New Gene Therapy Delivery Method May Open BRAVE New World in Parkinson’s Research

A new method allows researchers to develop adeno-associated virus (AVV) — commonly used as the vehicle for gene therapies — that accurately target and deliver genes to specific cells in the body.

This new technology may be suitable to target dopaminergic neurons that are damaged in Parkinson’s disease.

“We believe that the new synthetic [lab-made] virus we succeeded in creating would be very well suited for gene therapy for Parkinson’s disease, for example, and we have high hopes that these virus vectors will be able to be put into clinical use,” Tomas Björklund, PhD, Lund University, Sweden, said in a press release.

Björklund is lead author of the study “A systematic capsid evolution approach performed in vivo for the design of AAV vectors with tailored properties and tropism,” which was published in the journal Proceedings of the National Academy of Sciences. 

The adeno-associated virus (AAV) is a common, naturally-occurring virus, which has been shown to work as an effective gene therapy delivery vehicle for genetic diseases, such as spinal muscular atrophy. In gene therapy, scientists deliver a working version of a faulty gene using a harmless AAV that was modified and inactivated in the lab. This way the virus functions only as a delivery vehicle and does not have the capacity to damage tissues and cause disease.

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While AAVs have a natural ability to penetrate any cell of the body and infect as many cells as possible, their usefulness as a potential therapy requires the capacity to specifically deliver a working gene to a particular cell type, such as dopamine producing-nerve cells. Those are the ones hose responsible for releasing the neurotransmitter dopamine and that are gradually lost during Parkinson’s disease.

A team of Swedish researchers have developed a new method — called barcoded rational AAV vector evolution, or BRAVE — that combines powerful computational analysis with the latest gene and sequencing technology to produce AAVs that can specifically target neurons.

To make AAVs neuron specific, the team selected 131 proteins known to specifically interact with synapses (the junctions between two nerve cells that allow them to communicate).

They then divided the proteins into small sequences, called peptides, and created a large library where each peptide could be identified by a specific pool of genetic barcodes (a short sequence of DNA that is unique and easily identified).

The peptide is then displayed on the surface of the AAV capsid, allowing researchers to test the simultaneous delivery of many cell-specific AAVs in a single experiment.

The team then injected these AAVs into the forebrain of adult rats and observed that around 13% of the peptides successfully homed to the brain. Moreover, 4% of the peptides were transported effectively through axons (long neuronal projections that conduct electrical impulses) toward the nerve cell’s body.

Researchers then selected 23 of these unique AAV capsids and injected them into rats’ striatum, a brain region involved in voluntary movement control and affected in Parkinson’s disease. Twenty-one of the new AAV capsids had an improved transport capacity within nerve cells than in standard AAVs.

One particular capsid, called MNM008, showed a high affinity for rat dopaminergic neurons. Researchers then tested whether this viral vector also could target human dopaminergic neurons.

The team transplanted neurons generated from human embryonic stem cells into rats’ striatum. Six months later, they injected either MNM008 or a control AAV capsid and found that MNM008 was able to target these specific cells and be transported into dopaminergic neuronal cell bodies through axons.

“Thanks to this technology, we can study millions of new virus variants in cell culture and animal models simultaneously. From this, we can subsequently create a computer simulation that constructs the most suitable virus shell for the chosen application — in this case, the dopamine-producing nerve cells for the treatment of Parkinson’s disease,” Björklund said.

Overall, researchers believe the BRAVE method “opens up the design and development of synthetic AAV vectors expressing capsid structures with unique properties and broad potential for clinical applications and brain connectivity studies.”

The team has established a collaboration with a biotech company, Dyno Therapeutics, to use the BRAVE method in the design of new AAVs.

“Together with researchers at Harvard University, we have established a new biotechnology company in Boston, Dyno Therapeutics, to further develop the virus engineering technology, using artificial intelligence, for future treatments,” Björklund said.