The Valeria Association is committed to achieving that:
- [+] to promote knowledge about the existence and cure of ultra rare diseases.
Valeria has a mutation on the KCNT1 gene. To be more precise, c.1421 of the gene KCNT1 is showing an A instead of a G in Valeria. The human genome has about 3 billion base pairs A, G, C and T. We all have spontaneous mutations as described above. But most of them go unnoticed and have no influence on our development. Only some of them are the cause of serious diseases, such as those of Valeria.
Neuropaediatricians in children's hospitals have so far diagnosed epilepsy in such cases. Accordingly, anti-epileptic drugs are used to reduce seizures, although the seizures are not the cause, but only a symptom. If all these very rare mutations with severe consequences are added together, millions of people worldwide are affected. The basis of a mutation is the same for all, the gene and its base pairs. So if not every single mutation were considered, but its origin the gene, all these diseases together would no longer be "ultra rare". There are more than 7000 rare diseases. In total, more than 300 million people worldwide are affected by rare diseases. 80% of these rare diseases are genetic, chronic and life-threatening. This is an important reason why we should all be interested. This will enable us to drastically change the lives of those affected.
- [+] research into the treatment of ultra rare diseases is being driven forward.
Among others, this involves the groundbreaking technology of antisense oligonucleotides (ASO). The big difference to conventional methods is that this revolutionary technology does not aim to combat symptoms, but to eliminate the cause. This means that instead of inhibiting the function of proteins as it is the intention with conventional drugs, antisense oligonucleotides already prevent the formation of the protein by binding to the mRNA.
The more experience and data are gathered with this new technology, the easier and faster these processes will be in the future. The design and production of an oligo does not have to be "reinvented" every time. If the ASO approach is the right one, the processes are the same, regardless of the gene mutation. The standardization of various steps, such as the approval procedure by approval authorities and associated test procedures, should result in shorter and more cost-effective processes.
Just imagine that just a few years ago a WGS - Whole Genum Sequencing - the sequencing of an entire human genome cost one billion USD and took several years. Today, a WGS lasts one week and costs CHF 4,000 (and declining).
- [+] exchange of experiences between affected persons is made possible.
Alexandra and Mario Schenkel came across two parents whose children also suffer from ultra rare diseases. Parents always try to do the best for their children and usually know exactly what is good for them. Through these contacts, parents whose children had the same disease have already been connected several times. This enables a very specific and valuable exchange of experiences.
- [+] experts and scientists are linked.
It turns out that it takes a lot of time to find all the people who have the necessary know-how and bring them together. Parents of children with ultra rare diseases know that time is the most precious commodity. The process of bringing together the right people, universities or institutions until the right medicine is available must be faster and easier.
- [+] money is collected for research projects.
Parents who have to bear such difficult fates are confronted with an unbelievably great burden and an additional almost impossible "Herculean task". They have to raise a lot of money themselves.
With intensive planning over several weeks, incredible commitment and support from family and friends, Alexandra and Mario Schenkel launched a crowdfundig campaign in mid-May 2019. They experienced a huge wave of solidarity and were delighted with a huge donation success. They had only achieved this success thanks to the great support of family and friends.
It cannot be the case that all affected families also have to go down this road. It needs the support of foundations and people who want to be part of something revolutionary. Do YOU also help?
- [+] therapies are made possible.
With the support of various specialists, a program was put together for the development of a drug based on the ASO approach.
"The development of drugs for rare diseases is a challenge. The one size fits all - approach to drug development does not work in this context. That is why the pharmaceutical industry is not interested in the problem of genetically caused ultra rare diseases," says Mario Schenkel, father of Valeria and member of the board of the Valeria Association.
There are even more questions to be asked. Can an oligo be patented when it is merely a counterpart to a human gene strand? "Such questions do not concern us. We want to save human lives. It is long overdue for more research to be carried out in this area. It is our intention to use our commitment to change the way the pharmaceutical industry and the authorities think," adds Alexandra Schenkel, mother of Valeria and board member of the Valeria Association.
Our Research and Our Goal
Together with two teams at Harvard Medical School and Yale School of Medicine, we are developing an antisense oligonucleotide (ASO) drug to suppress the de novo mutation on the KCNT1 gene. This form of therapy gives those affected the chance of development in their lives. With our commitment and the research we have done so far, we are committed to ensuring that further gene mutations can also be treated with this approach in the near future.
How does the antisense oligonucleotide (ASO) approach work?
The antisense oligonucleotide (ASO) approach produces a particle consisting of bases (opposite base pairs - "antisense") that can bind to the mRNA formed by the gene. The particle causes the mRNA to be deactivated or the gene to be switched off, thus stopping the production of the changed protein. This revolutionary technology tackles the problem at its root. This means that the cause of the problem is solved and not just the symptom, as it is done with conventional methods. In other words, conventional drugs are intended to inhibit the function of proteins, whereby antisense oligonucleotides already prevent the formation of proteins by binding to the mRNA.
The path of drug development according to the ASO approach
The following illustration shows the individual steps which are required until the drug can be administered to Valeria.
|Gene sequencing. |
When it was not yet known what Valeria was suffering from, a gene sequencing was carried out as part of the exclusion procedure. The entire genome of Valeria was examined. The mutation carried by Valeria on the KCNT1 gene was found by this procedure. In Valeria, c.1421 of the gene KCNT1 is replaced by the base G instead of the base A.
|effect of the mutation |
Depending on the type of mutation, the effect is different. In Valeria's case, a different amino acid is formed due to the wrong base. Since amino acids are the building blocks of proteins, a modified protein is produced.
|Preparing Valeria's cells for testing the drug. |
In order to test the drug produced for Valeria on her cells, Valeria's skin cells are cultivated into stem cells and these turned into neurons / nerve cells. This procedure is difficult and time-consuming.
|Design and prepare drugs. |
The drug is designed and processed in such a way that it functions as a "counterpart" to the gene mutation in the body.
|Check the knockdown effect of the drug in test celllines. |
The ASO prototypes produced are tested on simpler cells and their effect is investigated. The hypothesis is that the better the ASO prototype, the lower the production of the modified protein or the less potassium flows into the nerve cells.
It is also part of the investigation to find out which ASO prototype achieves good results even at low doses. The data obtained are presented in a concentration-response curve (CRC).
|Check the effect of the drug in Valeria's nerve cells. |
The best ASO prototypes that have completed the previous tests will now be tested in Valeria's nerve cells (in a dish). Thur the lower potassium influx the electrical voltage of the nerve cell is changed . This is also an important factor and is a decisive factor in the selection of the best ASO prototype for proof of concept.
|Manufacturing of the drug. |
In this step, the ASO prototype that performed best in the tests before is produced. The ASO is produced in such a pure "clinical grade" form that it is not toxic in the human body.
10-12 weeks (in parallel with other steps)
|Safety Studies |
In order to exclude as many dangers as possible, the manufactured drug is subjected to various safety tests in other organisms before it is administered to Valeria. This step is required by the U.S. Food and Drug Administration (FDA).
8-10 weeks (in parallel with other steps)
|FDA Approval |
The FDA requires a 1-patient approval (n of 1) for drug administration.
|Treatment start. |
Since this is a new drug and just few data is available yet on how high the dose of the drug to be administered should be, very small doses are used at the beginning of the treatement. It will take several months before the target dose is reached. The drug is administered with an injection into the spinal cord, as the ASOs must act directly in the central nervous system. This is the usual method of administration, which is also used for other similar drugs such as Spinraza.