Genetic defects are very common, and it’s not surprising when considering how many cells, including germ cells, make up our bodies. Most of these defects have no minor or minor effects, but some are fatal in serious things. One of these defects is in the CPS1 gene, and those who are affected have shortened their lifespan as the only real solution with intensive treatment and snacks. Since then, there may be a change First successful gene therapy Infant with CPS1 deficiency.
Carbamoyl phosphate synthetic enzyme I (I (CPS1) Is an important enzyme for breaking down ammonia formed when protein is decomposed. If the body does not produce enough enzymes in the liver, the ammonia accumulates in the blood and eventually reaches the level that can affect the nervous system. As a phase chromosome enthusiastic disorder, both parents with serious mutations must be a carrier.
In the case of infants affected, in the case of KJ MULDOON, the CPS1 deficiency was severe while keeping the child living while searching for the donor only with protein diet and ammonia deterioration (nitrogen elimination). In this context, the CRISPR-CAS9 therapy has been developed within a few months, and it seems to fix the defective genes in liver cells so far.
CPS1 gene deficiency
Despite the toxicity of living beings ammonia (NH3) Is mainly a must -have part of this living being. Amine (R-NH2), It itself is a somewhat indispensable part of amino acids, especially 22 Protein production amino acid Which protein is formed. Just as ammonia needs in the amination process, ammonia is also formed mainly inside the body. Transamination and Talamination Of these bioamines. This is a process that occurs mainly in the liver and includes the dehumidification of the waste protein overeating the body.
The rest should be neutralized because only a portion of the ammonia can be reused for the new amino acids. Due to the toxicity of ammonia, the level of blood is <50 µmol/L or High ammoemia It occurs. Where is this Urea cycle It works to maintain a healthy ammonia level.
The first stage of the element is to switch ammonia into a carbine phosphate.
NH3 + HCO−3 + 2ATP → 2ADP + Carbamoyl phosphate + Pi
In general, this is a very slow reaction, where enzyme CSP1 acts as a catalyst. In humans, the gene of this enzyme is located in the long arm of chromosome 2 of the gene left 2Q34. If there is a mutation that prevents it from acting as a catalyst in this gene, the ammonia level of the plasma continues to rise and eventually reaches the level of the nervous system. For infants, this is noticeable due to lack of lethargy, seizures and normal developmental traffic. Treatment, delayed development, intellectual disorders or death affect 50%of the baby.
Cancel the mutation
When KJ was born in August 2024, he was helpless with stiff muscles and other worried symptoms. After a serious CPS1 deficiency, KJ was hospitalized in five months after diagnosis was diagnosed through genome sequencing. KJ’s only hope seemed to be liver transplantation, listed on the donor agency, and at best it provided the most hope. Meanwhile, a team began to study the cause of KJ’s CPS1 deficiency and mutations.
like Dr. Eric Topol explained A summary of his Paywalled Gropman et al. ~ NejmBoth fathers and mothers have been found to be a CPS1 mutant carrier, and the father has a cut Q335X variant and a mother with another mother (E714X). If one of the two mutations can be corrected, the child can produce a sufficient CPS1 that can have a functional copy and theoretically have a functional element period without external subsidies.
The complex problem here is that despite many reports of genetic editing for CRISPR over the past few years, there are various gradients that Dr. Topol references from Crispr 1.0 to 3.0.
- CRISPR 1.0: CRISPR-CAS9 tools causes sufficient double strand damage to disable genes (rust out). It’s crude and it’s not related here. Also performed I live.
- CRISPR 2.0: A single stranded cut that allows limited basic editing.
- Crispr 3.0. Including basic editing by expanding the default editing I live and vain.
This method has already been used before I live In the context of cancer treatment, we produce modified T-cells for car T-cell immunotherapy. From a perspective vain Treatment, 2023 is exposed Protein between PCSK9 To reduce bad cholesterol levels and recent basic editing Fizz Mutation It is responsible for liver and lung damage. Also likeThis is a viral vector -based default editing method used to fix other element cycle disorders.
It was only CRISPR 2.0, but in the case of KJ, this was the first fully personalized basic edit therapy. vain It was developed within only six months.
I am crossing all TS
How experimental the gene therapy for KJ’s CPS1 disorder was, the researchers had to go through the entire test, including the animal model. The default editor developed to target the father’s Q335X mutation was re -written with the correct base pair, and in addition to the test for non -human primates, the mouse with the same CSP1 mutation was proved to verify the approach and obtain the FDA approval.
The goal of the default editor was to rewrite the wrong base in the Q335X location of Locus 2Q34. Concerns about the application of CRISPR are so -called editing other than so -called targets, but safety reviews appear to have been delivered here without serious problems.
Starting with a very low dose, the ammonia figures were carefully monitored without any outstanding changes. Three weeks later, the second, high doses were injected and had a positive impact on ammonia levels. The third dose was injected a while later, but the result of this is not yet known. Without a liver biopsy, as reported so far, it is difficult to say how true the true treatment is.
However, according to the report, KJ achieved developmental goals and caused two virus infections without the ammonia crisis. Further injections of treatment can be administered as an MRNA approach than the (estimated) virus vector used so far due to immunization with virus vectors. There is a public question about how many cells are truly edited in KJ’s liver and what the overall effect is.
This was a careful welcoming this news in the future of personalized gene therapy and realized that the road to KJ and the rest of us was still full of unknown and challenges. In other words, we hope for the best possible progress of KJ, and idealistically, genetic disorders such as CPS1 deficiency can serve as a sign of hope for others.
Main images: “Vivid“Ernesto del Aguila III, NHGRI, Courtes: National Human Genome Research Institute
