Parkinson’s disease has a complex aetiology, and is progressive and difficult to treat. It is, however, a prime example of how different medical technologies can be utilised in efforts to provide relief from suffering. This article discusses and compares these different approaches.
Characteristics of Parkinson’s
Parkinson’s disease is an incurable progressive disease. The incidence rises with age, from 17 in 100 000 for the group between 50 and 59 years to 93 in 100 000 between 70 and 79 years. Naturally, as life expectancy in many countries is increasing, the incidence of Parkinson’s is increasing and authoritative sources suggest that it will shortly affect approximately 1 in 800 people. The impact of the disease is therefore profound. The disease is caused by the failure of cells in the part of the brain known as the substantia nigra to produce adequate levels of dopamine, a neurotransmitter. The result is that the body experiences tremors, stiffness, slow movements and a loss of balance. These symptoms are not themselves life-threatening, but collectively they have a significant effect on the quality of life. Patients with Parkinson’s have a median life expectancy of approximately 15 years following diagnosis; death is often the result of complications from these physical limitations such as pneumonia. It is noteworthy that up to 90% of the dopamine-producing function of these cells may be lost before the disease becomes symptomatic.
Why these dopaminergic neurons fail is still not clear. Most cases of Parkinson’s disease are considered to be sporadic, that is, occurring in individuals with no apparent history of the disease in the family, probably as the result of a complex interaction of environmental and genetic factors. Certain drugs may cause Parkinson-like symptoms, and various environmental toxins have been claimed to be associated with the disease. Approximately 15 percent of those diagnosed with Parkinson’s do have a family history of the disease, these familial cases are often caused by mutations in the LRRK2, PARK2, PARK7, PINK1 or SNCA genes.
A series of factors conspire against the development of fully effective therapies for Parkinson’s. First there is this uncertainty about the cause of the disease and the lack of clear genetic markers in the majority of cases. Second, the site of the target for any therapy is deep within the brain where drugs may face the problem of overcoming the blood–brain barrier. Third, surgical interventions are far from trivial. It is no wonder that there is no single effective therapy at this time. It is also of no surprise that numerous approaches have been, and are being, developed that rely on diverse technologies, ranging from pharmaceutical agents to cell therapy, gene therapy and surgery.
We should deal with the pharmaceutical approach first, partly because this was the first type of therapy to be used with any
success, partly because this is still the frontline approach in all patients, and partly because some recent developments with biomaterials components appear to be interesting. It may seem an obvious approach to tackle the loss of an ability to produce a chemical by cells within the body by regularly supplying the body with a quantity of that chemical. After all, that is what we do when pancreatic islets fail to produce enough insulin and cause diabetes. It is not possible to supply dopamine directly to the body, but we can supply the molecule levadopa, which is converted to dopamine within the brain. Levadopa can be converted too rapidly to dopamine outside the brain and has some unpleasant side effects, thus it is usually combined with carbidopa, for example in the drug Sinemet. This is the major Parkinson’s drug, however, it loses effectiveness over time and symptoms gradually re-appear, even with increased dose levels. Other drugs include dopamine agonists, which mimic the function of dopamine; monoamine oxidase B inhibitors, which slow down the degradation of dopamine; and anticholinergics, which help to control the tremors.
The slow progressive loss of dopamine-producing neurons suggests that an alternative strategy may be based on neuroprotection through the delivery of neurotrophic factors, which could protect the neurons from cell death and promote their regeneration.
Neurotrophic factors derived from glial cell lines have the ability to promote repair, but limited clinical trials have not been successful as yet. Issues of optimal delivery of the molecules and the apparent development of anti-neurotrophic-factor antibodies in recipients have been reported. The concept is still valid, however, and we can expect to see better results when superior delivery systems involving the incorporation of these factors into biomaterial based systems, possibly in the form of nanoparticles, are developed.
Gene and cell therapies
The requirement for a constant delivery of a neurotrophic factor over a prolonged period of time will always be a challenge. One alternative is to alter the cells so that they themselves produce the factor in situ. This is the basis of gene therapy, where the delivery of the appropriate gene would allow the cells to constantly express the factor. As with virtually all areas of gene therapy, the principle is easier to understand than the method to deliver the therapy. Also, as with most cases of gene therapy, the first delivery method to be tried has been through the use of a virus; adenovirus, adeno-associated virus and lentivirus have all been successfully tested in animal models. There are still serious issues to resolve as far as safety is concerned. Again, alternatives may eventually be found through the use of new biomaterials in the form of nonviral polymeric vectors for the genes, or through the use of microencapsulated, ex vivo genetically modified cells that have been programmed to express a neurotrophic factor.
The next approach involves the transplantation of immature dopamine producing cells into the brain, a type of cell therapy. This was first started over twenty years ago through the use of embryonic or foetal neurons obtained at abortion. Leaving aside the ethical issues, there have been many problems with this technique. Although some patients have considerably improved following this transplantation, success is difficult to achieve because so many of the cells are lost during sourcing and implantation procedures. It is possible that other types of stem cells may be beneficial in this therapeutic approach in the future.
Deep brain stimulation
We now come to the surgical/medical device option. This involves the deep brain stimulator and is generally used as an adjunct to medication. The goal of the procedure is primarily to improve the condition in the “off” medication state. Patients with Parkinson’s disease have both “on” and “off” states. The “on” state is when the medications appear to be working and when the patient is reasonably mobile. The “off” state is when the patient is slower and stiffer. Deep brain stimulation does not usually improve the “on” state, which is the best condition, but improves the patient when he/she is in their worst state.
This technology requires the placement of an electrode deep inside the brain. This is attached to a subcutaneously placed electronic device that generates electrical signals that stimulate the brain and counter those effects that produce the Parkinson’s symptoms. There are a number of situations in which the electrode can be placed, most involving the thalamus or the sub-thalamic region. The procedure, which is more complex for the sub-thalamic stimulation device, is usually performed in two stages: the first involves the placement of the electrode and the optimisation of its position; the second involves implantation of the stimulator and connections. This procedure was first used clinically in the 1990s and its use has become widespread. As one may expect, there are some complications to anticipate, including those associated with the surgery and the hardware such as infection, migration and erosion, and those associated with the response of the patient to the stimulation, including numbness, vision problems and poor balance. Some long-term clinical studies of reasonable size are now becoming available for scrutiny. The procedure appears to have significant beneficial advantages over those achieved with medication by itself, and there is good evidence that the benefits last at least five years. There are indications that these benefits may be reduced at longer periods of time and it is clear that not all patients will benefit from this treatment. Obviously, it is not inexpensive.
The next steps
Drugs are good, but up to a point; the body gets used to them and they do not cure the condition, only ameliorate the symptoms. Cell and gene therapies are good concepts, but safety and efficacy are currently problematic. The deep brain stimulator works well, albeit in the short and medium term and is not for everyone. There have been enormous strides in the approaches to Parkinson’s, but it remains a huge social and medical problem. The one factor that all of these technologies face is the enormous destruction of neurons that has taken place before the condition is symptomatic. On the one hand this is good because it indicates a high level of redundancy in the system, but on the other hand it means that a great deal of damage has been done before any therapy is applied. If diagnosis was made much earlier, then the choice of therapy could be much easier and the cell, gene or pharmacological therapies may stand a much better chance. The surgical option is unlikely to be relevant in early stage treatment, but kept in reserve for the long established cases that need relief from the symptoms later in life. The development of better diagnostic markers to be used in routine screening is a priority.
Professor David Williams DSc, FREng
Professor Williams retired from the University of Liverpool, after 40 years, at the end of 2007. He retains the position of Emeritus Professor there and now has a series of professorial appointments in the USA, Australia, South Africa and China. In the USA he is Director of International Affairs for the Wake Forest Institute of Regenerative Medicine. He offers consulting services from his company Morgan & Masterson, based in Brussels, Belgium. He is Editor-in-Chief of Biomaterials, the leading journal in the biomaterials field.