LIKE ELEPHANTS ON A FIAT PANDA
The fact that there are more than 10 Usher genes means that we will need various therapies for treating Usher Syndrome. Most Usher genes are way too large for the existing treatments of replacing the genes.
Therefore, these genes are like elephants sitting on a Fiat Panda, so they cannot be transported to the eye and the ear.
Researchers are now taking up the challenge to find alternative means of transport or to make the elephants smaller and lighter.
The absorption capacity of the presently available AAV vectors is only 4,800 bases and therefore way too small to deliver most Usher genes in the body.
DOUBLE AAV VECTOR
A healthy copy of an Usher gene is split in two and each part is packed in an AAV vector. After application of the 2 AAV vectors to the eye, the cells in the retina should reconnect the information from both vectors and so create a correct protein.
The USH 1B gene fits into 2 AAV vectors. USH 2A needs has at least 5 AAV vectors and USH 2C even a lot more! Consequently, the strategy of a double AAV vector is not an option for the last mentioned Usher genes.
Instead of an AAV vector, it is also possible to make use of a lentiviral vector, called EIAV. A lentiviral vector has a larger capacity to deliver an Usher gene.
The @USHStat study conducted in 2019 showed that the lentivirus randomly settles itself in the human eye and so causes other undesirable problems. Therefore the studies concerning the lentivirus have been stopped for the time being.
Develop minigenes to make the Usher genes small enough to fit into an existing AAV vector.
This strategy could possibly be applied to the large Usher genes, such as USH 2A, USH 2C, USH 1D and USH 1F. The proteins of these mentioned Usher genes fall under the same type of protein.