Neurological conditions such as Parkinson’s disease and Alzheimer’s disease have long evaded satisfactory treatment. Despite the best efforts and the investment of billions by pharmaceutical companies, they continue to pose threats to public health – especially as life expectancies around the world increase and exposure to risk factors such as pollution multiply.
Around the time of World Parkinson’s Day in 2018, Professor Sir Ian Wilmut announced he himself has Parkinson’s disease as he backed new research into the condition. Professor Wilmut is best known for the cloning experiments that created Dolly, a sheep who became the first mammal to be cloned from an adult cell in 1996. This was a controversial landmark in research which had some exclaiming that science had gone too far. Some even condemned the act as “playing god”.
Despite controversy at the time, could Professor Wilmut’s prior research hold the key to treating degenerative diseases such as Parkinson’s?
Parkinson’s disease, still without a cure
Parkinson’s disease remains poorly treated. Currently, the best hope for those living with the disease is symptom management. This can effect improvements to quality of life; however, this does not detract from the harsh reality that we still have no means of fully curing the disease.
The hallmark symptoms of Parkinson’s disease are involuntary movements known as tremors; slow and difficult movement; and stiff and inflexible muscles. Loss of balance is also common due to these movement issues. This can result in dangerous falls that can put elderly patients in particular at risk of injury.
Issues such as anxiety and depression are common in patients, though whether these are a result of disease pathology or the circumstances of the condition are unclear. Psychological issues such as loss of memory and insomnia are also noted.
Around one in five hundred individuals are thought to develop the symptoms of Parkinson’s disease in their lifetimes. These symptoms most commonly manifest in those aged over fifty, though one in twenty patients will have apparent symptoms before the age of forty. Actor Michael J. Fox – diagnosed in 1991 when he was 29 years old – is perhaps the most notable example of this.
While the exact cause of Parkinson’s disease is unknown, its mechanism is well documented. The condition is intrinsically linked to the loss of dopamine producing neurons within a region of the brain known as the substantia nigra. Currently, there is no known reason why these specific cells are killed off. Theories range from genetic to environmental effects, though neither explanation has been proven.
Dopamine is linked to a number of processes within the brain. Movement is a primary characteristic affected by the loss of dopamine, but it is also involved in memory, mood and sleep cycles. All of these can be affected to some degree in a patient suffering from Parkinson’s disease, with symptoms getting worse as the disease progresses and more dopamine-producing neurons are lost.
As mentioned above, treatments for the disease are entirely related to symptom management, as these lost neurons cannot currently be replaced. A commonly used therapy is the use of Carbidopa/Levodopa, drugs which are absorbed and converted to dopamine within the brain. Anticholinergics are also commonly administered to reduce the motor dysfunctions.
Stem cells and the potential for tissue replacement
While Professor Wilmut’s research was deemed controversial, in reality, the cloning experiments were an attempt to prove that specialised cells could be derived from the stem cells of a donor organism. Indeed, the rise of stem cell research is considered Dolly’s main legacy in lieu of cloning. This concept gave new hope for many with degenerative conditions such as Parkinson’s disease that one day their own stem cells would be used in treatment for their conditions.
The work on Dolly the sheep led the way to the creation of induced pluripotent stem cells, or iPSCs. Embryonic stem cells are a type of progenitor cell that all specialised cells within our body are derived from. They hold the capacity to replicate into more stem cells, or specialise into any other variety of cell, such as neurons or muscle cells. It is for this reason that they are of interest in medical research, as they hold the potential to replace and repair damaged or destroyed cells, thereby healing damaged tissue.
iPSCs differ from embryonic stem cells in that they are not embryonic, but derived from human skin cells. A procedure that is mediated by a retrovirus is used to artificially insert four transcription factors (or genes): Oct4 (Pou5f1), Sox2, cMyc, and Klf4. Through the insertion of the four genes, some cells are reprogrammed into iPSCs, capable of proliferating indefinitely while also creating specialised cells.
This method was discovered by Shinya Yamanaka in 2006, who went on to win the Nobel Prize in Physiology or Medicine for the discovery in 2012.
Issues have arisen due to some research suggesting iPSCs and embryonic stem cells function slightly differently. This is likely due to the fact that iPSC are not true stem cells. Due to this, it is difficult to predict the effect they will have when used in human treatment, though it is theorised that stem cell therapies using iPSCs could have great impact due to them not being rejected by the host’s immune system.
The first clinical trials of iPSCs for Parkinson’s are currently underway in Japan, though are as of yet in their initial stages.
Similar neurological conditions: Also find no luck in finding a cure
The inability to find any means of curing or reversing the effects of a disease are common throughout many neurological disorders.
Alzheimer’s disease, for example, has had no new medications released in over a decade. This has resulted in pharmaceutical giant Pfizer announcing their plans to leave the field of Alzheimer’s research. This could become a consistent trend within the industry as more and more companies report significant financial losses from failed attempts at the creation of Alzheimer’s medication.
Similarly, Huntington’s disease has no current cure, and uses similar treatment methods as Parkinson’s to manage the symptoms. Recent research has created a potential medication, IONIS-HTTRx, which targets the mutant huntingtin known to be a causative factor in the disease. Initial human trials of this new therapy were a success, though it is worth noting that the medication has been a decade in the making and the trial only involved 46 individuals.
Myriad of causative factors and blood brain barriers
Why are neurological disorders more difficult to treat than diseases occurring in other organs? The reason is likely to be the blood brain barrier (BBB). The BBB is a specialised group of cells encasing the brain and nervous tissue that creates a selectively permeable barrier that simultaneously allows the entry of nutrients into the brain while also keeping out unwanted material.
The issue faced by those seeking to create medicines for these disorders is that the BBB also recognises the medicines as an unwanted material. This means that the medicine will not be able to permeate the membrane and will never reach the intended target area within the brain, rendering the medication useless.
Efforts to create potential medications must therefore take this into consideration. A medication that reduces, for example, the amyloid beta plaques (a known causative factor of Alzheimer’s disease) in a cellular model may not work in a human host as the active compound may never reach the plaques.
Medication design may therefore have to involve another compound that allows passage across the BBB. This in itself causes new issues, as side effects may be observed due to the sudden passage of unwanted compounds across the BBB.
New research has suggested the use of a surgical technique to use the patient’s own tissue to create a semipermeable “window” into the brain could prove effective. The mouse based trial showed success in allowing the passage of molecules 1000 times larger than those excluded by the BBB.
However, even if drugs can be delivered to the brain, our often poor understanding of what causes neurological disorders limits the potential for success. The aforementioned stem cells may replace lost neurons in the case of Parkinson’s disease, but if the mechanism by which these cells are being killed off is not resolved, the stem cell treatment would likely have to be both regular and life-long.
Neurological disorders are notoriously difficult to treat. Slowing the progression of the disease or managing the symptoms are often the best we can accomplish with current medications. Multiple expensive failures have made research in this area a very risky endeavour, which may dissuade investors in the future and damage the chances of ever finding a cure for many of these diseases.