Antisense, assemblies of molecules able to specifically block a mutated gene and the production of an abnormal protein, find their first clinical applications in an orphan disease, hereditary amyloidosis.
Two different antisens, complex molecules that can be produced industrially, are able to block the production of an abnormal protein in excess (mutated transthyretin) and improve to a level hitherto never reached in patients with an abnormality rare genetics at the origin of hereditary amyloidosis with polyneuritis.
Both studies are published simultaneously in the New England Journal of Medicine. The 2 Antisens are different, their effectiveness is close and there is a difference of tolerance. These studies finally pave the way for the large-scale therapeutic use of molecules that were discovered more than 15 years ago.
In theory, Antisense, or "interfering RNA", are able to be developed specifically for each disease (and even for each patient) where the secretion of an abnormal protein is produced in excess in the body.
Antisense is a therapeutic interfering RNA
All the genetic information necessary for the constitution of the living is inscribed in our chromosomes which are transmitted by the parents to the child and are contained in the nucleus of the cells.
The chromosomes consist of 2 strands of DNA, each strand of DNA being a very long sequence of oligonucleotide molecules. At regular intervals on these DNA strands are small sequences of oligonucleotides that correspond to the genes, the DNA fragments that code for the production of a protein.
When it is necessary to produce a protein, the DNA strands diverge, a complementary sequence ("mirror") of the gene is manufactured as a "messenger RNA". This one will leave the nucleus of the cell and be "translated" (or transcribed) in protein by the organelles of the cell. This process is normally regulated by interfering RNAs.
Block the production of an abnormal protein
In hereditary amyloidosis with polyneuritis (and renal and ocular cardiac disorders), there is an excess of production of an abnormal protein, transthyretin mutated, due to a genetic abnormality on the gene encoding this protein. This protein will then be deposited throughout the body and in particular in the nerves, heart, kidneys and eyes) to cause lesions.
So far, to avoid these deposits, we tried to destroy or eliminate the abnormal protein, but it does not work very well. It is also possible to correct the abnormal gene with genetic therapy, but it is risky and very difficult.
Antisense, or "therapeutic interfering RNA", can be manufactured outside the body, in mirror of the abnormal gene, in an industrial process which is not now very complicated provided to have the complete sequence of the mutated gene. They can then be reinjected by the venous or subcutaneous way in the patient to enter the nuclei of the cells and very specifically block the abnormal genes on the DNA, without touching the other genes or causing a side effect.
A remarkably powerful tool
In the 2 studies presented, the results are incredible with a drastic reduction in the production of mutated tranthyretin and a regression of 70 to 80% of neurological lesions in 18 months: an exceptional result in patients with severe disabilities who are at risk of dying.
There is still work to be done to compare the 2 Antisens, but already, the results obtained demonstrate the validity and the power of the therapeutic concept. Thus, the treatment of any disease where the blockage of a gene secreting an abnormal protein, whether in an overload disease or in cancer, is likely to be completely revolutionized.
The Antisense technique has no limit and we can even individualize the treatment for each person and focus on much less serious diseases. It is even possible to consider manipulating the living by blocking any gene, temporarily or permanently to improve the physical and intellectual abilities of a person.