Basic research usually takes place in a laboratory setting at a University or similar institution. It is conducted to investigate the fundamental causes of a disease and researchers often focus on a specialised area. Basic research has provided many insights about disease action, which have led to new medical treatments and advances in diagnosis.
A better understanding of disease mechanisms can then direct the next stage – pre-clinical research. For instance, many cell lines have been developed that contain the same mutations or mistakes that are found in a patient with NCL. A cell line is a population of cells derived from a single cell so that they all have the same genetic makeup. Researchers can then look at the differences between these cells and unaffected cells. In addition to giving information about what is going wrong, cell lines carrying NCL mutations can be used to screen panels of drugs to see whether any improve or rescue the affected cells.
Recently scientists have discovered how adult human cells, for example skin cells or hair cells, can be changed in the laboratory into cells with the characteristics of embryonic stem cells; cells that have the ability to make any cell type in our body. These engineered embryonic stem cells are called induced pluripotent stem cells and when made from patient cells, such as from individuals with NCL, they can be an effective platform for drug screening. This is not only because these cells carry the human disease mutation but also because they can be made to turn into a specific cell type that is relevant for the disease being studied.
This is the next key step in the development of a potential treatment and usually involves testing this treatment in an animal model. Investigating how effective this may be is an important part of this phase, but equally important is looking at its safety.
The disease models used must be well characterised, as they must be a valid representation of the disease to be treated. There are many types of model and each may give different information, so often a drug will be tested in more than one model in order to build up a more complete picture of the effects of a potential treatment. Development of such models does take considerable expertise and resources, especially in the case of the larger animal models, such as dogs or sheep.
The aim of translational research is to accelerate the process from basic and pre-clinical research into clinical trials. This is one of the most challenging areas of research, as it often requires the interest and involvement of pharmaceutical companies.
Clinical research is medical research that is carried out on humans. This can include both clinical trials and studies which involve collecting and analyzing data such as natural history and registry data.
Therapeutic Approaches for the NCLs
Since the first mutations or mistakes in genes that cause the different types of Batten disease were identified, over 400 mutations in 13 different genes have been described.
Genes are templates (or patterns) for the manufacture of proteins and so mistakes in a gene can mean that the protein that is made will not function properly or will not be made at all and this can cause disease. In consequence each NCL gene encodes a different protein with a different function. Therefore many therapeutic approaches will be specific for a given type of NCL e.g. CLN3 or CLN2.
Possible Therapeutic Approaches
There are several strategies that are in development for the NCLs, which aim to replace or to try to replenish the activity of the protein that is affected, or to compensate for its loss of function.
For NCLs that are caused by a defect in an enzyme, such as CLN1 and CLN2, therapeutic interventions will probably require giving the enzyme as a therapy. Cerliponase Alfa has been licensed for the treatment of CLN2 disease.
In disorders such as the NCLs gene therapy aims to introduce a functioning copy of the gene affected into the cell. This “new” gene will then direct the production of a correctly functioning protein.
In some cases gene expression can be modified. In genes there are signals called ‘stop codons’ that tell the cell when protein production is complete. Some NCL mutations create stop signals in the wrong place causing a protein to be made that is too short. Some antibiotics can enable the cell to ‘read-through’ these stop signals increasing the amount of functional protein that is made. Promising basic research has shown the possibility of using this approach to modify protein expression by genes that carry specific mutations that cause CLN1 and CLN2 disease.
Therapies that could block key events
Research from studying both NCL models and NCL patients has shown that there are many key events that occur during disease progression. Many are common to all forms of NCL such as loss of nerve cells, while some are more specific and/or occur at different times in the disease course, for example an immune response. It may therefore be possible to develop treatments that target these key events in the hope that they will slow down the progression of the disease.
Small Molecule Therapies
These are approaches that aim to test if certain drugs or other small molecules can block key events and/or help to slow down disease progression. For instance in CLN1 or CLN2, to enhance the activity of any small amount of enzyme that is being produced, small molecules – often referred to a chemical chaperones – could be used.
Sometimes multiple treatments are required in order to fight a particular disease or condition. This might mean the use of more than one drug or the use of a drug together with a different form of treatment.
The information below is provided by the MHRA, and is included to give an overview of how clinical trials are conducted.
There are 4 phases of a clinical trial and a product can only go to the next phase if it has passed the safety and effectiveness tests of the previous one.
Phase I trials, sometimes called first-in-human trials, test a small number of subjects to find out how the treatment works in the body. This type of trial aims to find the lowest dose at which the treatment is effective (the minimum therapeutic dose) and the highest dose at which it can be taken without causing harm.
Phase II trials test the treatment in several hundred people with a given disease or condition. They aim to find out how well the treatment works in larger numbers, identify common side effects, and refine the dose and length of treatment.
Phase III trials typically compare the treatment across several thousand patients to gather more detailed information on how well it works in groups of patients and its safety. The results influence the prescribing and patient information of a medicine once it is marketed.
Trials are carried out after a medicine has been licensed and put on the market. These trials are designed to find out more about the long term benefits and harms of a medicine and to discover new uses for it.
In trials for rare diseases some phases may be combined.
Please see the Medicines and Health Care Products Regulatory website for more information.
Research Studies and Clinical Trials
There are currently ongoing clinical trials and research studies. To find out more information about such studies please visit this US located website: www.clinicaltrials.gov