What is the difference between the three antisense therapies of Ionis in the treatment of neurodegenerative diseases?

In 2016, at the Oligonucleotide Therapeutics Society meeting held in Montreal, the biotechnology company Ionis released a drug later named Spinraza, which won endless applause from the audience.
This drug can significantly change the type of spinal cord.
Muscular dystrophy
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What’s more exciting is that the antisense technology based on this drug may bring a glimmer of hope to patients suffering from other incurable neurological diseases, such as the neurodegenerative disease Huntington’s disease (Huntington’s disease).
disease, HD) and amyotrophic lateral sclerosis (ALS, gradual freezing syndrome)
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In 2018, Roche and Ionis began a cooperative development of drugs for Huntington's disease
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But in 2021, these research and development suffered a major setback
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In March 2021, Roche and Ionis announced that the medication of Huntington's disease patients actually caused the patient's condition to deteriorate
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Just days after the news, a similar drug from Wave Life Sciences also failed
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Just a few weeks ago, Biogen and Ionis announced that the drugs they developed for gradual freezing had not shown a significant effect on patients
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These disappointing failures inspired the industry to ask a simple question: What happened? Why did Roche and Bojian's antisense therapy drugs for Huntington's disease and frostbite fail, but Spinraza has such a huge success? Anastasia Khvorova, who leads the Therapeutic RNA Laboratory at UMass Medical School, attributed the failure of drug development to the treatment of Huntington’s disease and gradual freezing in part to the difference between the two antisense molecules: RNA blockers And RNA degrading agent
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Antisense drugs are a kind of antisense oligonucleotides (antisense oligonucleotides)
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Our body’s genes are composed of DNA.
DNA contains special codes that promote cell functioning.
Using this information, it can produce a variety of proteins that maintain cell functions.
Antisense oligonucleotides can interfere with DNA and protein.
The critical stage between the time, that is, the process by which DNA is transformed into messenger RNA (mRNA)
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Antisense drugs themselves consist of short strands of nucleotides, which are part of DNA and RNA
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After antisense drugs intercept messenger RNA, they will do one of two things: either mark them for destruction, or slightly alter the code to change the protein they make
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These are two very different processes
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For myeloid muscular atrophy, it is caused by genetic mutations
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Spinraza binds to the wrong RNA in the patient's body, and only needs to change one of the sites to correct the error and regenerate the correct protein
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However, antisense drugs to treat Huntington's disease and gradual freezing disease need to destroy RNA
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Huntington's disease is caused by an unusual genetic defect in which the three letters in a key gene called huntingtin are repeated over and over again to produce a toxic protein
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The task of antisense drugs in the treatment of these two diseases is to destroy the messenger RNA that produces these proteins
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In order to destroy the false messenger RNA in these two diseases, Ionis needs its drugs to find its target, such as the Huntington gene, and then send a signal to the cell to eliminate it
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Ionis has previously achieved this through at least three different approved therapies, including the treatment of AIDS-related diseases, a rare heart disease, and the most recent amyloidosis characterized by the accumulation of toxic proteins throughout the body
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However, among these, only amyloidosis drugs are widely used
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The drug targets the liver, which is the easiest part of the body to track
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The degradation of messenger RNA presents a unique biological obstacle: Because the antisense drug must be recognized by the cell, Ionis cannot add a large amount of sugar and phosphate scaffolds to Spinraza to stabilize it
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This means it is exposed to cells and can be degraded by various nucleotide degrading enzymes floating around
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And this degradation may release toxic by-products, which is one possible explanation for why patients taking Huntington's drugs are less effective than patients taking placebo
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At the beginning of the establishment of Ionis, Antisense Technology was the only gene technology available at the time, and now many gene technologies have emerged
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The most striking are gene therapy (gene therapy) and RNA interference (RNAi)
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Especially RNA interference has proven to be very effective in explaining RNA in recent years
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The researchers pointed out that tofersen, jointly developed by Ionis and Bojian, has shown some improvement in patients with gradual freezing, but an RNAi molecule has been shown to be 70 times stronger than antisense drugs in degrading SOD1
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Alnylam, Regeneron, and Genentech are working towards the goal of using RNAi to treat Huntington's disease and gradual freezing disease, including the use of Khvorova's laboratory technology, but their methods have not yet been confirmed
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At the same time, in Huntington's disease, some small biotech companies are developing antisense drugs that target only the mutant huntingtin protein.
These drugs do not harm healthy genes
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Biogen is still waiting for data to see if tofersen can delay the onset of gradual freezing in patients
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Everything is in progress, we will wait and see
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Reference source: Antisense technology changed one devastating disease.
Why hasnt it transformed others?