We are currently collecting funds to put together a team of scientists who will be looking for a treatment of diseases underlying a KCNT1 mutation. Our interest is not, or certainly not mainly, to found a pharmaceutical company and to patent the applied technology. Our intensive research has shown that KCNT1 mutations are curable. We want to show this to the pharmaceutical industry which in a second step should undertake investments to obtain marketing authorization for the treatment of the KCNT1 gene mutations.
Dr. David Bearden from the Children's Hospital of Philadelphia treated a child with Quinidine (a potassium channel blocker, originally a heart medication) in 2014. He described that the child was able to laugh and even walk after the treatment. Therefore, potassium channel blockers (as the name implies) seem to be an option to prevent the passage of too much potassium through the potassium channels in order to reduce seizures and thus enabling development. Unfortunately, quinidine does not help Valeria and most other people suffering from KCNT1 mutations. Other potassium channel blockers should be considered. In the literature, it is described that Clofilium and Bepridil have shown to work in in vitro studies and block the channels.
As to Clofilium, it is unknow how it affects the human organism because it has never been used as an active ingredient in a licensed drug.
By contrast, Bepridil was already used to cure humans. There was a drug with the trade name Vascorã by Johnson & Johnson until the 1990ies. Unfortunately, most neurologists assume that the molecule Bepridil is not capable of passing the blood-brain barrier and therefore cannot have an effect on the KCNT1 channels in the brain. However our investigations have shown that there are some steps to be gone further:
1. Approaches for small molecules
a. The most obvious option would be to find a clinician willing to try to test molecules like Bepridil or Clofilium under very controlled conditions.
b. Both Quinidine and Bepridil were not originally designed to selectively inhibit KCNT1 and certainly not the disease-causing mutations. They were also not optimized to pass the blood-brain barrier and efficiently access the brain. Thus, a long-term strategy would be the development of a new small molecule therapy which crosses the blood-brain barrier and operates on the mutated KCNT1 channel. There are pharmaceutical companies in the field who have been doing research on the KCNT1 gene and have also found suitable molecules as possible candidates for treatment. Unfortunately, this research was not further undertaken because there was a change in strategy in the company and probably research was targeted at more lucrative therapies for more common diseases.
2. Antisense (ASO) approaches
Ionis Pharmaceuticals has developed a number of successful therapies using a DNA-like molecule that recognizes mRNA and modulates its function or expression. The most recent example is Spinraza, which is used to treat children with spinal muscular atrophy (MSA). This is also a brain disorder and the ASO is delivered directly to the brain.
3. Gene Therapy with RNAi
a. Similar to ASO, you can also inhibit the expression of the mutant gene by RNAi (RNA interference). This is typically done using viral vectors from adeno-associate viruses (AAV) and lentiviruses. Companies focusing on the use of gene therapy in the brain are using AAV vectors are among others. Avexis / Novaritx (with the added benefit that Avexis AAV technology) allows the virus to be dosed in the blood since the virus can enter the brain so that direct injections into the brain can be avoided.
b. It will probably take several more years for the development of these RNAi vectors to be ready, but similar to the ASO strategy, the mild phenotype of mouse KCNT1 knock-out suggests a therapeutic window.