Nature improves the delivery of gene therapies to the central nervous system

The blood-brain barrier (BBB) is a formidable enemy
of gene therapy.
The blood-brain barrier is formed by cells tightly bound together, which prevents toxins and pathogens that may be present in the blood from entering brain tissue, but it also blocks potential treatments
for diseases that affect the central nervous system (CNS).
Researchers have found that some transport vectors — adeno-associated virus (AAV) — can cross barriers in some cases, but most of the time, AAV is inefficient at delivering gene therapies
.
Researchers at Brigham and Women's Hospital, a founding member of Brigham and Women's Hospital, Massachusetts, are working to optimize AAVs as gene delivery vectors, increasing their efficiency and potential to deliver drugs to treat brain cancers such as malignant gliomas and genetic disorders
affecting the central nervous system 。 In a paper published in the journal Nature Biomedical Engineering, the research team reports a new variant of AAV, tested in a preclinical model, that is significantly more efficient
than previously developed delivery vehicles.

"Our study is exciting because it shows that we are one step closer to gene therapy that can cross the human blood-brain barrier," said
Dr.
Fengfeng Bei of the Department of Neurosurgery at Brigham University.
"Our findings suggest that AAVs could provide valuable tools
for developing systemic gene therapies for glioblastoma and other diseases that require central nervous system transmission.
"

AAV is a small, non-pathogenic virus that can be engineered to carry and deliver DNA sequences to target cells
.
Previous studies have found that they are safe carriers for gene therapy, which aims to directly modify genes in cells to treat disease
.

Recent advances have led to the discovery of a new generation of AAVs that can penetrate the blood-brain barrier in mouse models, but most AAVs identified to date are not effective enough to be considered for use
in clinical settings.
To improve on existing AAVs, Bei and colleagues turned to cell-permeable peptides — a group of short peptides known to be able to cross biofilms, such as the blood-brain barrier
.
The team collected about 100 such peptides and inserted them into various AAVs, testing them one by one to find the most effective
.

"We were lucky," Bey said
.
"We found the answer
near number 16.
"

The team tested their findings in preclinical models, looking at mice and non-human primates
.
And they identify AAV - lucky number AAV.
cpp
。 Compared to previously tested AAVs, which show significant improvements in transmission efficiency across the blood-brain barrier, Bei's lab is looking for further improvements
.

"We wanted to develop a more effective version
that is more confined to the central nervous system.
" Our research so far tells us that we are moving
in the right direction.
”

These data suggest that this novel vector could be used to treat genetic diseases, where initiating protein production in a specific number of cells can reverse the disease
.
Dr.
Yulia Grishchuk, who leads a lab at the Center for Genomic Medicine at Massachusetts General Hospital, recently collaborated with Bei and saw potential applications
for his research team based on advances in the lab.

"Neurometabolic diseases, lysosomal storage diseases, and other diseases that affect central nervous system tissues and other tissues in the body urgently require new treatments
," Grishchuk said.
"It's exciting that this work could represent a way to treat a wide range of central nervous system diseases that are difficult to target with current treatments
.
"

Disclosure: Bei and co-author E.
Antonio Chiocca receives royalties
from the patents generated by this research.
Brave Bio Inc.
Co-founder and scientific advisor, this is an AAV gene therapy startup
.
Other authors declare no competing interests
.

Funding: This study was supported
by the Brigham and Women's Hospital Miscellaneous Fund.