A recent webinar from Neuroscience News & Research (NNR), part of Technology Networks, featured neurologist Dr. Roger Barker from the University of Cambridge (UK).  Dr. Barker discussed the present state and future potential of therapies that could allow for actual healing of the brain in Parkinson’s disease (PD).  We at Stanford Parkinson’s Community Outreach listened to the webinar and are sharing our notes.

Dr. Barker is a Professor of Clinical Neuroscience at the University of Cambridge and Consultant Neurologist at the Addenbrooke’s Hospital Cambridge, in the UK. His research focuses within PD and Huntington’s disease (HD) on characterizing the different ways these diseases present in different people, and the implications for gene and cell-based research.

The recorded webinar, it is available here.

Our notes from the webinar follow…

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Webinar Notes by Lauren Stroshane, Stanford Parkinson’s Community Outreach

Webinar:  Can we repair the brain in Parkinson’s Disease?

Hosted by NNR (Neuroscience News & Research), Technology Networks Ltd.

November 25, 2019

Speaker:  Dr. Roger Barker, University of Cambridge (UK)

For context, the major chronic neurodegenerative disorders of the Central Nervous System (CNS) include Alzheimer’s disease (AD), PD, HD, and other dementia types. These are characterized by a loss of neurons (nerve cells), glial cells which support neurons, and inflammation around the sites of cell loss. Glia may actually be as important as neurons, and, much like with an injury to the skin which causes swelling and redness, the inflammation that occurs in the brain where cells are dying might contribute to the disease process as well.

How could we potentially treat these types of cellular disease?

• For nerve cells and supporting glial cells, we could give growth factors or replace cells with neural grafting to replace never cells or glial cells that are diseased.
• For inflammation around the areas of cell death in the brain, we could give anti-inflammatory drugs.

To focus specifically on PD:

• PD is a movement disorder characterized by tremor (typically a pill-rolling motion while at rest), bradykinesia (slowed movement), and muscle rigidity
• The area of the brain that is affected in PD is the substantia nigra, an area of brain tissue in the middle of the brain, where nerve cells that produce dopamine start to die off.  
• Once half of the cells in that region are lost, typically PD symptoms develop. Thus, by the time a person starts to exhibit physical symptoms, a great deal of neuronal death has already occurred. Many neurons die off, and those that remain develop an abnormal buildup of protein, called alpha-synuclein.

Many drugs currently in use for PD target the dopaminergic network that is made up of these cells, helping to synthesize more dopamine or to prolong the effects of the limited dopamine that is still being produced. These drugs are helpful but can’t address all aspects of the disease; they treat symptoms only but do not repair the brain.

An important question in PD research is whether all patients with PD actually have the same tissue pathology; the disease can manifest differently among patients and at different times in life. A longitudinal study in the UK called CamPaIGN followed patients over 10 years and found two major subtypes of PD:

• Younger patients, who may exhibit subtle executive deficits in cognition when the disease starts to present symptoms; they usually function quite well initially.
• Older patients, who may have Mild Cognitive Impairment (MCI) when the disease presents, and often have poor semantic fluency and shape drawing.

These differences in disease presentation and cognition can occur for three main reasons: age, genetic factors (Tau haplotype vs GBA mutations), and chronic inflammation.  

Trying to classify and quantify the differences between PD patients is vital for research:

1.    Develop predictive disease models

2.    Explore the biological basis for different PD types

3.    Trial new therapeutic applications

When it comes to cell death, more can be done for younger patients whose disease has not yet progressed as far. We can try to give growth factors to stimulate the remaining dopamine cells to grow, or we can replace the diseased dopamine cells with grafts.

Challenges in treating PD using growth factors:

1. It can be difficult to deliver the growth factor into the substantia nigra deep in the brain
2. Deliver directly into the fluid filled cavities in the brain (intraventricular)
   • This is akin to spraying the whole garden
3. Deliver into the structure of the brain itself (intraparenchymal)
   • Put it on the specific plant you’re trying to grow
4. Deliver into the brain by injecting a virus that delivers the growth factor
   • Putting an irrigation system in locally

Studies of glial cell-derived neurotropic factor (GDNF) have looked at the use of growth factor and how to deliver it, but results have been mixed; studies were inconclusive and had issues in their study design that may have contributed to the mixed results. A new double-blind, randomized controlled trial was done in Bristol in 2019 to look at this question again and try to address some of the issues with past studies. Brain scans of patients who received GDNF treatment versus those who received the placebo showed some minor improvement in nerve cell growth, but the imaging results didn’t translate into clinical benefit – patients felt the same. After 40 weeks, when the placebo group was eventually treated with GDNF as well, there remained no difference clinically between the two groups. A substitute for GDNF, called Neurturin, could theoretically be delivered into the brain using a virus. However, so far, growth factor treatments are interesting but do not yet show evidence of therapeutic benefit.

Some factors that could help resolve the issues in this promising area of research:

• Disease staging – it might be better to administer this therapy much earlier in the disease course, before the sharp drop-off of dopamine loss that occurs after a few years.  
• Dose and volume – perhaps different dosing would prove move effective.
• Virus type – perhaps a different virus would make a better delivery model.

Even if we do use growth factors, eventually the dopamine cells will continue to die off. Is It better to transplant healthy cells instead?

What are possible sources for dopaminergic cells to use in transplantation?

•  The adrenal medulla and carotid body contain dopaminergic cells, but harvesting these did not work well when explored in the 1990s.
•  Fetal dopamine cells collected from aborted human fetuses, which presents major ethical issues, particularly in the United States.
• Embryonic stem cells, which could be used to make dopaminergic cells, harvested from the spare embryos used in in-vitro fertilization (IVF) programs.

Dopamine cells from fetuses

• When they work, they can be extremely effective, with demonstrated long-term clinical benefits, improved long-term survival, and better quality of life for the few patients who have been transplanted with these cells.
• However, limited supply of these cells and ethical concerns remain major barriers.

Another challenge in studying cell transplantation therapies is that there are no clear guidelines for how such studies should be conducted.

• What criteria for participants?
• What doses? How should they be administered?
• Should participants receive immunosuppressive therapy to prevent rejection?
• What are the study endpoints?
• How long should participants be followed?

This is a new field and these conventions have not yet been established, which results in scientific research that is not consistent from study to study.

Dr. Barker’s group tried to better control several key factors with their TransEuro study, but had to stop their research early in the study because they lacked sufficient graft tissue to continue implanting. Each PD patient would need tissue from three fetuses. This highlights the need for a better source of these cells.

Stem cells could prove a good alternative to using fetal tissue. A stem cell is a blank slate, a cell that can become (“differentiate”) into many different cell types. They have several advantages:

• Unlimited amounts of them can be produced.
• They are ethically less contentious than fetal cells, though still controversial.
• The cells’ differentiation into specific cell types can be controlled.
• This yields a product that is defined and standardized, aiding research.

Embryonic stem cells have been used since the 2010s for spinal cord repair and treatment of macular degeneration.

Induced pluripotent stem (IPS or IPSC) cells are normal adult cells that have been reprogrammed to act like stem cells, and can become other types of cells. These have shown some promise in a 2018 Kyoto study and could be useful for therapeutically and for disease modeling for future research.

• Advantage: They offer the potential for autologous grafting (using the patient’s own tissues in the graft), and are more ethically neutral, particularly in the US.
• Disadvantage: Their long-term safety is unknown; they are too expensive; and they carry the risk of disease reoccurring in the graft, if it is from the patient’s own tissues.

Embryonic stem cell lines come from human embryos.  

• Advantage: They have already been used in clinical trials in some countries, and they can easily be expanded and made to produce dopamine.
• Disadvantage: There are substantial ethical issues with their derivation, worries about safety, and barriers within the US.

Parthenogenetic cell line uses cells derived from unfertilized human eggs.

• Advantage: They avoid the use of embryonic cells, so are ethically more neutral.
• Disadvantage: It is unclear exactly what these cells are genetically (no fertilization; no sperm DNA); also, they don’t seem to be as effective.

So, CAN we repair the chronically ill brain?

YES! It is possible. Whether it will be clinically useful, Dr. Barker says we will know in the next few years as studies continue and conclude. His main takeaways:

1. Growth factors are still unproven but may help repair the brain in PD and have been used to stimulate cellular growth (though it did not seem to improve symptoms).
2. Cell therapies for PD have a rational basis around dopamine cell replacement and have been successfully implemented in other conditions such as spinal cord injury.
3. Fetal dopamine cell trials have produced mixed results and have significant ethical concerns, particularly in the US.

For the future:

• We need more and larger trials, to replicate and expand on these therapies.   
• Eventually, we may consider stem cell transplant at diagnosis of PD or shortly after, before cell death progresses.
• What about in prodromal PD? Could consider doing stem cell transplant even at this stage, eventually.

Q&A session:

Q: Implications for other diseases of these therapies?

A: PD has a number of advantages in the application of these techniques, as compared to other diseases.

• PD involves a smaller area and number of cells that need to be repaired.
• We know that dopamine clearly helps treat the symptoms; many other diseases do not have such a well-established relationship.
•  Targeted approaches to metabolic disease such as in PD (metabolism of dopamine) seem promising.
• Repairing something like a stroke would be extremely hard due to the large area of the brain typically affected.

Q: Why are growth factors not the main focus of your research?

A: It is always nice to repair something that is already there, if possible. If earlier in the disease, maybe will be more effective. But there are a number of reasons why growth factors don’t seem like the most promising area of research here.

• We do not know if they can be used long-term; it may be that eventually they become ineffective over time as the disease progresses.
• Theoretically, cell transplants should be more resistant to the disease process in the host as compared to treating your own diseased cells with growth factor.
• He likes the idea of maybe someday combining these therapies, getting the best of both worlds.
• Ultimately, to Dr. Barker, it seems like there is more mileage in stem cells rather than growth factors for treatment of brain disease.

Q: Could these treatments potentially be used by DBS patients or those with Duopa?

A: Yes, they could still potentially be good candidates for some of this research.

Q: How to access stem cell treatments?

A: Stem cells is a tricky term; it’s a cell that divides and give rise to different progeny, but it varies between stem cell sources. In PD research, we have to make sure these cells turn into the right type of dopamine-producing cell. He discourages “stem cell tourism” – people traveling to other countries for these treatments – because these treatments are likely not yet validated or consistent. He can’t say that the treatments definitely won’t work, but there is currently no evidence that they will work. There are also significant concerns that the stem cells could turn in to the wrong type of cells and even become tumors!

Q: What do you think about starting to treat patients earlier, even in the prodromal phase (before they are showing most symptoms)? How involved is the operation?

A: For those early in the disease, they may not feel it is worth pursuing expensive or invasive treatment. Research would have to demonstrate tolerability and efficacy; if all of those are satisfied, then people would be interested.

The surgery itself is not a very “tricky” one but would take several hours. It could be beneficial for some patients, particularly younger ones, to be able to put off taking medication for longer into the disease.

Last question: if these therapies truly work, what is the time frame when they will be available to patients and at what point can we say we have a cure for PD?

• Investment from Pharma in this field has skyrocketed in the past 3 years alone!
• In Europe, more trials in this area are beginning in 2021; by 2026-2027, they should have useful data from those studies.
• So he thinks within 10 years, we will know whether cell-based therapies are working and whether they have an advantage over existing treatment.  
• Now that pharma is involved, there is a lot of investment in this field.
• Growth factors, he feels are still unproven. Not clear to what extent they will be competitive with cell-based therapies.