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Written by Koala King's Eucalyptus Editor | Xi's new crown vaccine allows RNA drugs to enter the public eye, and the earliest nucleic acid drugs are antisense oligonucleotides (ASOs)
.
ASOs are single-stranded oligonucleotide molecules with a length of 18-30, usually containing some backbone and base modifications to enhance their pharmacological properties [1]
.
Combining with target mRNA through base complementary pairing leads to RNAseH-mediated gene knockdown.
It can also achieve the function of inhibiting gene expression through methods such as altering mRNA shearing and inhibiting ribosomal translation [2]
.
At present, 8 ASO drugs have been approved for marketing, and inois is a well-deserved leader in the field of ASO drugs
.
Due to its high specificity and ability to target targets that cannot be achieved by traditional therapies, ASO has become an ideal drug candidate for the development of human neurological diseases [3]
.
However, due to the existence of the blood-brain barrier and the blood-cerebrospinal fluid barrier, usually only hydrophobic small molecule drugs with a molecular weight of <450Da can pass these barriers [4]
.
Therefore, ASOs are usually administered by invasive cerebrospinal fluid injection, which is still one of the most important obstacles in the clinical application of ASO in central nervous system diseases
.
Although existing experience has shown that cerebrospinal fluid administration is well tolerated in most individuals, intrathecal injection is more invasive than intravenous injection and may be difficult for patients with severe lumbar scoliosis or combined anticoagulation therapy [ 5]
.
Therefore, a method that can effectively transport ASO from the blood to the brain will be very beneficial
.
On August 12, 2021, the team of Professor Takanori Yokota from Tokyo Medical and Dental University published a work titled Cholesterol-functionalized DNA/RNA heteroduplexes cross the blood–brain barrier and knock down genes in the rodent CNS in Nature Biotechnology, which they developed A cholesterol-modified DNA/RNA hybrid double-stranded oligonucleotide molecule (Chlo-HDOs) can be injected subcutaneously or intravenously to inhibit the expression of target genes in brain and spinal cord cells
.
By more effectively crossing the blood-brain barrier, Chlo-HDOs can overcome the problem of ASOs targeting the central nervous system without the need for cerebrospinal fluid administration
.
In order to find a modification that can smoothly pass through the blood-brain barrier, the authors synthesized and evaluated 14 lipophilic compounds, including 9 natural fatty acids and sterols, for gene knockout in the mouse central nervous system
.
Single-stranded ASO targeting MALAT1 and lipid-modified HDO were injected intravenously into mice, and qRT-PCR was used to detect the level of MALAT1 RNA in the cerebral cortex
.
The results show that ASO has no knockdown effect, and most lipophilic molecule-modified HDO has no obvious knockdown effect in the CNS, but a single intravenous injection of cholesterol-modified HDO (Chol-HDO) can reduce the level of MALAT1 by about 60%
.
Next, the author further optimized the structure of HDO and the number of injections.
After multiple injections of Chol-HDO, the level of MALAT1 in the brain was reduced by 90%
.
In areas of the central nervous system, including the cerebral cortex, cerebellum, striatum, hippocampus, brainstem, and spinal cord, Chol-HDO also showed similar effects
.
After demonstrating that intravenous injection of Chol-HDO can reduce the expression of MALAT1 gene in the CNS, the authors evaluated the ability of the technology to inhibit clinically relevant gene targets
.
Disease-related DMPK, SOD1 and GFAP genes were successfully knocked down in different brain regions
.
The pharmacokinetic and pharmacodynamic analysis of Chol-HDO in the central nervous system showed that Chol-HDO mainly exists in the cytoplasm of cerebral cortex neurons and spinal anterior horn cells, and its half-life (28.
9 days) in the cerebral cortex is longer than that in the liver.
Or in the kidney, indicating that the clearance of Chol-HDO from the cerebral cortex is slower than the clearance of the liver or kidney
.
Next, the author conducted a series of experiments to compare the efficiency of systemic delivery (iv) Chol-HDO and direct cerebrospinal fluid (icv) injection of single-chain ASO
.
A single intravenous administration of Chol-HDO showed a PK/PD curve comparable to that of single-chain ASO injected with cerebrospinal fluid
.
Of course, to achieve the same effect requires a larger injection volume, and higher levels of the drug are detected in the liver and kidneys
.
In summary, this article developed a cholesterol-modified DNA/RNA hybrid double-stranded oligonucleotide that can be injected intravenously across the blood-brain barrier to inhibit gene expression in the central nervous system
.
Chol-HDO has a good PK/PD spectrum in mice and rats, and only shows slight toxicity, which can achieve the similar efficacy of ASO injection by cerebrospinal fluid
.
At present, there are more than 50 ASO drugs in the clinical research stage around the world, and a large number of them are aimed at central nervous system diseases.
The small lipid molecule modified ASO strategy proposed in this article may shine in the treatment of neurodegenerative diseases in the future
.
Original link: https:// Platemaker: 11 References 1.
Nature Reviews Drug Discovery 19.
10 (2020): 673-694.
2.
Nature Reviews Neurology 14.
1 (2018 ): 9-21.
3.
Nat.
Rev.
Drug Discov.
11, 125–140 (2012).
4.
Journal of neurochemistry 70.
5 (1998): 1781-1792.
5.
Lancet Neurol.
11, 443–452 (2012).
Reprinting instructions [Original Articles: BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
.
ASOs are single-stranded oligonucleotide molecules with a length of 18-30, usually containing some backbone and base modifications to enhance their pharmacological properties [1]
.
Combining with target mRNA through base complementary pairing leads to RNAseH-mediated gene knockdown.
It can also achieve the function of inhibiting gene expression through methods such as altering mRNA shearing and inhibiting ribosomal translation [2]
.
At present, 8 ASO drugs have been approved for marketing, and inois is a well-deserved leader in the field of ASO drugs
.
Due to its high specificity and ability to target targets that cannot be achieved by traditional therapies, ASO has become an ideal drug candidate for the development of human neurological diseases [3]
.
However, due to the existence of the blood-brain barrier and the blood-cerebrospinal fluid barrier, usually only hydrophobic small molecule drugs with a molecular weight of <450Da can pass these barriers [4]
.
Therefore, ASOs are usually administered by invasive cerebrospinal fluid injection, which is still one of the most important obstacles in the clinical application of ASO in central nervous system diseases
.
Although existing experience has shown that cerebrospinal fluid administration is well tolerated in most individuals, intrathecal injection is more invasive than intravenous injection and may be difficult for patients with severe lumbar scoliosis or combined anticoagulation therapy [ 5]
.
Therefore, a method that can effectively transport ASO from the blood to the brain will be very beneficial
.
On August 12, 2021, the team of Professor Takanori Yokota from Tokyo Medical and Dental University published a work titled Cholesterol-functionalized DNA/RNA heteroduplexes cross the blood–brain barrier and knock down genes in the rodent CNS in Nature Biotechnology, which they developed A cholesterol-modified DNA/RNA hybrid double-stranded oligonucleotide molecule (Chlo-HDOs) can be injected subcutaneously or intravenously to inhibit the expression of target genes in brain and spinal cord cells
.
By more effectively crossing the blood-brain barrier, Chlo-HDOs can overcome the problem of ASOs targeting the central nervous system without the need for cerebrospinal fluid administration
.
In order to find a modification that can smoothly pass through the blood-brain barrier, the authors synthesized and evaluated 14 lipophilic compounds, including 9 natural fatty acids and sterols, for gene knockout in the mouse central nervous system
.
Single-stranded ASO targeting MALAT1 and lipid-modified HDO were injected intravenously into mice, and qRT-PCR was used to detect the level of MALAT1 RNA in the cerebral cortex
.
The results show that ASO has no knockdown effect, and most lipophilic molecule-modified HDO has no obvious knockdown effect in the CNS, but a single intravenous injection of cholesterol-modified HDO (Chol-HDO) can reduce the level of MALAT1 by about 60%
.
Next, the author further optimized the structure of HDO and the number of injections.
After multiple injections of Chol-HDO, the level of MALAT1 in the brain was reduced by 90%
.
In areas of the central nervous system, including the cerebral cortex, cerebellum, striatum, hippocampus, brainstem, and spinal cord, Chol-HDO also showed similar effects
.
After demonstrating that intravenous injection of Chol-HDO can reduce the expression of MALAT1 gene in the CNS, the authors evaluated the ability of the technology to inhibit clinically relevant gene targets
.
Disease-related DMPK, SOD1 and GFAP genes were successfully knocked down in different brain regions
.
The pharmacokinetic and pharmacodynamic analysis of Chol-HDO in the central nervous system showed that Chol-HDO mainly exists in the cytoplasm of cerebral cortex neurons and spinal anterior horn cells, and its half-life (28.
9 days) in the cerebral cortex is longer than that in the liver.
Or in the kidney, indicating that the clearance of Chol-HDO from the cerebral cortex is slower than the clearance of the liver or kidney
.
Next, the author conducted a series of experiments to compare the efficiency of systemic delivery (iv) Chol-HDO and direct cerebrospinal fluid (icv) injection of single-chain ASO
.
A single intravenous administration of Chol-HDO showed a PK/PD curve comparable to that of single-chain ASO injected with cerebrospinal fluid
.
Of course, to achieve the same effect requires a larger injection volume, and higher levels of the drug are detected in the liver and kidneys
.
In summary, this article developed a cholesterol-modified DNA/RNA hybrid double-stranded oligonucleotide that can be injected intravenously across the blood-brain barrier to inhibit gene expression in the central nervous system
.
Chol-HDO has a good PK/PD spectrum in mice and rats, and only shows slight toxicity, which can achieve the similar efficacy of ASO injection by cerebrospinal fluid
.
At present, there are more than 50 ASO drugs in the clinical research stage around the world, and a large number of them are aimed at central nervous system diseases.
The small lipid molecule modified ASO strategy proposed in this article may shine in the treatment of neurodegenerative diseases in the future
.
Original link: https:// Platemaker: 11 References 1.
Nature Reviews Drug Discovery 19.
10 (2020): 673-694.
2.
Nature Reviews Neurology 14.
1 (2018 ): 9-21.
3.
Nat.
Rev.
Drug Discov.
11, 125–140 (2012).
4.
Journal of neurochemistry 70.
5 (1998): 1781-1792.
5.
Lancet Neurol.
11, 443–452 (2012).
Reprinting instructions [Original Articles: BioArt original articles are welcome to be shared by individuals.
Reprinting is prohibited without permission.
The copyrights of all published works are owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
