Research
The only way that we will find effective treatments for Batten disease is through scientific and medical research – and though it’s not a mainstream topic, there are specialist researchers all over the world investigating different elements of NCL disease.
But how is research carried out, and why does it go through so many stages before a treatment is available?
Basic Research
Basic research, also known as discovery 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 how disease arises, which have led to new medical treatments and advances in diagnosis.
Each of the different NCLs is associated with a mutation in one of 13 genes and which one is affected will determine the subtype. This can be complicated as there is no single mutation that is responsible for each subtype. Researchers sequence the genes to understand more about the different types of mutations that occur, how they affect the function of the gene and the protein it produces, and how this impacts on cells and influences the course of the disease.
The more they can find out about this, about how these genes mutate and about how this affects different cells in the body, the more they can build up a full ‘picture’ of the whole disease. This means that they are in a much better position to work out how to correct the things that go wrong.
Even in the cases where they haven’t yet been able to find out much about a gene except for its name and location, they have often been able to establish, for instance, how mutations in this gene affects proteins that control cell growth or cell function. In cases like this, they have another possible starting point for treatment: they may be able to address these downstream problems, rather than the gene itself.
Many researchers have developed ‘cell lines’ – a population of cells derived from the same original cell, so that they all have the same genetic makeup, and which have the same mutation as one of the NCL diseases. 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 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.
A better understanding of disease mechanisms can then direct the next stage – pre-clinical research.
Pre-clinical Research
This is the stage where the researchers investigate whether a potential treatment might be effective and, just importantly, if it’s safe to take further. It usually involves an animal model, in order to get an idea of how humans may react to the same treatment.
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 models, 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. Mice with the disease are often used as models. Development of such models does take considerable expertise and resources, especially in the case of the larger animal models, such as dogs or sheep. Looking after the animals in the lab or farm, and breeding the numbers required for experiments, is expensive.
Even if a treatment doesn’t work out at this stage, that is useful knowledge too. It is just as important to know what doesn’t work as what does: we still know so little about the NCL diseases that all information is important.
Translational Research
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 and is expensive.
Clinical Research
Clinical research is medical research that is carried out on humans. This can include both clinical trials and studies which involve collecting and analysing data such as natural history and registry data.
Clinical Trials
The information below is provided by the UK government’s Medicines and Healthcare products Regulatory Agency (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
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. This phase is also important to pick up any safety concerns.
Phase II
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
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.
In trials for rare diseases some phases may be combined especially phases I and II, in which case one clinical trial is designed to provide all the basic information needed before a treatment can be approved for routine use in the clinic.
Timing
Clinical trials take a long time. The most straightforward treatments, which have no hitches along the way, will still take at least five years to get from the first idea to licensed treatment. Quite apart from the issues of getting funding, the researchers need to go very carefully, to ensure that every step is safe and that patients are actually benefiting.
Please see the MHRA website for more information.
www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency
Possible Therapeutic Approaches For 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.
Enzyme Replacement Therapy (ERT)
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. Following a successful clinical trial, cerliponase alfa has been available on a Managed Access Agreement since 2019 for treating CLN2 Batten disease. Work is ongoing to try and develop an ERT for CLN1 disease.
Gene Therapy
In disorders such as the NCLs, gene therapy aims to introduce a functioning copy of the gene affected into cells. This “new” gene will then direct the production of a correctly functioning protein. There are several trials currently ongoing using this method to correct NCL gene function.
Antisense Therapy
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. Antisense oligonucleotides are synthetic short DNA or RNA molecules designed to bind (hybridised) to target sequences in genes. They can be designed to have lots of different effects such as preventing protein expression in some diseases, but for NCLs they are being developed to restore more normal protein production.
The first trialled in a Batten patient (CLN7) was called Milasen. It was custom made for a single patient’s specific mutation and more information can be found here: https://www.wbur.org/news/2019/10/11/designer-genetic-drug-therapy-milasen. Research is ongoing to see if this approach can be used to design specific drugs for other children.
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. Miglustat is a molecule that prevents the build up of storage material in Gaucher disease type 1 that is in trials for use in CLN3 Batten disease.
Combination Therapies
Sometimes multiple treatments may be required in order to treat 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. For example, one treatment may be for the brain and another for the eye.
Research Studies and Clinical Trials
There are currently ongoing clinical trials and research studies. To find out more information about such studies please visit: www.clinicaltrials.gov