The first in vivo gene editing therapy announced the first data
September 07, 2018 Source: US and Chinese medicine source
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];Today, American biotechnology company Sangamo has published early data on its Hunter's disease (also known as MPS II) in vivo gene editing therapy SB-913. There was no response in the two low-dose patients, but the two mid-dose patients had a significant decrease in glycosaminoglycan (GAGs) levels after 16 weeks of SB-913 (urinary GAG decreased by 51%, dermatan sulfate decreased by 32%, sulfuric acid) Heparin decreased by 61%). However, no enzyme (IDS) was detected in the peripheral blood. Sangamo said that the decrease in GAGs was sufficient to indicate that the IDS gene was repaired. IDS did not detect that the detection method was not sensitive enough. Second, IDS may be synthesized but was required to be organized. Fast absorption.
Drug source analysis
Hunter's disease is one of the lysosomal storage diseases and is a rare genetic disease with an incidence of about one in 100,000. Patients cannot degrade complex polysaccharides due to IDS gene variation, resulting in the accumulation of these substances in a variety of tissues. Today's enzyme replacement therapy, such as Shalal's Elaprase, is only suitable for mild patients and can only improve some symptoms. Now Elaprase is administered intravenously, but the most serious central symptoms cannot be improved because the enzyme cannot pass the blood-brain barrier. Even if it can be directly administered in the central administration, it will be very inconvenient to use. Last year, the CLN2 enzyme replacement drug Brineura needs to enter the drug into the cerebrospinal fluid once every two weeks in a sterile environment for 4 or 5 hours each time. SMA gene therapy delivered by AAV has been shown to be partially accessible to the central nervous system, so it is a possible advantage over enzyme replacement therapy. In addition, gene therapy does not require weekly injections like Elaprase, which is an advantage.
Of course, it is not easy to turn these ideals into reality. SB-913 is not a traditional gene therapy, but a gene editor, which can selectively insert therapeutic genes into the target chromosome, which can reduce the risk of insertional mutation in gene therapy. Strictly speaking, SB-913 is not a true gene editor, because this technique does not only modify the variant base, but uses a nuclease called ZFN to cleave the DNA and then provide a whole IDS donor gene, which is in gene repair. May be programmed into the chromosome. This year, the genetic editing company Beam, founded by three Chinese, is developing single-base repair therapy.
Sangamo, a trial called CHAMPIIONS, recruited the first patient in November last year and is a milestone in gene editing technology in the body. Today's data can be considered mixed. It is a good thing to see the decline in GAGs, but the lack of IDS levels and the lack of other methods to evaluate gene editing efficiency is a serious problem. These patients are still using enzyme replacement therapy while using SB-913, making the results more difficult to interpret. If SB913 is really effective then the patient should stop the enzyme replacement therapy and the level of GAGs should be reduced, but experts say that only if the IDS level reaches 50% or more of normal, this risk will be taken. In addition to the low-dose data published today, they have now completed the recruitment of patients in the high-dose group, hoping that the IDS level of the high-dose group will reach a level sufficient to stop the enzyme replacement therapy to conceptually validate the technique.
SB913 as a pioneer can also benefit from other gene editing techniques if it can establish a development path for such therapies. CRISPR is much simpler than ZFN and may be more effective in expanding the range of indications for gene editing technology. Another more mature technique is the TALEN commonly used in in vitro CAR-T gene editing. These techniques are essentially similar to the small-molecule protein degradation technology PROTAC, which is to close the spatial distance between the enzyme and the substrate by targeting molecules. Of course, PROTAC utilizes endogenous E3 linkase. These technologies are truly black technology, and they are completely different from aspirin, which has been used for more than 100 years and we don't know how to improve it. This bottom-up design relies on our understanding of biological processes, but it is more controllable. Although aspirin does not want any biological knowledge, it is entirely dependent on the day, of course, more modern screening techniques can increase the chances of going to the cloud. Now that the pharmaceutical industry is still in its infancy and has to walk on two legs, both models have a lot of work to do.
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