This usually takes place in a laboratory setting at a University or similar Institute. Basic research is conducted to investigate the fundamental causes of a disease and researchers often focus on a specialised area or conduct experiments to answer a particular question. 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, preclinical research.
This is the next key step in 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 how safe is the treatment.
The models used must be well characterised, that is they must be a valid representation of the disease to be treated. There are many types of model which may give different information, and often a drug will be tested in more than one 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 in translational research is to accelerate the process from Basic and Preclinical research into the clinical trial phase. 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.
NCL Disease Registries
Registries are of vital importance for a number of different reasons. Scientists and pharmaceutical companies are more likely to conduct research on a given rare disease if they find a patient registry in place. Registries also assist in understanding the disease, recruiting patients for clinical trials, tracking how the disease progresses, monitoring the safely and how effectiveness of possible treatments.
The collection of Batten patient data will also assist in achieving earlier diagnosis and proactive interventions for those affected; increasing quality of life and supportive care.
Clinical Trials Phases
Source: Medicines and Healthcare products Regulatory Agency (MHRA) https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency
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. Your application must specify the phase.
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.
Phase IV 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.
Therapeutic Approaches for the NCLs
Since the first mutations or mistakes in genes were identified that cause the different types of Batten disease over 400 mutations in 14 different Genes have been described.
Genes control 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. 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 in the NCLs
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 which are caused by a defect in an enzyme such as CLN1 & CLN2 therapeutic interventions will probably require giving the enzyme as a therapy.
Brineura is currently undergoing a successful clinical trial in CLN2 disease and is available in England under a Managed Access Agreement.
In disorders such as the NCLs gene therapy aims to introduce into the cell a functioning copy of the gene affected. This “new” Gene will then direct the production of a correctly functioning protein. There are many companies now working in this area for most types of NCL, with a few reaching clinical first stage clinical applications.
In some cases, the expression of the gene 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. Researchers are looking at ways to “read through” these stop codons so the cell can make the full protein.
A recent area of interest is to try to produce synthetic copies of the RNA molecule that translates the message to allow cells to make the proteins needed.
Therapies that could block key events
Research has shown there are many key events that occur within the cell in Batten disease. These lead to changes in the brain in animal model systems and NCL patients. Many are common to all forms of NCL, some more specific and/or occur at different times in the disease course. It may therefore be possible to develop treatments, which would slow down the progress of the disease.
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.