In Vivo Platforms

In Vivo Is Now Possible

With our holistic approach to viral vector research and development and interdisciplinary expertise, including a deep familiarity with viral modalities, viral vector engineering and immunology, Vyriad is leading the way towards an in-vivo future that transforms medicine for patients.

Like cell therapies, in vivo approaches have the potential to address a wide range of diseases, including inherited disorders and diseases with significant unmet needs. In contrast to cell therapy, however, in vivo therapies may be easier on patients, less logistically challenging and more accessible. Instead of extracting cells and editing them in a lab before re-administration, patients receiving an in vivo therapy are simply given a single dose of a targeted genetic medicine, which edits cells inside their body to achieve a therapeutic outcome.

An innovative approach to G protein targeting

Vyriad takes a unique approach to re-targeting lentiviral vectors, informed by innovations in G protein selection and engineering, which were honed during successful clinical development of the VSV oncolytic virus.

Vyriad’s development of viral vectors with optimized and engineered G proteins achieves:

Improved transduction efficiency, favorable compared to ex vivo infusions
Highly cell-specific targeting
Stability and resistance to neutralization by complement in human whole blood
Long-term durability of therapeutic response

Engineering Lentiviral Vectors

Lentiviral vectors are well established in the lab and in the clinic because they can deliver large amounts of DNA with minimal immune response. But, to turn a lentivirus into the optimally targeted, stable and efficient delivery vehicle for a medicine, it must be genetically engineered. One common method of viral vector engineering is pseudotyping – where a virus is engineered with non-native envelope proteins that are responsible for cell-binding and cell-fusion.

Lentiviral vectors are commonly pseudotyped with VSV-G, which is native to the Vesicular stomatitis virus, because the protein is stabilizing, and because VSV-G binds to host-cell receptors that are expressed on the surface of a wide range of human cells, providing lentiviral vectors with broad tropism (the ability to infect multiple cell types).

In order to accomplish cell-specific targeting, VSV-G pseudotyped lentiviral vectors are re-targeted through additional viral engineering.

1. The G protein must be engineered so it does not recognize LDL receptors (a process called blinding) while maintaining its fusogenic capacity.

2. The virus must display ligands that specifically bind the target cell of interest.

Why Lentivirus for viral vectors? Established method for ex vivo transduction of T cells for CAR T cell therapy. Compatible with G-protein pseudotyping for specific cell targeting. Infects dividing and nondividing cells. Integration of transgenes into the host cell genome provides long-term stable gene expression. Low immunogenicity. Can deliver large amounts of DNA (~8 kb), allowing a wider range of payloads to be incorporated versus non-lentiviral technologies.

Overcoming Barriers to In Vivo Delivery

Administering genetic therapies in vivo requires perfecting the delivery vehicle. Limitations of first generation viral vectors have hampered the potential of in vivo therapies:

First-generation vectors vs. Vyriad's vector approach compared for targeting, stability, and efficiency.

At Vyriad, world-class science comes together with purposeful collaboration to make highly targeted in vivo gene therapy possible with efficiency, stability and durability. Our approach to engineering viral vectors leverages years of experience developing and de-risking oncolytic virus therapies.