caused by the
amplification of the CAG trinucleotide repeat in the HTT gene, leading to a Mutant
Huntingtin (mHTT) protein that dysregulates transcription, promotes protein
aggregation, induces neuroinflammation, and impairs mitochondrial function. Motor
dysfunction, cognitive decline, and mental disorders are manifestations of these
biochemical abnormalities. Effective disease-modifying treatments are still limited,
even with recent improvements. This review investigates the increasing relevance of
Klotho, an anti-aging protein with neuroprotective, antioxidant, and anti-inflammatory
characteristics, as a possible therapeutic target in Huntington disease.
We did a comprehensive literature search across PubMed, Scopus, and
Web of Science databases. Klotho's molecular functions in neural protection, energy
metabolism, oxidative stress reduction, and anti-inflammatory signalling were
investigated in the context of HD pathogenesis.
Klotho appears to influence critical neurodegenerative processes involved in
HD. It inhibits NF-κB and NLRP3 inflammasome activity, stimulates antioxidant
enzyme expression (SOD, catalase), promotes GluN2B-NMDA receptor-mediated
synaptic plasticity, and increases astrocytic aerobic glycolysis via FGFR1-ERK
signaling. These functions may mitigate mHTT- induced neuronal damage.
Pharmacologic treatments (e.g., PPAR-γ agonists), vitamin D, and lifestyle
interventions can all modulate klotho expression.
Klotho exhibits neuroprotective effects in Huntington’s disease by
reducing NF-κB/NLRP3- mediated inflammation, strengthening antioxidant defenses,
promoting GluN2B-NMDA– dependent synaptic plasticity, and improving astrocytic
metabolic support via FGFR1–ERK signaling. One intriguing treatment approach for
mutant huntingtin-induced neurotoxicity is the modification of klotho expression.
Klotho is a promising neurochemical modulator with disease-modifying
properties in HD. Its multifunctional protective activities are consistent with important
pathological markers of HD, necessitating more preclinical and clinical studies to
confirm its translational value.
Shikha Singh, Avnesh Kumar, Falguni Goel et al.· Current molecular medicine· 0 citations
INTRODUCTION
Cardiovascular diseases continue to be the leading cause of death worldwide. Traditional medicines relieve symptoms and slow the advancement of the disease, but fail to fix genetic problems at their roots. Cardiovascular science has dramatically changed thanks to advancements in genome editing tools, such as CRISPR/Cas9 and its successor technologies. These types of genome editing tools enable researchers and physicians to precisely and programmatically manipulate specific genetic loci related to cardiovascular diseases, offering hope for developing new curative therapies.
METHODS
This article is based on a complete review of peer-reviewed literature published between 2020 and 2025. A systematic search of databases (PubMed, Web of Science, Scopus, and others) for literature using the keywords (genome editing; CRISPR/Cas9; base editing; prime editing; cardiovascular disease; cardiomyopathy; atherosclerosis; etc.) was completed.
RESULTS
CRISPR/Cas9 makes it easy and fast to create genetically modified cardiac model organisms to evaluate pathogenic variation. Using base editing is an effective way to perform precise single- nucleotide corrections, particularly with respect to PCSK9 targeting and its association with long-lasting reductions in LDL cholesterol levels in humans. Prime editing extends this capability to complex mutations, including RBM20 in dilated cardiomyopathy. Early-stage clinical trials targeting transthyretin amyloidosis demonstrate the feasibility of in vivo genome editing. Secondgeneration cardiotropic AAV vectors and lipid nanoparticles continue to improve cardiac delivery and safety profiles.
DISCUSSION
Genome editing shifted cardiovascular research from associative genetics toward causal intervention. Next-generation editors reduce double-strand break-associated risks, enhancing clinical suitability. Still remaining challenges include efficient delivery in a tissue-specific manner, off-target effects, immunity, and ethical considerations related to permanent genomic modification.
CONCLUSION
Genome editing is a paradigm-shifting development within the field of cardiology that promises a long-term genetic remedy. Yet further optimization and development within genome editing and its guidelines will be important for making such a paradigm shift successful.
Tushar Verma, R. Singh, M. Chaudhary et al.· Current Gene Therapy· 0 citations
