Gene Therapy at a Glance

Published on: March 15, 2021


Genomic medicine researchers at Sanofi are investigating new ways to deliver therapeutic genes directly to cells, so they can repair the body's ability to make key proteins. This work is paving the way for new possibilities to treat or even cure diseases for which few or no other options are available.

Adeno-Associated Viruses: A DNA delivery system

Gene and cell therapies are designed to address diseases caused by a missing or faulty gene. New, low-cost technologies like CRISPR gene editing have made it possible to repair missing or damaged sections of DNA, much like using cut and paste in a document. By inserting a therapeutic DNA sequence into immune cells, for example, it is now possible to boost the immune system's ability to detect and destroy tumor cells. 

To insert a "DNA repair kit" into a cell's genome, scientists need a sophisticated delivery system. To achieve this goal, they exploit the natural ability of inactive, non-pathological viruses to insert DNA into host cells.

Adeno-Associated Viruses (AAV) are one such gene-delivery system. AAVs are widely used in gene therapy research because they are relatively simple to engineer. They can be crafted to transport therapeutic DNA sequences into the nucleus of different types of cells, like liver, muscle, or nerve.  

The delivery of DNA repair kits can be made either directly in the body (called "in vivo" gene therapy) or into a sample of the patient's cells in the lab, which are injected back into the patient after the repair is made (called "ex vivo" gene therapy).

One challenge for AAVs is the immune system, which is built to identify viruses, create antibodies to neutralize them, and commit them to memory. If an AAV were introduced to the body twice, neutralizing antibodies would be generated the second time, preventing it from reaching its target. That is why gene therapies are thought to have only "one shot on goal".

A second challenge is getting AAVs to deliver their DNA repair kit to specific cells involved in the disease, for example nerve or muscle. This must be done without wasting any of the precious dose on other cells – particularly those that get recycled before any benefit could be conferred.

AAVs and capsid engineering

To solve both problems, Sanofi researchers are using a proprietary technology platform that allows them to engineer a wide variety of AAVs. Engineering AAVs that can deliver therapeutic DNA hinges on the capsid: a protein "shell" that protects a viral genome. An AAV's capsid determines how visible it is to the immune system, and how easily it can deliver its DNA into different types of cells.

The overall shape of a capsid is like a soccer ball with little spikes sticking out. These spikes help the AAV interact with proteins on the surface of a cell. Their precise arrangement determines how easily the AAV will be detected, and whether it will target one type of cell or another. The arrangement depends on a specific sequence of amino acids, and that sequence can be engineered in the lab. 

Sanofi researchers are hunting for specific sequences on the surface of capsids that will help AAVs enter specific cells–and bypass others. This bioengineering approach could lead to capsids that help gene therapies make a beeline for target tissues, for example liver, muscle, or nerve. It could also help researchers craft a fleet of different AAVs that are all equipped to deliver DNA repair kits. Having a fleet of different capsids could help a therapeutic AAV evade the immune response, such that a patient could receive more than one dose.

"To engineer a capsid with the features we need, we can evolve thousands of generations of capsids in the lab over a short period of time," explained Sourav Choudhury, who leads Sanofi's capsid engineering and AAV immunology laboratories. "We use AI and bioinformatics to predict how each one of them will function–whether they are likely to make it easier for an AAV to deliver DNA to a neuron, for example. Basically, we are cramming millions of years of evolution into a few days of lab work, making very minor changes in the amino acid sequence that can lead to major changes in what the capsid can do."

Capsids that target disease-specific cells and deliver their cargo efficiently have the added benefit of requiring a much lower number of therapeutic AAVs per dose. That could be an important consideration for patient safety, manufacturing, and ongoing research.

Accelerating genomic medicine

Sanofi's genomic medicine R&D teams are deploying a fleet of genomic technologies to address challenges in genetic rare and neurological diseases, as well as some common diseases. With unique capacity in R&D and manufacturing, streamlined operations and well-matched partnerships, the company is accelerating toward the delivery of practice-changing medicines that can benefit society.


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New Frontiers in Genomic Medicine at Sanofi


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MAT-GLB-2004191 v 1.0 | March 2021