Schut Menno H, Pepers Barry A, Klooster Rinse, van der Maarel Silvère M, El Khatabi Mohamed, Verrips Theo, den Dunnen Johan T, van Ommen Gert-Jan B, van Roon-Mom Willeke M C
Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
Neurol Sci. 2015 Mar;36(3):429-34. doi: 10.1007/s10072-014-1971-6. Epub 2014 Oct 8.
Huntington disease is caused by expansion of a CAG repeat in the huntingtin gene that is translated into an elongated polyglutamine stretch within the N-terminal domain of the huntingtin protein. The mutation is thought to introduce a gain-of-toxic function in the mutant huntingtin protein, and blocking this toxicity by antibody binding could alleviate Huntington disease pathology. Llama single domain antibodies (VHH) directed against mutant huntingtin are interesting candidates as therapeutic agents or research tools in Huntington disease because of their small size, high thermostability, low cost of production, possibility of intracellular expression, and potency of blood-brain barrier passage. We have selected VHH from llama phage display libraries that specifically target the N-terminal domain of the huntingtin protein. Our VHH are capable of binding wild-type and mutant human huntingtin under native and denatured conditions and can be used in Huntington disease studies as a novel antibody that is easy to produce and manipulate.
亨廷顿病是由亨廷顿基因中CAG重复序列的扩增引起的，该重复序列被翻译成亨廷顿蛋白N端结构域内的一段延长的聚谷氨酰胺链。这种突变被认为在突变的亨廷顿蛋白中引入了毒性功能的获得，通过抗体结合来阻断这种毒性可以减轻亨廷顿病的病理症状。针对突变型亨廷顿蛋白的骆驼单域抗体（VHH）因其体积小、热稳定性高、生产成本低、细胞内表达的可能性以及通过血脑屏障的能力，成为亨廷顿病治疗药物或研究工具的有趣候选物。我们从骆驼噬菌体展示文库中筛选出了特异性靶向亨廷顿蛋白N端结构域的VHH。我们的VHH能够在天然和变性条件下结合野生型和突变型人类亨廷顿蛋白，并且可以作为一种易于生产和操作的新型抗体用于亨廷顿病研究。
