July 23, 2024

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RNA drugs for patients with rarer genetic diseases are coming

RNA drugs for patients with rarer genetic diseases are coming


RNA drugs for patients with rarer genetic diseases are coming.



On November 3, researchers published an article in “Science” that indicated that personalized RNA drugs may soon be used for rarer genetic diseases. RNA drugs may even completely break the traditional thinking of drug development.

The design idea of ​​the drug is as follows: Which protein in the human body is responsible for making people sick, or which protein can be treated as long as it is eliminated. Design a short RNA strand that can complementarily bind to the RNA sequence of which protein and inject it.

To the human body, that’s it. Neuroscientist Tim Yu announced on ASHG the development of this personalized RNA drug, which is treated through a customized ASO to match DNA defects. ASO will adhere to the RNA during the process of processing RNA into mature mRNA, hiding errors so that the patient’s cells can make the protein correctly.


Three years ago, neuroscientist Tim Yu announced at the American Society for Human Genetics (ASHG) annual meeting that in just 10 months, his team at Boston Children’s Hospital had developed, tested and used a- -The news of a drug targeting a unique genetic mutation that caused a fatal brain disease in a 7-year-old girl shocked colleagues. milasen (to the girl Mila named) story has sparked the use of short-chain RNA (called antisense oligonucleotides (ASOs)) for more personalized treatment of hope , this treatment can overcome the genetic defect .


At this year’s ASHG conference held last month (online), Yu shared a thought-provoking update: Mila passed away earlier this year-this is a tragic evidence that for neurodegenerative diseases, “intervene early to Important .”


But Yu’s team and others are now expanding the custom ASO method, called “n of 1” , because the drug is only designed for one or a few patients . A foundation has been formed to provide customized RNA for free. The U.S. Food and Drug Administration (FDA) is developing guidelines for the results of trials, manufacturing, and monitoring of personalized treatments.

At the ASHG meeting, Yu balanced Mila’s results with a more promising story, which told the story of another young girl who received a customized ASO treatment and saw her condition temporarily stabilize .


On November 3 , the researchers published an article titled ” Personalized RNA drugs may soon be available for more rare genetic diseases ” in ” Science ” .


RNA drugs for patients with rarer genetic diseases are coming


It usually takes many years to develop a treatment for a genetic disease . But after sequencing Mila’s genome, Yu’s team discovered that she had an extra piece of DNA in a gene called CLN7, which disrupted the mRNA or protein construction instructions produced by the gene . Yu realized that it might be necessary to quickly synthesize ASO to overcome this problem . ASO will adhere to RNA during the process of processing RNA into mature mRNA, hiding errors so that Mila’s cells can make proteins correctly .


Yu’s team passed toxicological testing and FDA approval. In a life-threatening situation, when the drug was injected into Mila’s spinal fluid for the first time in early 2018, Mila was blind and unable to walk without assistance.

Although this helped her reduce seizures and restore some muscle strength, her condition eventually deteriorated. But her story has led more families to seek help from Yu. Yu estimates that 10% to 15% of genetic disease patients have genetic mutations similar to Mila, which can be treated with customized ASO to match the defect .


Among them are Ipek Kuzu, born in March 2017, suffering from ataxia-telangiectasia (AT) , a neurodegenerative disease caused by defects in DNA repair genes . Ipek started receiving spinal injections of custom ASO in January 2020. At that time, Ipek had only mild symptoms, such as slow speech. After nearly two years, Ipek’s condition has not deteriorated. However, the more severe symptoms of AT do not appear until around 5 years of age. “It’s too early to declare success ,” Yu said at the meeting.


Capek’s father Mehmet Kuzu is very realistic: If Ipek didn’t need a wheelchair until he was a teenager, instead of the usual 9 or 10 years old, “it would be a big difference,” he said. Other children may also benefit. Yu has already met four AT children with the same mutations as Ipek. “We feel a little guilty about the improper use of these drugs as individualized,” he said in an online speech.


Similarly, researchers, patient advocacy agencies, and biotechnology company Ionis Pharmaceuticals hurriedly adopted regulatory measures in 2019 to customize an ASO drug for 26-year-old Jaci Hermstad to treat her rare hereditary early-onset amyotrophic lateral sclerosis Disease (ALS) . Her condition was serious when the treatment started and she died in May 2020. However, Columbia University neuroscientist Neil Shneider, who led these studies, said that 10 other ALS patients with the same genetic mutations also started using ASO (jacifusen), and some of them have improved their clinical symptoms .


In April, Ionis launched a 64-patient clinical trial comparing jacifusen with a placebo. Applying a customized ASO to other patients can help pay for the staggering cost of conducting the molecular safety test on animals—usually more than $1 million.


For non-progressive genetic diseases, early use of customized ASO treatment may not be so important. Rush University Medical Center neurologist Elizabeth Berry Kravis led an ASO trial for Angelman syndrome , in which children developed intellectual disabilities. The drug binds to the mRNA of a protein that turns off the paternal copy of the gene called UBE3A, so the gene is activated and compensates for the problem with the maternal version.


She said at the ASHG meeting that in all five participants, her team saw significant changes, including learning new words and sleeping better. Although young children have made more progress, young people have also made progress. Berry-Kravis added: “The neurons are still there, but they are not connected properly .”


The trial was stopped a year ago because of the inflammation around the injection site that caused the patient’s temporary leg weakness , but it restarted with a lower drug dose outside the United States. At the ASHG meeting, the retired Ionis CEO Stanley Crooke warned that this side effect is a potential obstacle to the implantation of ASOs into the spinal cord .


Nonetheless, he created the n-LROM Foundation in January 2020 to accelerate customized ASOs for mutations in “superviral” diseases-less than 30 people shared it, which is not of interest to most drug companies . It is working with more than 35 families and hopes to treat the first patient early next year, a boy with a developmental disorder caused by a rare mutation .


Academic groups in some countries are also working on customizing ASO . Yu reminded that as researchers further adopt n-of-1 ASO treatment , they must “avoid raising expectations too early.” But Mehmet Kuzu said that even if the result is uncertain, the risk is worth taking . Regarding his daughter Ipek’s illness, “ If we do nothing, we know what will happen .”






RNA drugs are coming to patients with rarer genetic diseases

(source:internet, reference only)

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