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▎ WuXi AppTec content team editor When talking about his child, Agustin, his father Alberto repeatedly used the term "rebirth" to describe it
.
Recalling the days when little Augustine was ill, Alberto often thought of a scene in his home in Buenos Aires, Argentina.
He and his wife were wearing personal protective equipment to comfort little Augustine, and always kept the eldest son away.
The younger brother stayed away to prevent passing on the cold to him
.
For little Augustine, who suffers from X-linked severe combined immunodeficiency (SCID-X1), a cold may easily kill him
.
This disease is more commonly known as the "bubble boy".
Due to the IL2RG gene mutation, the bone marrow of the child cannot produce T lymphocytes, and the immune function is greatly weakened
.
Image source: 123RF and his rescue is the team of Dr.
David Williams and gene therapy at Boston Children's Hospital
.
In 2010, Dr.
Williams managed to make the retroviral vector carry the correct gene copy and introduced it into Augustine.
When his hematopoietic stem cells absorbed these foreign genes, they began to produce functional T cells
.
Ten years later, Augustine has grown up and can participate in daily life, and gene therapy is also saving more children and adults with complex genetic diseases
.
In theory, by repairing gene defects in specific brain cells, Huntington's disease patients can also benefit from it.
The problem is how to make the carrier break through the blood-brain barrier and work
.
In addition, gene therapy may still produce side effects that some scientists don't want to see.
Leukemia and severe liver toxicity are the worst results
.
Over the years, researchers have tried to change the characteristics of viral vectors, from self-inactivating retroviruses to lentiviruses, which have greatly reduced the risk of leukemia
.
Recently, researchers from the California Institute of Technology have developed a gene delivery system based on adenovirus vectors.
This new concept system can specifically target brain cells while avoiding liver cells, which is more stable and safe
.
The research has been published in "Nature-Neuroscience"
.
Adenovirus has two main components, a capsid made of protein and internal genetic material.
Researchers have managed to replace the viral genes with specific genes or coding information of tiny therapeutic molecules.
The recombined virus loses its ability to replicate.
, Which reduces the risk of side effects
.
In addition, the researchers redesigned the capsid protein of adenovirus.
Through library screening and mouse models, they found the capsid protein AAV.
CAP-B10, which is highly enriched in central nervous system tissues and rarely found in other organs
.
This means that carriers using this capsid protein can break through the blood-brain barrier and avoid other cell types in the body
.
▲Expression of vectors with different capsid proteins in brain and liver tissues (picture source: reference [3]) The study managed to track the recombinant virus with green fluorescent protein.
Compared with the control adenovirus, it is brand new After the recombinant adenovirus vector is injected into mice, it will appear more in the spinal cord and brain, but it is hard to find a trace in the liver
.
In addition to being effective in mice, this new adenovirus vector can play the same role in marmosets.
Six weeks after the recombinant vector enters, the virus library is highly expressed in the entire cerebral cortex and cerebellum of marmosets, while in the liver.
It is only slightly expressed.
Compared with conventional adenovirus, the level of viral RNA in the brain is 6 times higher, while the liver is only 1/5 of the control. .
The researchers pointed out that this new adenovirus vector can work in non-human primates is of great significance, which means that they can then promote the clinical testing of gene therapies based on it
.
"The study found that changing the adenovirus capsid protein can change their specificity to nerve cells," said the lead author of the study, Dr.
David Goertsen.
"This may bring new treatments for many brain diseases
.
" References: [ 1] New technology is one step closer to targeted gene therapy.
Retrieved Dec 14th, 2021 from https://medicalxpress.
com/news/2021-12-technology-closer-gene-therapy.
html[2] A rebirth in Boston: Gene therapy turns 10.
Retrieved Dec 14th, 2021 from https://answers.
childrenshospital.
org/gene-therapy-turns-ten/[3] David Goertsen et al, AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset, Nature Neuroscience (2021).
DOI: 10.
1038/s41593-021-00969-4
.
Recalling the days when little Augustine was ill, Alberto often thought of a scene in his home in Buenos Aires, Argentina.
He and his wife were wearing personal protective equipment to comfort little Augustine, and always kept the eldest son away.
The younger brother stayed away to prevent passing on the cold to him
.
For little Augustine, who suffers from X-linked severe combined immunodeficiency (SCID-X1), a cold may easily kill him
.
This disease is more commonly known as the "bubble boy".
Due to the IL2RG gene mutation, the bone marrow of the child cannot produce T lymphocytes, and the immune function is greatly weakened
.
Image source: 123RF and his rescue is the team of Dr.
David Williams and gene therapy at Boston Children's Hospital
.
In 2010, Dr.
Williams managed to make the retroviral vector carry the correct gene copy and introduced it into Augustine.
When his hematopoietic stem cells absorbed these foreign genes, they began to produce functional T cells
.
Ten years later, Augustine has grown up and can participate in daily life, and gene therapy is also saving more children and adults with complex genetic diseases
.
In theory, by repairing gene defects in specific brain cells, Huntington's disease patients can also benefit from it.
The problem is how to make the carrier break through the blood-brain barrier and work
.
In addition, gene therapy may still produce side effects that some scientists don't want to see.
Leukemia and severe liver toxicity are the worst results
.
Over the years, researchers have tried to change the characteristics of viral vectors, from self-inactivating retroviruses to lentiviruses, which have greatly reduced the risk of leukemia
.
Recently, researchers from the California Institute of Technology have developed a gene delivery system based on adenovirus vectors.
This new concept system can specifically target brain cells while avoiding liver cells, which is more stable and safe
.
The research has been published in "Nature-Neuroscience"
.
Adenovirus has two main components, a capsid made of protein and internal genetic material.
Researchers have managed to replace the viral genes with specific genes or coding information of tiny therapeutic molecules.
The recombined virus loses its ability to replicate.
, Which reduces the risk of side effects
.
In addition, the researchers redesigned the capsid protein of adenovirus.
Through library screening and mouse models, they found the capsid protein AAV.
CAP-B10, which is highly enriched in central nervous system tissues and rarely found in other organs
.
This means that carriers using this capsid protein can break through the blood-brain barrier and avoid other cell types in the body
.
▲Expression of vectors with different capsid proteins in brain and liver tissues (picture source: reference [3]) The study managed to track the recombinant virus with green fluorescent protein.
Compared with the control adenovirus, it is brand new After the recombinant adenovirus vector is injected into mice, it will appear more in the spinal cord and brain, but it is hard to find a trace in the liver
.
In addition to being effective in mice, this new adenovirus vector can play the same role in marmosets.
Six weeks after the recombinant vector enters, the virus library is highly expressed in the entire cerebral cortex and cerebellum of marmosets, while in the liver.
It is only slightly expressed.
Compared with conventional adenovirus, the level of viral RNA in the brain is 6 times higher, while the liver is only 1/5 of the control. .
The researchers pointed out that this new adenovirus vector can work in non-human primates is of great significance, which means that they can then promote the clinical testing of gene therapies based on it
.
"The study found that changing the adenovirus capsid protein can change their specificity to nerve cells," said the lead author of the study, Dr.
David Goertsen.
"This may bring new treatments for many brain diseases
.
" References: [ 1] New technology is one step closer to targeted gene therapy.
Retrieved Dec 14th, 2021 from https://medicalxpress.
com/news/2021-12-technology-closer-gene-therapy.
html[2] A rebirth in Boston: Gene therapy turns 10.
Retrieved Dec 14th, 2021 from https://answers.
childrenshospital.
org/gene-therapy-turns-ten/[3] David Goertsen et al, AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset, Nature Neuroscience (2021).
DOI: 10.
1038/s41593-021-00969-4
