Efficiently crossing the blood-brain barrier? A breakthrough is coming for incurable brain diseases

Author: Xu Sijia, PhD, Kyoto University School of Medicine

Genetic brain diseases, such as Alzheimer's disease and Huntington's disease, are usually caused by genetic defects or mutations in brain cells, which lead to abnormal brain development or function. Although traditional drugs and surgical treatments can relieve symptoms, they often cannot cure these diseases. In recent years, genetic treatments have been highly anticipated. However, because the brain has a protective mechanism called the blood-brain barrier, which strictly restricts substances entering and leaving the brain tissue, it makes it difficult for molecular tools of gene therapy to reach brain cells. This has long been a major challenge in treating brain diseases.

In a new study published in Science on May 16, Ben Deverman's team from the Broad Institute of the United States demonstrated a new type of vector they developed that can effectively penetrate the blood-brain barrier and efficiently deliver healthy genes for treatment to the brain. This technology is expected to break through the current bottleneck of brain gene therapy. What is going on?

The genes in the cell's DNA are the blueprints for producing various functional proteins. Genetic defects and mutations in brain cells may lead to the production and accumulation of abnormal proteins, causing brain dysfunction.

Gene therapy is a technology that treats diseases by repairing, replacing diseased genes or supplementing healthy genes.

In order to enter the cell for treatment, a tool called a vector is needed. Vectors, as the name suggests, are like mini trucks loaded with healthy genes that can cross the cell membrane and deliver the molecules used for treatment to the inside of the cell.

Adeno-associated virus (AAV) is a commonly used gene therapy vector approved by the FDA (U.S. Food and Drug Administration). When designing this type of vector, people took advantage of the natural mechanism of virus infection of cells. There are many receptor proteins on the surface of cells to receive external signal molecules. The virus can bind to these receptors, take this opportunity to cross the cell membrane into the cell, and then release the viral genes wrapped in the shell to replicate. And this ability to enter the cell is exactly what gene therapy needs.

Compared with other viruses, the modified AAV is safer and milder, and can still effectively enter specific cells and deliver genes, so it is used as a vector. There are multiple versions of AAV vectors, which are used for gene therapy of different organs. In 2009, the AAV9 type vector that can cross the blood-brain barrier was first discovered. It is approved by the FDA for the treatment of central nervous system diseases, but in fact, its and its subsequent improved versions still have relatively low delivery efficiency to the brain.

The blood-brain barrier is a biological barrier between the brain and the circulatory system. It is composed of tightly connected vascular endothelial cells, smooth muscle cells, and glial cells. This barrier is strictly selective for substances entering and leaving the brain, usually only allowing small molecules such as oxygen, glucose, amino acids, and certain fat-soluble substances to pass through. This protects the brain from a large number of metabolites and most pathogens in the blood circulation, but also excludes many treatments.

Researchers have long used animal experiments to screen for new vectors that can effectively cross the blood-brain barrier. Although sometimes successful, the effect is greatly reduced when changing species.

In order to find a vector that is more likely to be effective in the human body, the Broad Institute team adjusted their strategy to directly screen and modify AAVs for receptors in the human blood-brain barrier, and selected the transferrin receptor, a receptor densely expressed in the blood-brain barrier and a key molecule for targeting brain diseases with antibody drugs.

Since the virus binds to the target receptor through its shell, the researchers screened from the AAV9-based virus shell library. They added a gene sequence that can be recognized by the transferrin receptor to the initially selected shell, and finally designed a new AAV shell that can specifically bind to the human transferrin receptor and enhance the transmembrane transport ability of brain endothelial cells.

To further confirm the effect of the new vector in vivo, the researchers injected it into a "humanized mouse". The transferrin receptor gene of this mouse was replaced with the human version to better simulate the characteristics of the human blood-brain barrier. The experimental results showed that the content of the new AAV in the mouse brain was 40-50 times higher than that of the traditional AAV9, and it diffused well in the brain and could effectively reach most neurons and astrocytes.

The research team further tried to use the new vector to deliver the healthy GBA1 gene to the mouse brain. Mutations in the GBA1 gene are closely related to a variety of neurological diseases such as Parkinson's disease and Gaucher disease. The experimental results showed that the expression level of the GBA1 gene delivered by the new AAV vector in the mouse brain was 30 times that of the AAV9 gene, and it was widely distributed.

The two properties of efficient brain delivery and wide distribution are very important for the treatment of whole-brain diseases such as Alzheimer's disease and Parkinson's disease.

Next, this new vector needs to be tested clinically. If it also shows good results in humans, it will be expected to significantly improve the quality of life of many patients.

original:
Huang Q, Chan KY, et al. An AAV capsid reprogrammed to bind human transferrinreceptor mediates brain-wide gene delivery. Science. Online May 16, 2024. DOI:10.1126/science.adm8386.

This article is a work supported by the Science Popularization China Creation Cultivation Program

Author: Xu Sijia

Reviewer: Li Chong, Director of the Research Office, School of Clinical Medicine, Tsinghua University, Associate Professor

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.