January 27, 2023

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AAVS: Another step towards targeted gene therapy!

AAVS: Another step towards targeted gene therapy!


AAVS: Another step towards targeted gene therapy!

Gene therapy continues to develop in the treatment of diseases, and its potential is still being explored.

Recent research has developed a gene delivery system to specifically target brain cells while avoiding the liver.

The key to this technology is the use of adeno-associated viruses, or AAVs, which have long been considered promising candidates for delivery vehicles.

This study provides a new approach for basic research and treatment possibilities through the ability of neurons to specifically cross the blood-brain barrier in rodents and non-human primates.

Gene therapy is a powerful development technology that has the potential to solve countless diseases. For example, Huntington’s disease, a neurodegenerative disease, is caused by mutations in a single gene.

If researchers can access specific cells and correct this defect, in theory those cells can regain normal functions.


However, a major challenge is to create the correct ” delivery vector ” that can carry genes and molecules to the cells that need treatment, while avoiding cells that do not need treatment.


Now, a research team led by researchers at the California Institute of Technology (Caltech) has developed a gene delivery system that can specifically target brain cells while avoiding the liver .

This is important, for example, because gene therapy aimed at treating brain diseases may also produce side effects that produce a toxic immune response in the liver, so it is hoped to find a delivery vehicle that only reaches its intended target.

The results of the study have been shown in both mouse and marmoset models, and this is an important step in the transfer of this technology to humans.


The paper describing this new discovery was published in the journal Nature Neuroscience on December 9 , entitled ” AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset “. Headed by Viviana Gradinaru , professor of neuroscience and bioengineering at the California Institute of Technology, and director of the Center for Molecular and Cellular Neuroscience .


AAVS: Another step towards targeted gene therapy!


The key to this technology is the use of adeno-associated viruses , or AAVs , which have long been considered promising candidates for delivery vehicles.

In the course of millions of years of evolution, viruses have evolved effective methods to gain access to human cells.

For decades, researchers have been developing methods to use the Trojan horse-like capabilities of viruses to benefit mankind.


AAVs are composed of two main components: a shell (called a capsid ) constructed from proteins and the genetic material enclosed in the capsid .

In order to use recombinant AAVs for gene therapy, researchers remove the viral genetic material from the capsid and replace it with the required goods, such as specific genes or coding information for small therapeutic molecules.


The paper’s co-first author graduate student David Goertsen said: “Recombinant AAVs are deprived of the ability to replicate, which leaves a powerful tool that is biologically designed to gain access to cells. We can use natural biology to derive it. Special tools for neuroscience research and gene therapy.”


The shape and composition of the capsid is a key part of how AAV enters the cell.

Researchers in the Gradinaru laboratory have been working on the transformation of the AAV capsid that can cross the blood-brain barrier ( BBB ) for nearly ten years , and have developed methods to select and combat certain traits, so as to be more specific to certain cell types in the brain. Viral vector.


In the new study, the research team developed a capsid that spans the BBB , especially one of them- AAV.CAP-B10 , which can efficiently enter brain cells, especially neurons, while avoiding the presence of liver cells.

Many systemic targets within. Importantly, the decrease in neuron specificity and liver targeting occurred not only in mice (a common research animal), but also in laboratory marmosets .


Gradinaru said: “With these new capsids, the research community can now test multiple gene therapy strategies in rodents and marmosets and establish the evidence necessary to bring such strategies to the clinic.

We can transform the AAV coat.

Decreased neuronal tropism and liver targeting of the shell are important features that may lead to safer and more effective treatment options for brain diseases.”


The development of AAV capsid variants that work well in non-human primates is a big step towards the transformation of technology for use in humans, because the previous AAV capsid variants are not in non-human primates. success.

The system in vivo method of Gradinaru laboratory, which uses a process called directed evolution to modify the AAV capsid at multiple sites, has successfully produced variants that can span different strains of mouse BBB, such as in the marmoset in this study. Shown.


Gradinaru said: “The results of this study show that the introduction of diversity in multiple locations on the surface of the AAV capsid can increase transgene expression efficiency and neuron specificity.

AAV engineering confers new tropism and tissue specificity, just as we say What the brain and liver have shown broadens potential research and preclinical applications and can enable new treatments for brain diseases. “






AAVS: Another step towards targeted gene therapy!

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