New Gene Therapy Vectors Better at Targeting Liver: Hem B Mouse Study

'Gene taxis' effectively delivered genetic cargo to liver, restored clotting activity

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Two new gene therapy vectors designed for liver diseases show promising effects in a mouse model of hemophilia B, according to a recent study.

The study, “Adeno-associated virus serotype 2 capsid variants for improved liver-directed gene therapy,” was published in Hepatology.

Hemophilia B is caused by mutations in the gene that provides instructions for making the clotting protein factor IX (FIX). The objective of gene therapy for hemophilia is to deliver a healthy copy of the mutated gene to cells in the body — particularly in the liver, which is where most clotting factors are produced.

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Gene therapies use viral vectors to deliver genetic payload

To deliver the genetic cargo, gene therapies commonly use viral vectors — the viral envelope, called the capsid, is wrapped around the genetic payload, and when the capsid binds to a cell, it transfers the cargo inside. Most gene therapies in development specifically use vectors engineered from a family of viruses called adeno-associated virus (AAV).

In the study, a team led by scientists in Germany set out to create new AAV-based vectors that would be better at targeting the liver.

To do this, the researchers used a peptide display library approach. Put simply, they started with the capsid of the AAV2 virus as a foundation. Then, the researchers used genetic engineering to make a bunch of new forms of the capsid with slight differences in the molecular structure.

Finally, the researchers screened all the potential capsids in the library in a mouse model, looking specifically for vectors that could effectively deliver cargo to the liver, but not to other tissues. The mice had functional immune systems; an antibody-driven immune response against the viral vector can reduce the effectiveness of gene therapy.

“In our work, we looked for AAV variants that, on the one hand, target the liver precisely and do not stray into other tissues and, on the other hand, escape the neutralising antibodies,” Nadja Meumann, PhD, a postdoctoral researcher at Hannover Medical School and first author of the study, said in a press release.

From this screen, the researchers identified two candidate vectors, which they dubbed MLIV.K and MLIV.A.

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[The new vectors] may represent a valuable advance in the field of liver-directed gene therapy

In a battery of experiments, the researchers demonstrated that these two vectors were better at delivering genetic material to liver cells than the unmodified AAV2 vector. Notably, the two vectors were able to effectively deliver cargo to mouse cells and human cells, both in cell experiments and in live animal experiments.

“This cross-species application possibility is very important for the development of new therapeutic strategies, because it enables the necessary preclinical trials in the mouse model and their transfer to the later clinical trials in humans,” Meumann said.

The scientists then tested these vectors in a mouse model of hemophilia B.

Results showed that an unmodified AAV2 vector could restore clotting activity, with FIX activity increased to 100% of the typical physiological range. The MLIV.K and MLIV.A vectors also restored clotting activity — but FIX activity was substantially higher, up to 400% of the normal physiological range at the same dose.

Although more studies are needed before therapies based on these vectors can be tested in people, the researchers said the development of these new vectors “may represent a valuable advance in the field of liver-directed gene therapy.”