Tremulous journey

In 1817, James Parkinson published An Essay on the Shaking Palsy, describing what is now known as Parkinson’s Disease. Over 200 years later, it still has no cure and affects more than 10 million people worldwide.

Parkinson’s Disease (PD) is a neurodegenerative disorder caused, in part, by the loss of dopamine-producing brain cells. Dopamine is crucial for movement, coordination, and cognitive function. PD is characterised by tremors, bradykinesia (slow movement), muscle rigidity, difficulty with voluntary movement, and postural instability. It also significantly increases the risk of dementia.

Professor Roger Barker, a Clinical Neuroscience Professor and Honorary Neurology Consultant at the University of Cambridge and Addenbrooke’s Hospital in the UK, has spent over four decades studying treatments for neurodegenerative diseases.

The substantia nigra in the brain contains about 5,00,000 dopamine-producing neurons essential for movement, as shown by Nobel Laureate Arvid Carlsson. Prof Barker notes that over half — around 2,00,000 to 2,50,000 — of these neurons are already lost by the time the first motor symptoms appear. The main obstacle to slowing PD is that no disease-modifying treatments exist that can stop the progression of the disease. The disease can have a pre-clinical phase lasting up to 15 years, with movement symptoms like tremors often appearing much later. Additionally, 30–40% of cases do not present with typical tremors, leading to many undiagnosed cases.

Treatment challenges

Current PD treatments aim to restore dopamine levels using Levodopa or dopamine agonists, which directly stimulate dopamine receptors. Levodopa, a dopamine precursor, was a breakthrough for managing motor symptoms and improving quality of life. However, long-term use can cause side effects like dyskinesia — uncontrolled, writhing movements.

Dr Guruprasad Hosurkar, a Parkinson’s and movement disorder specialist, notes that managing PD is complex due to both motor and non-motor symptoms, such as depression, anxiety, behavioural changes, and cognitive decline. Treatment depends on age, co-morbidities, and disease stage, often involving drug combinations and sustained-release medications, especially at night. After 4–5 years, drugs become less effective, requiring higher doses and negatively impacting quality of life. Dr Hosurkar also points out that PD typically begins about a decade earlier in India. Here are some advanced treatment options:

Deep Brain Stimulation (DBS)

Developed in 1987 in France, DBS involves surgically implanting electrodes in the subthalamic nucleus, which are connected to a battery-powered device delivering electrical signals. DBS can significantly improve PD symptoms, reduce medication use, and lessen side effects. Dr Hosurkar notes that DBS is the preferred treatment for many PD patients.

Focused Ultrasound (FUS)

Dr Fabio Danisi, Section Chief of Movement Disorders at Westchester Medical Centre and Associate Professor at New York Medical College, USA, describes FUS as a non-invasive technique that uses high-frequency sound waves to target specific brain areas. Unlike other methods, FUS does not require surgery, and it causes less brain swelling than other non-invasive surgeries like gamma knife thalamotomies. FUS is permanent, typically applied to one side of the brain to avoid issues with balance or speech. However, unlike DBS, FUS cannot be adjusted, making it less suitable for patients who need ongoing programming.

Stem cells

Research into stem cell therapy for PD began in the 1980s and 1990s, when early studies showed that transplanting dopamine-producing cells could repair brain damage. While foetal tissue trials showed promise, they were not scalable due to variability and limited availability. In 2011–12, researchers discovered that stem cells could be converted into dopamine-producing cells, renewing hope.

Dr Agnete Kirkeby, an expert in human neural development at the University of Copenhagen, explains that pluripotent stem cells — including both embryonic and induced pluripotent stem cells (iPSCs) — can generate dopamine-producing neurons. Some private clinics, however, use mesenchymal or haematopoietic stem cells, which do not have this ability, in unproven therapies. Producing dopamine-generating cells is a complex process that requires years of research and precise application of growth factors. Lab manufacturing takes 16 days, and one stem cell line can generate thousands of consistent, high-quality dopamine cells. In collaboration with Malin Parmar’s team at Lund University, Dr Kirkeby and Prof Barker have used embryonic stem cells to produce dopamine-producing neurons, which were transplanted into PD patients in Sweden and the UK. Early trials have shown that this approach is safe, with no evidence of tumour formation. The trial targets moderate-stage PD patients who are experiencing motor fluctuations and may soon need more invasive treatments like DBS.

Stem cell transplants offer the advantage of being a one-time procedure, which, if successful, could help avoid the side effects of dopamine medications. These cells are grafted directly into the putamen, the region with the most significant dopamine loss in PD. Dr Kirkeby notes that these grafted cells can last up to 30 years inside the brain.

Research is also underway at BlueRock Therapeutics in the US. Prof Claire Henchcliffe, a leading PD expert and Chair of Neurology at UC Irvine School of Medicine, is leading a Phase 1 trial using bemdaneprocel, derived from embryonic stem cells. The treatment was well-tolerated in 12 patients, and Prof Henchcliffe hopes these early results will lead to larger trials with meaningful benefits. Similar results have been reported by Dr Jun Takahashi’s team in Kyoto, Japan. Trials using iPSCs are being conducted at Kyoto University under Prof Takahashi. iPSCs, which can be derived from adult cells such as skin cells, can be reprogrammed into induced pluripotent stem cells (iPSCs), which can then be differentiated into dopamine-producing cells. Prof Barker highlights that iPSCs may offer a significant advantage, as the cells are grafted directly into the putamen — the brain region with the greatest dopamine loss.

Unregulated use

The International Society for Stem Cell Research (ISSCR) and Parkinson’s UK have expressed concerns over the global misuse of unproven stem cell therapies. These treatments are often marketed as cures without scientific evidence or regulatory approval, sometimes resulting in physical harm and financial loss. Parkinson’s UK recommends caution when considering therapies that rely solely on anecdotal evidence. In India, the Indian Council of Medical Research (ICMR) has acknowledged that unethical promotions and stem cell therapies for Parkinson’s are not permitted outside of approved clinical trials.

(The author is a consultant haemato-oncologist with a special interest in stem cell transplantation at Royal Wolverhampton NHS Trust, UK. He can be reached at [e-mail].)