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Gene therapy for neurological diseases possible with new brain-targeting viral vectors

A major challenge in the field of gene therapy is ensuring that treatments are delivered to the correct location in the body. However, some destinations, like the brain, are more difficult to reach.

A family of adeno-associated viral vectors (AAV) that can enter the brain has now been developed by researchers at the Broad Institute of MIT and Harvard. The study, which was published in Med, described the selection and screening procedure used to develop these AAVs. This new family of vectors may be superior to AAV9 – the only viral vector for the nervous system that has received FDA approval.

Gene therapy

Gene therapies can correct an underlying genetic problem by delivering therapeutic DNA, RNA, gene editing machinery or other molecules, using vectors. AAVs are viral vectors, which means that they are able to enter cells to deliver the genetic cargo.

The problem with AAVs is that most of the injected dose gets processed by the liver before it can circulate to the target tissue.  A very high dose is therefore required to deliver AAVs to the brain. Although some of the dose will reach the brain, the majority is metabolised by the liver and causes severe liver damage. 

Researchers at the Broad Institute of MIT and Harvard used a selection process on mouse and macaque models to develop the proline arginine loop (PAL) family of AAVs. The PAL AAVs effectively transduced neurons in the macaque brain and were three times more effective than AAV9 at generating therapeutic mRNA.

Allie Stanton, study lead author and a Harvard Medical School graduate student in the Sabeti lab said, “We generated a massive pool of randomly generated AAV capsids and from there narrowed down to ones able to get into the brain of both mice and macaques, deliver genetic cargo, and actually transcribe it into mRNA.”

DELIVER-ing results

The researchers first generated millions of capsids. The capsid library was then screened to select the AAVs that reached the target cells in the brain. This was achieved using a method developed in the Sabeti lab called DELIVER (directed evolution of AAV capsids leveraging in vivo expression of transgene RNA) (figure 1).

The DELIVER methods selects for variants that get both delivered and transcribed in the target cell. Selection was achieved because the expression of the genetic cargo was under the control of a neuron specific promoter. This favoured capsid variants that preferentially targeted neurons.

Figure 1: Schematic of AAV selection using DELIVER. In the first round of selection, AAV variants were infused into animal models and capsid mRNAs that were expressed in the brain were identified. In the second round, successful first round variants were infused into animal models and the top capsid variants were identified. Published in Med.

The researchers found that the engineered viruses were able to effectively cross the blood brain barrier, and also accumulated less in the liver in macaques. The PAL family variants were potent in macaque models but not in mouse models. Since, macaques are a more clinically relevant animal model to mouse models, the study is still promising for future applications in human medicine. However, mouse models of disease are more accessible in research, which will make future testing of the PAL AAVs challenging.

Future applications

A safer and more efficient viral vector opens up avenues for gene therapy to treat a wide-range of neurological diseases. The preclinical research presented in the study serves as a foundation for the development of viral vectors that could be more effective with further rounds of selection.

Professor Pardis Sabeti, member at the Broad Institute of MIT and Harvard said, “We are encouraged by the early results of the PAL family AAVs, and can see several promising lines of investigation using directed evolution and engineering to further increase their efficiency.”

More on these topics

Gene Therapy / mRNA / Neurological