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Written | Edited by Wang Cong | Typeset by Wang Duoyu | Water-based gradual freezing disease, also known as Amyotrophic Lateral Sclerosis (ALS), is one of the five terminal diseases recognized by the World Health Organization (WHO).
A chronic, progressive degenerative disease involving upper/lower motor neurons and their innervated trunk, limbs, and head and facial muscles.
It often manifests as progressively worsening muscle weakness caused by combined damage to the upper/lower motor neurons , muscle atrophy and muscle bundle fibrillation
.
Gradual frost syndrome is the most common type of motor neuron disease.
There are about 200,000 gradual frost syndrome patients in China alone.
The age of onset of patients is mostly between 30 and 60 years old, and there are more men than women
.
There is currently no specific treatment for frostbite, and the treatment is mainly to improve the quality of life of the patient and delay the development of the disease
.
Famous physicist Hawking, "People's Hero" Zhang Dingyu, and JD vice president Cai Lei are all patients with frostbite
.
Previous studies have shown that abnormal amplification of the hexanucleotide repeat sequence (GGGGCC) in the C9orf72 gene is the most common genetic cause of gradual freezing (ALS) and frontotemporal dementia (FTD) (accounting for 40% of familial gradual freezing).
%, accounting for 10% of sporadic frostbite, and 25% of frontotemporal dementia)
.
After this abnormal amplification occurs, it will interfere with the growth and expression of the C9orf72 gene, and also produce a neurotoxin protein called Dipeptide Repat Proteins (DRP)
.
On December 23, 2021, researchers from the University of Massachusetts Medical School published a research paper titled: Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide in the top international medical journal Nature Medicine
.
Antisense oligonucleotides (ASO) are artificially synthesized short single-stranded oligonucleotides, which are a kind of small nucleic acid drugs.
After entering the cell, they will pass through the base under the action of ribonuclease H1.
The principle of complementary pairing is to combine with its complementary target mRNA sequence, thereby inhibiting the expression of the gene and reducing the production of protein
.
How ASO works So far, four ASO drugs have been approved by the US FDA, of which three are used to treat Duchenne muscular dystrophy (DMD) and one is used to treat spinal muscular atrophy (SMA)
.
For a long time, scientists have confirmed that knocking out single-gene mutations that cause neurodegenerative diseases may have therapeutic benefits, but it is not easy to safely deliver nucleic acid drugs to neurons
.
Moreover, in the case of eliminating the mutant protein, it is necessary to retain enough functional protein, which is also a major obstacle in the treatment
.
Therefore, when treating patients with C9orf72 gene mutation, we cannot simply knock out all the C9ORF72 protein from the patient’s neurons
.
The research team first tested the C9orf72 gene mutation in cells derived from patients with frostbite and transgenic mice, and constructed sequence-optimized antisense oligonucleotides (ASO), which can selectively inhibit the transcription of GGGGCC repeats.
This expression can effectively inhibit the level of Dipeptide Repat Proteins (DRP)
.
Then, the research team chemically modified the ASO to improve its safety, distribution and stability in the brain and spinal cord.
Without a delivery vector, naked ASO can be injected directly through the spinal cord
.
Next, the research team conducted a human clinical trial of the ASO drug on a patient with gradual freezing disease with abnormal amplification of the C9orf72 gene GGGGCC
.
The test results showed that ASO drugs significantly reduced the toxic protein dipeptide repeat protein (DRP) in the spinal fluid of this patient
.
During the experiment, the patient's gradual freezing syndrome score and other impact indicators were basically stable or slightly improved, and there were no neurological or medical adverse reactions after treatment
.
This human test shows that ASO drugs can effectively and safely inhibit the abnormally amplified transcript of the C9orf72 gene, and can significantly reduce the level of toxic proteins expressed by the abnormal transcript
.
It is reported that this is the first time that the level of dipeptide repeat protein (DRP) caused by the abnormal amplification of the C9orf72 gene has been reduced in the human body
.
This study strongly supports that the suppressed mutation of C9orf72 gene has clinical benefits for patients with gradual freezing disease and is worthy of further exploration
.
In May of this year, Nature Medicine published a clinical report that found a rare mutation in the SPTLC1 gene of patients with early onset frost syndrome (ALS).
This mutation can lead to uncontrolled production of sphingomyelin and Accumulate in human motor neurons
.
The research team also conducted experiments with siRNA.
Experiments on patients' skin cells showed that siRNA can not only reduce the expression level of SPLTC1 gene, but also restore sphingomyelin to normal levels
.
These findings indicate that the use of precise gene silencing strategies such as ASO or siRNA is a very promising method for the treatment of patients with gradual freezing caused by gene mutations.
.
Link to the paper: https:// open for reprinting, welcome to forward to Moments and WeChat groups
A chronic, progressive degenerative disease involving upper/lower motor neurons and their innervated trunk, limbs, and head and facial muscles.
It often manifests as progressively worsening muscle weakness caused by combined damage to the upper/lower motor neurons , muscle atrophy and muscle bundle fibrillation
.
Gradual frost syndrome is the most common type of motor neuron disease.
There are about 200,000 gradual frost syndrome patients in China alone.
The age of onset of patients is mostly between 30 and 60 years old, and there are more men than women
.
There is currently no specific treatment for frostbite, and the treatment is mainly to improve the quality of life of the patient and delay the development of the disease
.
Famous physicist Hawking, "People's Hero" Zhang Dingyu, and JD vice president Cai Lei are all patients with frostbite
.
Previous studies have shown that abnormal amplification of the hexanucleotide repeat sequence (GGGGCC) in the C9orf72 gene is the most common genetic cause of gradual freezing (ALS) and frontotemporal dementia (FTD) (accounting for 40% of familial gradual freezing).
%, accounting for 10% of sporadic frostbite, and 25% of frontotemporal dementia)
.
After this abnormal amplification occurs, it will interfere with the growth and expression of the C9orf72 gene, and also produce a neurotoxin protein called Dipeptide Repat Proteins (DRP)
.
On December 23, 2021, researchers from the University of Massachusetts Medical School published a research paper titled: Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide in the top international medical journal Nature Medicine
.
Antisense oligonucleotides (ASO) are artificially synthesized short single-stranded oligonucleotides, which are a kind of small nucleic acid drugs.
After entering the cell, they will pass through the base under the action of ribonuclease H1.
The principle of complementary pairing is to combine with its complementary target mRNA sequence, thereby inhibiting the expression of the gene and reducing the production of protein
.
How ASO works So far, four ASO drugs have been approved by the US FDA, of which three are used to treat Duchenne muscular dystrophy (DMD) and one is used to treat spinal muscular atrophy (SMA)
.
For a long time, scientists have confirmed that knocking out single-gene mutations that cause neurodegenerative diseases may have therapeutic benefits, but it is not easy to safely deliver nucleic acid drugs to neurons
.
Moreover, in the case of eliminating the mutant protein, it is necessary to retain enough functional protein, which is also a major obstacle in the treatment
.
Therefore, when treating patients with C9orf72 gene mutation, we cannot simply knock out all the C9ORF72 protein from the patient’s neurons
.
The research team first tested the C9orf72 gene mutation in cells derived from patients with frostbite and transgenic mice, and constructed sequence-optimized antisense oligonucleotides (ASO), which can selectively inhibit the transcription of GGGGCC repeats.
This expression can effectively inhibit the level of Dipeptide Repat Proteins (DRP)
.
Then, the research team chemically modified the ASO to improve its safety, distribution and stability in the brain and spinal cord.
Without a delivery vector, naked ASO can be injected directly through the spinal cord
.
Next, the research team conducted a human clinical trial of the ASO drug on a patient with gradual freezing disease with abnormal amplification of the C9orf72 gene GGGGCC
.
The test results showed that ASO drugs significantly reduced the toxic protein dipeptide repeat protein (DRP) in the spinal fluid of this patient
.
During the experiment, the patient's gradual freezing syndrome score and other impact indicators were basically stable or slightly improved, and there were no neurological or medical adverse reactions after treatment
.
This human test shows that ASO drugs can effectively and safely inhibit the abnormally amplified transcript of the C9orf72 gene, and can significantly reduce the level of toxic proteins expressed by the abnormal transcript
.
It is reported that this is the first time that the level of dipeptide repeat protein (DRP) caused by the abnormal amplification of the C9orf72 gene has been reduced in the human body
.
This study strongly supports that the suppressed mutation of C9orf72 gene has clinical benefits for patients with gradual freezing disease and is worthy of further exploration
.
In May of this year, Nature Medicine published a clinical report that found a rare mutation in the SPTLC1 gene of patients with early onset frost syndrome (ALS).
This mutation can lead to uncontrolled production of sphingomyelin and Accumulate in human motor neurons
.
The research team also conducted experiments with siRNA.
Experiments on patients' skin cells showed that siRNA can not only reduce the expression level of SPLTC1 gene, but also restore sphingomyelin to normal levels
.
These findings indicate that the use of precise gene silencing strategies such as ASO or siRNA is a very promising method for the treatment of patients with gradual freezing caused by gene mutations.
.
Link to the paper: https:// open for reprinting, welcome to forward to Moments and WeChat groups
