就在费城儿童医院的一名新生儿被诊断患有一种罕见的危及生命的代谢紊乱症六个月后，医生们能够开发出一种个性化的治疗方法，其中包括一种首创的基因编辑方法，这种方法最终可能会改变他的人生历程，并在未来帮助其他患有罕见疾病的人。
这种代谢疾病称为氨甲酰磷酸合成酶1缺乏症，会影响尿素循环，并可能导致血液中积累致命水平的氨，导致严重和永久性的脑损伤。它影响着大约130万人中的1人。在被诊断患有这种疾病的婴儿中，50%在婴儿早期就死于这种疾病。
费城医院的婴儿“患有与尿素循环相关的最严重的代谢疾病的最严重变种，”Dr。阿伦斯-尼克拉斯这项研究的主要作者，费城儿童医院代谢疾病项目和人类遗传学部门的代谢儿科医生告诉ABC新闻。“这意味着我们必须加快我们已经在进行的个性化治疗的进程。”
虽然肝脏移植可以改善结果，但许多婴儿在长到足以接受肝脏移植之前，就会出现与血液中氨含量高有关的问题，这些问题可能会导致神经并发症，如发育迟缓、智力残疾和严重的大脑肿胀或损伤。
这种治疗方法在新英格兰医学杂志上发表的一项新研究中进行了描述，并在美国基因和细胞治疗学会会议上提出，它依赖于一种称为CRISPR的复杂疗法，这是一种强大的基因编辑工具。CRISPR的工作原理就像一把分子剪刀，允许科学家精确地切割和修复有缺陷的基因。利用CRISPR，该团队能够创造出针对婴儿特定基因突变的治疗方法。
医生们通过创建一种简化的碱基编辑治疗方法开始了这一过程，这是一种改变婴儿基因组中特定的单一成分以匹配其病情变化的技术。然后，医生使用脂质纳米颗粒将改变的DNA直接输送到肝细胞，脂质纳米颗粒是一种微小的脂肪基载体，有助于将治疗药物输送到身体的正确位置。这种方法是专门为这位患者设计的，标志着个性化医疗向前迈出了一大步。
Ahrens-Nicklas解释说，目标是重复使用治疗的关键部分，如脂质纳米颗粒和mRNA，并简单地针对每个患者的特定基因突变更换一套定制的指令。
“把它想象成一个GPS信号，”Dr。基兰·穆苏努鲁宾夕法尼亚心血管研究所遗传和表观遗传疾病起源项目的主任告诉ABC新闻。“你可以根据你想要改变的特定基因序列来改变GPS的走向。”
这种基因编辑的新方法可以为这种疾病和其他罕见疾病带来更快的个性化治疗。医生指出，另一个优点是，与其他给药系统不同，如果患者需要，可以在以后的生活中再次给药。
值得注意的是，这种疗法是在婴儿出生后仅六个月内开发出来的。该儿童分别在7个月和8个月时接受了两次输液。在七周的随访中，患者能够获得更多的膳食蛋白质，并将药物剂量减少了50%，并且没有不良副作用。
Musunuru说，这一进展给医生带来了患有罕见遗传疾病的患者的希望，否则他们将没有其他治疗选择。
“下一步将是建立卓越的基因组中心，在那里患者可以实时获得为他们创造的独特疗法，”他说。
Doctors save baby's life with first-ever gene fix for deadly rare disease
Just six months after a newborn at Children's Hospital of Philadelphia was diagnosed with a rare and life-threatening metabolic disorder, doctors were able to develop a personalized treatment involving a first-of-its-kind approach to gene-editing that could end up changing the course of his life -- and help others with rare diseases in the future.
The metabolic condition, called carbamoyl-phosphate synthetase 1 deficiency, affects the urea cycle and can cause deadly levels of ammonia to build up in the blood, leading to severe and permanent brain damage. It affects about 1 in 1.3 million people. Among babies diagnosed with it, the disease kills 50% of them by early infancy.
The baby at the Philadelphia hospital "had the most severe variant of the most severe metabolic condition related to the urea cycle," Dr.Ahrens-Nicklas, the study's lead author and a metabolic pediatrician within the metabolic disease program and the division of human genetics at Children's Hospital of Philadelphia, told ABC News. "This meant that we had to expedite the pathway for personalized therapy we were already working on."
While a liver transplant can improve outcomes, many infants develop issues related to the high levels of ammonia in their blood that can lead to neurological complications such as developmental delay, intellectual disability, and severe brain swelling or damage, before they are large enough to get a liver transplant.
The treatment, described in a new study published in The New England Journal of Medicine and presented at the American Society of Gene and Cell Therapy meeting, relies on a complex therapy known as CRISPR, a powerful gene-editing tool. CRISPR works like a pair of molecular scissors, allowing scientists to precisely slice and repair faulty genes. Using CRISPR, the team was able to create a treatment tailored to the baby's specific genetic mutation.
Doctors began the process by creating a streamlined approach to base-editing therapy, a technique where a single component of the baby's genome specific was changed to match the variant of his condition. Doctors then delivered the altered DNA directly to liver cells using a lipid nanoparticle -- a tiny, fat-based carrier that helps transport treatment to the right place in the body. This approach was designed specifically for this single patient and marks a major step forward in personalized medicine.
The goal is to reuse key parts of the treatment -- like the lipid nanoparticle and mRNA -- and simply swap in a custom set of instructions for each patient's specific gene mutation, Ahrens-Nicklas explained.
"Think of it like a GPS signal," Dr.Kiran Musunuru, director of the Penn Cardiovascular Institute's Genetic and Epigenetic Origins of Disease Program, told ABC News. "You can change where the GPS is going depending on what specific sequence of genes you want to change."
This new approach to gene editing could lead to faster personalized therapies for this and other rare diseases. Another advantage, the doctors pointed out, is that it can be given again later in life should the patient require it, unlike other delivery systems.
Of note, the therapy was developed within just six months of the baby's birth. The child received two infusions at 7 and 8 months, respectively. At the seven-week follow-up, the patient was then able to receive more dietary protein and reduce the dose the medication dose by 50% with no bad side effects.
This development is giving doctors hope for patients with rare genetic disease who would otherwise have no other treatment options, Musunuru said.
"The next steps would be to build genomic centers of excellence where patients can get unique therapies created for them in real time" he said.
