Huntingtin-Lowering Therapies Study

Huntington's disease is a common genetic neurodegenerative disorder with a characterization of uncontrolled chorea hyperkinesia, cognitive impairment, and emotional deficits. Much evidence suggests that the pathogenesis of HD is caused by mutations in the Huntingtin (HTT) gene and abnormal expansion and aggregation of the HTT protein. With the service of mHTT aggregation/lowering assay, Creative Biolabs is your best choice for an in-depth study of the pathogenic mechanisms of mHTT and to advance your research further.

Backgrounds and Pathology of Huntingtin protein

The HTT gene is located on the upper part of chromosome 4 and encodes the HTT protein. This protein does not have great structural homology with other human proteins, so it is difficult to determine its function and participation mechanism under normal conditions. The HTT protein is composed of approximately 3200 amino acids (depending on the length of the polyQ bundle). Like other proteins, it consists of repeat sequences, each of which consists of about 40 loosely conserved amino acids, in which polyQ is the polyglutamine fabric encoded by the CAG codon. One of the important achievements of modern molecular biology and pathology is to prove that the cause of HD is the mutant and expansion of CAG repeats and the elongation of polyQ.

Many studies showed that the probability and the age of onset of HD are directly related to the number of CAG triplet repeats on the mutant HTT (mHTT). The highly repetitive CAG triplet results in an additional elongated polyQ extension at the N-terminus of the HTT protein, a structure that leads to nuclear aggregation of HTT, known as inclusions of neuronal nuclear (INN). The presence of INNs was associated with behavioral deficits, and their numbers also determined the severity of HD symptoms. HTT proteins with extended polyQ interfere with their interaction with the respective receptors, causing both receptors to become hypersensitive, eventually leading to cell death.

ASO Drugs in Huntington's Disease

Due to the single-gene pathogenic pattern of HD and the important role of huntingtin protein in the pathogenesis, the current in vitro intervention methods for HD mainly focuses on HTT-lowering strategies. Therapies for lowering HTT include antisense oligonucleotides (ASO), RNA interference compounds, zinc-finger transcriptional inhibitors, and CRISPR/Cas9 methods, the former two of which function by targeting mRNA while the latter two by targeting the process of DNA transcription. ASO refers to a synthetic oligonucleotide with a short sequence. The chemically-modified nucleotide containing a specific sequence can complement and polymerize with the mRNA through the Watson-Crick model, increasing its binding affinity to the target sequence to trigger the cell's RNA degradation mechanism.

Fig 1. Three generations of ASOs and native DNA. (Wild, et al., 2017)

mRNAs are accessible in the nucleus or cytoplasm, and they are not protected by repair mechanisms like DNA, so lowering HTT content by reducing the translation of HTT mRNA is easier to achieve than transcriptional regulation or changing the gene itself. Several ASOs, is currently being studied in HD models, some of which have begun in human trials.

The single-gene disease nature of HD makes the study of Huntingtin-Lowering therapies more attractive. Creative Biolabs here provides accurate, comprehensive, and repeatable one-stop services for Huntingtin-Lowering therapies studies. If you want to advance your experiments or need a drug test for HD, please contact us for our professional and efficient R&D team, we will provide and discuss detailed and feasible options for you.

Reference

1. Wild, E.D.; et al. Therapies targeting DNA and RNA in Huntington's disease. Lancet Neurol. 2017, 16(10): 837-847.