CDKL5 Research has come a long way in recent years. Initial credit for this goes to the Italian Association (www.cdkl5.org) and also to the International Foundation for CDKL5 Research (IFCR) (www.cdkl5.com).
The President of the Italian Association supported the development of a protein replacement therapy project. As such the Italian Association contributed a large amount of funding into the initial stages the project, with a relatively small donation from CDKL5 UK. This project is now being privately funded.
One of the early projects of the IFCR was to create a CDKL5 knock-out mouse model. A knock-out mouse is basically a mouse that has been genetically created NOT to have the CDKL5 gene. Although this mouse model does not have seizures, which is the predominant early feature of CDKL5 disorder, it has still proved useful in characterising other features of the disorder.
Subsequently there have been several knock-in mice models (mice which have a specific CDKL5 mutation) that have been created in order to further characterize the condition, and there is now also a rat model under development in the UK. Certain mutations at the genetic level, such as nonsense mutations also known as truncated mutations, provide useful models in both mice and iPS due to the nature of the mutation. A nonsense mutation is a mutation that produces a premature stop-codon, which in basic terms means the CDKL5 protein is not formed. There are drugs in development that unblock the stop-codon and allow for whole or partial rescue of the gene thus making nonsense mutant mice ideal candidates for studies to see whether symptoms can be reversed. There are also studies with drugs that have already been given Orphan Drug Designation currently being tested on mice and iPS Cells.
As well as using mice to characterise the disorder, there are a number of studies using Induced pluripotent stem cells (also known as iPS cells or iPSCs). For more information about the usefulness of iPS cells see our infographic.
Although little is known about the protein’s function, it is believed that it may play a role in regulating the activity of other genes. So far this research is ongoing in various labs around the world. The CDKL5 protein acts as a kinase, which is an enzyme that changes the activity of other proteins, by adding a cluster of oxygen and phosphorous atoms at specific positions.
Allied to the basic research, cell and animal model research, there is also a protein replacement therapy project underway and a small proof of concept gene therapy project which is being undertaken in Bologna, Italy. In December 2014, a 3 three year pre-clinical gene therapy project was also started in London, UK.
CDKL5 is rare and our understanding is still in its early stages. However, millions of pounds of committed research funding is now under way in the search for treatments and a cure. Although it may take many years there is considerable hope and cause for optimism. One reason for this is that the condition is a monogenic disorder, meaning the disorder seems to involve mutations just in a single gene. Therefore we know basically what we are targeting which narrows the field of research. This gives us hope that through collaborative research the future could be brighter for those living with a CDKL5 disorder.