研究表明在怀孕前三个月的胎儿发育期间治疗哺乳动物遗传疾病的前景
A 遗传 障碍是由基因中人的 DNA 的异常变化或突变引起的病症或疾病。 我们的 的DNA provides the required code for making proteins which then perform most of the functions in our body. Even if one section of our DNA gets altered in some way, the protein associated with it can no longer carry out its normal function. Depending upon where this change happens either it can have a little or no effect or it might alter the cells so much that it could then lead to a 遗传 disorder or illness. Such changes are caused by errors in DNA replication (duplication) during growth, or environmental factors, lifestyle, smoking and exposure to radiation. Such disorders are passed on to the offspring and start to occur when the baby is developing in mother’s uterus and are therefore referred to as ‘birth defects’.
Birth defects can be minor or extremely severe and may affect appearance, function of an organ and some aspect of physical or mental development. Millions of children are born annually with serious 遗传 conditions. These defects can be detected during pregnancy as they are evident within the first three months of pregnancy when the organs are still forming. A technique called amniocentesis is available for detecting 遗传 abnormalities in the foetus by testing amniotic fluid extracted from the uterus. However, even with amniocentesis, treating them is not possible as no options are available to make any corrections before birth of the baby. Some of the defects are harmless and require no intervention but some others can be of serious nature and may require long-term treatment or even be fatal for the infant. Some defects can be corrected shortly after birth of the baby – example within a week’s time – but mostly it is too late for treatment.
硫化 遗传 condition in an unborn baby
For the first time the revolutionary gene editing technique has been used to cure a ‘遗传 disorder’ in mice during foetal development in the uterus in a study by researchers at Carnegie Mellon University and Yale University. It is well established that during early development in the embryo (during first three months of a pregnancy) there are many stem cells (an undifferentiated cell type which can become any type of cell upon maturation) that are dividing at a fast rate. This is the pertinent time point where a 遗传 mutation if corrected would reduce the impact of the mutation on embryo-to-foetal development. There are chances that a severe 遗传 condition could even be cured and the baby is born without the unintended birth defects.
在本研究中发表 自然通讯 researchers have used a peptide nucleic acid-based gene editing technique. This technique has been used before to treat beta thalassemia – a 遗传 blood disorder in which haemoglobin (HB) produced in the blood is reduced considerably which then affects normal oxygen supply to various parts of the body leading to severe abnormal consequences. In this technique, unique synthetic molecules called peptide nucleic acids (PNAs) (made of a combination of synthetic protein backbone with DNA and RNA) were created. A nanoparticle was then used to transport these PNA molecules along with “healthy and normal” donor DNA to the location of a 遗传 mutation. The complex of PNA and DNA identifies the designated mutation at a site, PNA molecule then binds and unzips the double helix of mutated or faulty DNA. Lastly, donor DNA binds with the mutated DNA and automates a mechanism to correct the DNA error. The main significance of this study is that it was done in a foetus, thus researchers had to use a method analogous to amniocentesis wherein they inserted the PNA complex into the amniotic sac (amniotic fluid) of pregnant mice whose foetuses were carrying the 基因 导致β地中海贫血的突变。 注射一次 PNA 后，6% 的突变得到纠正。 这些小鼠的疾病症状有所改善，即血红蛋白水平在正常范围内，这可以解释为小鼠的病情“治愈”了。 他们还显示出更高的存活率。 这种注射在一个非常有限的范围内，但研究人员希望如果注射多次，可以获得更高的成功率。
该研究具有相关性，因为没有发现脱靶现象，并且只校正了所需的 DNA。 像 CRISPR/Cas9 这样的基因编辑技术虽然更容易用于研究目的，但它仍然存在争议，因为它会切割 DNA 并在损伤脱靶的正常 DNA 时执行异位错误。 由于这种限制，它们并不适合设计疗法。 考虑到这个因素，当前研究中显示的方法只与目标 DNA 结合并修复它，并且显示零异地错误。 这种有针对性的品质使其成为治疗的理想选择。 目前设计中的这种方法也有可能在未来用于“治愈”其他疾病。
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来源（S）
Ricciardi AS 等。 2018. 用于位点特定基因组编辑的子宫内纳米颗粒递送。 自然通讯. https://doi.org/10.1038/s41467-018-04894-2
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