Minigenes USH2A: General status
By Erwin van Wijk, lead researcher Radboudumc
Errors in the code of the USH2A gene explain the development of Usher syndrome in about 50% of all patients.
In addition to Usher syndrome, these errors can also lead to non-syndromic Retinitis Pigmentosa; loss of sight but without the hearing problems.
The USH2A gene contains the code for the protein usherin. After translation, the mistakes in the genetic code of USH2A also end up in the usherin protein, with the result that this protein loses its function and people lose their sight (and hearing). Giving patients a new copy of the USH2A gene that does not contain these errors could be an obvious solution. This is the principle of gene therapy.
However, for USH2A this is not as easy as it sounds.
New copies of genes are delivered with inactivated viruses, into which the genes are packaged. These viruses can be seen as small trucks. However, the loading platforms of the viruses are small. So small, in fact, that the USH2A gene simply doesn’t fit. Developing a classical gene therapy for USH2A is therefore extremely difficult from a technical point of view.
As an alternative, we have the “genetic patch” methodology, also known as exon skipping. The first patch tested is performed on patients tested in clinical trials.
Good news, but only for a limited target audience. QR-421a works for people with errors in a specific part of the USH2A gene: exon 13. This method can be extended to other USH2A genes and even to other Usher genes, but always remains only applicable for a limited number of patients.
Is there no alternative?
A few years ago we started with a new idea: can we not artificially shrink the USH2A gene, so that it fits in the loading platform of a virus and can therefore be delivered to the place where it is needed and can be used by all people with USH2A-related retinitis pigmentosa?
The main advantage is that, if effective, this method may be of value to all patients with USH2A-related retinal problems. The project “Minigenes USH2A” was born and made possible in part by a contribution from the Dutch Usher Syndrome Foundation (Stichting Ushersyndroom).
Four shortened USH2A genes were made and inserted into the retina of the USH2A zebrafish model. The shortened usherin proteins made from these minigenes in the zebrafish eye ended up in the right place in the light-sensitive cells of the retina, rods and cones. Functional tests by measuring electroretinograms (= ERG) indicate that these mini-usherin proteins are indeed (partially) functional. We have patented these results. How well they work remains to be investigated, but it is a promising starting point for further developing this method.
In the meantime, we are also looking into cultured cells to see where these mini-proteins go and whether they do not accumulate in a place where we would not want this. Fish, of course, are not people. It is therefore important to translate these results into models that are closer to humans.
We are currently trying to establish a partnership with a company that can help us take these important next steps.