Parkinson's disease is a progressive brain disorder in which a messenger molecule called dopamine is lost. To treat it, a drug is given that passes into the brain where it is converted into dopamine. Unfortunately, within 5-10 years, the effect wears off. Research continues on ways of slowing down the nerve damage and into the role of gene therapy.
Parkinson’s disease is a progressive, degenerative brain disorder, characterised by a loss of specialised nerve cells and their connections in parts of the brain called the substantia nigra and locus ceruleus. These cells contain the chemical messenger dopamine and become greatly depleted in advanced Parkinson’s disease. Dopamine is involved in many functions, including the control of movement and co-ordination - in other words, Parkinson’s is a dopamine deficiency disease.
The onset of Parkinson’s disease is gradual. Common symptoms are slowness in initiating movement, muscular rigidity - which may lead to a loss of facial expression - and shaking (in about 70 per cent). More debilitating symptoms such as speech and swallowing difficulties, depression and constipation may emerge later. The rate of progression varies from 3-30 years and not all people develop the more severe symptoms.
Parkinson´s disease affects between 150 and 200 people in every 100,000 population. Thus, some 800,000 people in Europe are estimated to have Parkinson’s disease and about 75,000 new cases are diagnosed annually. It most commonly affects those aged 60 or over, but younger people can also develop the disease.
Dopamine does not pass from blood to brain, so it cannot be given directly as a medicine. Instead, levo-dopa (L-dopa) is used, which does enter the brain and is converted there into dopamine. This transformation is brought about by the enzyme aromatic amino acid decarboxylase, which is also present in tissues outside the brain.
Formation of dopamine in the peripheral circulation leads to troublesome side-effects such as involuntary jerky movements (dyskinesia), and L-dopa is therefore given in combination with a DDC inhibitor that does not cross the blood/brain barrier. Such combinations form the mainstay of initial treatment. In addition, there are trans-dermal patches available containing a dopamine agonist, which provide a more constant blood level of the active ingredient and be convenient to use. Likewise, there is a controlled release formulation of another dopamine agonist.
Triple Parkinson’s therapy consists of one tablet of L-dopa, which mediates the anti-Parkinson’s effect, carbidopa and another compound that enhances L-dopa availability to the brain and reduces the “wearing-off” of treatment experience with long-term use of L-dopa alone. The formulation is clinically relevant for advanced Parkinson’s disease patients, who may have difficulty swallowing a large number of separate tablets.
Patients with impaired mobility and in whom tablet treatment does not provide satisfactory results can be treated by intraduodenal infusion with a combination of carbidopa and L-dopa. The medicines are delivered in a gel formulation by an ambulatory pump directly into the duodenum, thereby bypassing the stomach and providing a more continuous and even supply and uptake than a tablet formulation. The portable pump used is inserted during a minor surgical procedure and can stay in place for several years.
Dopamine is broken down through the action of the enzymes catechol-O-methyl transferase (COMT), and monoamine oxidase-B (MAO-B). Blocking these enzymes therefore provides a way of enhancing the action of dopamine in the brain. Medicines that work as a COMT inhibitor or as a MAO-B inhibitor are used for this purpose, alone or in combination with L-dopa.
Clinical status and function of patients in both “on” and “off” time have been shown to improve significantly when treated with MAO-B inhibitors. “Off” time makes patients unable to function properly, and research suggests that over one third of advanced Parkinson’s disease patients experience several hours of such time every day.
Unfortunately, L-dopa loses its effect in most people within 5-10 years, as well as causing fluctuations in motor ability and dyskinesias (uncontrollable facial and bodily movement), and alternative strategies are then needed. One is to use compounds that mimic dopamine and stimulate its receptor. Such dopamine agonists have been available for some time and another has been introduced more recently. Other more specific compounds are also available.
While formulations of L-dopa and its combinations with DDC-inhibitors are not likely to be displaced soon from their central role in the management of Parkinson’s disease, research continues into ways of improving current medical treatment.
One is to explore the role of alpha2-adrenergic receptor antagonists in countering the L-dopa-induced dyskinesia that is seen in up to half of patients later in the course of the disease. Another is the use of acetylcholinesterase (AChE) inhibitors to treat dementia in Parkinson’s disease. At clinical Phase 3, investigators are studying a new MAO-B inhibitor which is also an inhibitor of dopamine reuptake. Preliminary results indicate that it improves motor symptoms, but it has also shown an effect in improving cognition.
A new oral agent is in Phase 3. The compound combines dopamine activity with effects on the neurotransmitters noradrenalin and serotonin that may help with common symptoms such as depression and anxiety. Surveys have shown that 80 per cent of people with Parkinson’s disease also experience depression. Another compound is being explored for treating the L-dopa induced tremors and hallucinations that may develop with prolonged use.
Several companies are investigating the use of neuro-protective compounds to stem the neuronal cell damage characteristic of disease progression. An N-methyl-D-aspartate (NMDA) inhibitor, already approved for motor neurone disease, is one such compound. Also in development is a selective inhibitor of the stress-activated protein kinase pathway involved in neuronal cell death.
At the pre-clinical stage, selective dopamine D1-receptor antagonists, previously unexplored because it was believed that they would be likely to have unacceptable side-effects, are being investigated. In addition, clinical candidate compounds from a series of adenosine A2 receptor antagonists are being investigated. The neuro-modulator adenosine has an important influence on the activity of basal ganglia in the brain, which are believed to play a central role in generating the characteristic symptoms of Parkinson’s disease.
Another avenue might be allosteric modulation. Instead of turning a receptor on or off, the technique works like a dimmer switch to control the degree of impact a medicine will have. The approach targets the mGluR4 receptor and does not depend on the dopamine neurons. As already mentioned, therapy requiring the use of dopamine neurons loses effectiveness over time.
Parkinson’s has been seen as one of the key areas in which gene therapy might be of benefit. There is work on a lentivirus vector system to introduce the genes necessary for dopamine synthesis into non-dividing cells such as the neuronal cells of the brain. The technology for this treatment has been shown to work with model ‘marker’ genes and the company developing it plans to move into Phase 1/2 trials.
An adeno-associated virus (AAV) vector system is tested as a candidate to transfer appropriate genes into the central nervous system. There are first results of two phase 1 trials that used AAV to introduce the gene for the nerve growth factor neurturin, and the gene for the enzyme aromatic amino-acid decarboxylase into the striatum of the brain. Moderately to severely progressed Parkinson’s patients (in the “off” state) showed motor improvement, 6-12 months after one injection. Currently, one phase 2 trial is ongoing.
A similar vector is in use to insert genes for glial cell-derived neurotropic factor (GDNF), a nerve growth factor, into dopamine-producing neurons in the substantia nigra and striatum of the brain. This protects and repairs cells damaged during progression of the disease and has been demonstrated to work in tests with monkeys, but a means will have to be found of ensuring tight control over the expression of the inserted gene before human clinical trials can begin.
Other investigators are also using the AAV vector delivery system to introduce a gene for the enzyme glutamate decarboxylase. This enzyme produces the major inhibitory neurotransmitter in the brain, gamma-amino-butyric acid (GABA). Patients treated in this way showed an improvement in motor function one year after treatment, indicating that this approach may be of value in those with advanced Parkinson’s disease.