Big gene, small virus

We wrapped up 2017 with the news of the first gene therapy approved in the US to treat a genetic disease. It was Luxturna, approved for treating vision loss in patients carrying mutations in a particular gene that causes retinal dystrophy. The videos of vision improvement in patients treated with Luxturna that Spark Therapeutics has shown are breathtaking, and I trust gene therapy will one day be the go-to treatment for most genetic diseases.

There are in fact many genetic diseases! From the estimated 6000 to 8000 rare diseases, the large majority is thought to be also caused by gene mutations. And the most common consequence of those mutations is loss of function of the gene, so the approach that Luxturna used to deliver a backup healthy copy of the gene to the affected cells would be the ideal one.

But here is the catch: Luxturna uses a small virus, called Adeno-Associated Virus or AAV, to deliver the therapeutic gene to the affected cells. AAV is the gold-standard when it comes to gene therapies in development, with many advantages over other virus that are less infective (don’t get into as many cells) or might trigger an immune response. But AAV can only transport small genes, and not all diseases have mutations in small genes.

In a recent Dravet syndrome families meeting, a gene therapy expert explained to the parents that that scientists have been very good at developing cars able to transport a healthy gene copy to the patient, but that their particular disease will need a bus. I like the metaphor very much.

Many diseases will need virus larger than AAV to be able to have a gene therapy. We need a bus.



In some diseases that have “big genes” it might be possible to develop shorter versions of the gene that could fit into an AAV and retain sufficient functionality to have therapeutic benefit. The main example that comes to mind is the mini-dystrophin gene, which is currently in clinical trials (here and here). This approach is only possible because dystrophin is a large scaffold protein that needs to attach to multiple partners and can be reduced to only those main protein domains retaining functionality.

Dravet syndrome is caused by mutations in the SCN1A gene, which produces an ion channel that needs to cross the plasma membrane 24 times. Such a large protein needs to go in an out the membrane the right number of times and to have the right loops inside and outside to be able to form the correct channel structure and functionality. There is no spare protein bit that we could chop out of the gene to reduce it to a size where it could fit into an AAV. We need a bus.



Dravet syndrome is not the only disease caused by mutations in a gene too large to exploit the great advances in using AAV as therapeutic vehicles for gene therapy. The entire field of gene therapy needs to find the best solution for the next-generation therapies that go beyond what AAV can give us.

Within Dravet syndrome, these next-generation therapies are being led not by companies but by academic groups with the support of patient organizations:

||   Dravet Canada and the US Dravet Syndrome Foundation are supporting a gene therapy project at Toronto University that will use AAV to deliver compensatory genes (not SCN1A) for the treatment of Dravet syndrome. Because the AAV technology is the most advanced one this approach offers the fastest gene therapy path to the clinic, but it doesn’t represent the ultimate ideal treatment that would involve the delivery of a healthy copy of the SCN1A gene to the affected neurons.

||   One of the projects aiming to develop that ideal treatment is led by Simon Waddington and Rajvinder Karda from UCL. This team is working on one type of “bus”, Lentivirus, that has enough capacity to carry the SCN1A gene and become a treatment for Dravet syndrome. They have received the support from Dravet Syndrome UK and share updates with other interested patient groups.

||   And a larger collaboration was recently awarded a European grant to also look for a different type of bus. This time scientists from Spain, France and Israel are trying to develop a gene therapy for Dravet syndrome using Adenovirus, another type of high-capacity virus. They are collaborating with Dravet Syndrome Foundation Spain and the Dravet Syndrome European Federation, and have also developed a close relationship with patient groups.

If everything goes well, one or more of these programs will "cure" a mouse with Dravet syndrome using one of these virus within the next 2 to 3 years. The next step are clinical trials. This all used to look like a very distant future, but with the approval of Luxturna it has now become a reality. Soon someone will get a gene therapy using a big virus approved, and that day Dravet and many other syndromes caused by mutated large genes will have found a bus.


Ana Mingorance PhD