Part 5: Restorative Therapies on the Horizon

Above is Panacea, the Greek Goddess of universal remedy. In Greek mythology she traveled the earth curing those in need with her divine potions.

But chances are Panacea isn’t going to visit us anytime soon. While some still dream that a single therapy will come along and be enough, the far more likely scenario is that this is going to be a slow incremental ascent towards a cure.

While we can despair at the cruel pace of advance, it is important to remember how far we have come. Here are some of the major milestones that have gotten us to where we are today…

 

Delphine Charvin et al. Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs Nature Reviews Drug Discovery volume17, pages804–822 (2018)

 

As you can see, things have picked up considerably over the last few decades. One organization that has arguably done more than any other in getting us to where we are is the Michael J. Fox Foundation. Here is Dr. Todd Sherer, CEO of MJFF, on his definition of a cure as well as the future of therapies for PD from an interview I did with him earlier this year…

 

“In the broadest sense it would mean no one ever gets Parkinson’s disease; we would be able to detect and intervene before anyone ever develops any of the symptoms of the disease.

But we also break it down into several tiers of ‘cure’. There is also the goal of trying to keep people at the stage of disease where they are. Meaning that once someone is diagnosed, could we develop a treatment that keeps someone at that level for the rest of their lives? So we are looking at a balance between trying to treat the symptoms as well as the underlying disease process.

The biggest change over the last five to ten years has been a focus on the different forms of Parkinson’s disease. A lot of this is driven by some of the genetic findings. We are moving more and more towards a ‘precision medicine’ approach, where we will have specific treatments for specific subsets of Parkinson’s. This is already happening for individuals that have GBA and LRRK2 mutations. There may not be one silver bullet for everyone with Parkinson’s, but as we start to better define the disease we can find treatments that help subsets of the population and then try to apply those treatments more broadly.”

 

That is essentially where we are, trying to identify subsets of the disease and tailor therapies for them. However, those too will not be cures, not for those already diagnosed. They may prevent future generations from getting it, and if lucky they may stop the disease from progressing in those already affected, but they will not reverse the damage that has been done.

So, any talk of a cure then must have in mind strategies that can also restore lost function. Listed below are some of our best ideas for how to help people regain some of what has been lost.

 

DBS 2.0

 

Here is an excerpt from my interview with Dr. Alfonso Fasano, professor of medicine in the Division of Neurology at the University of Toronto, on the latest developments in DBS:

“I should start by saying that pacemakers for the heart began in the 1950’s and it only took them 12 years to move from a continuous pacemaker to an adaptive one. This was because EKG’s gave us a good biomarker that allowed us to give this stimulation on demand. DBS for movement disorders started in 1987, yet we still haven’t moved to adaptive DBS mainly because the brain is more complicated than the heart and we haven’t had a biomarker that would enable us to build an adaptive system. But recently the scientific community found that deep brain neurons oscillate with a given frequency called ‘Beta band’ during the Off times of Parkinson’s patients. This allowed us to start developing machines that can be turned on or off by these Beta bands. This would have been impossible in the past because of all the noise created by the stimulation, but now we also have filters that can block out this noise. This seems to give us better results with less negative effects. There is still some unknown but we will be starting a randomized double blind trial for it soon.”

 

Cell Replacement Therapy

 

The idea behind cell replacement therapy (CRT) for Parkinson’s disease (PD) is pretty simple – the motor symptoms of PD are primarily the result of dysfunction and/or death of a specific kind of cell in a specific part of the brain. So, why not go in and replace those cells?

The late 80’s and 90’s saw a few trials of CRT for PD using cells from aborted fetuses, but these had mixed results and ran up against ethical issues and technical limitations. However, we now have a much better understanding of what kind of cells to use, how to culture and store those cells, when and how to implant them, as well as new cell types such as induced-pluripotent stem cells (iPSCs) that don’t have any of the associated ethical issues.

As a result, there are now a number of clinical trials around the world pushing forward this new era of CRT for PD. The results of these trials over the next few years will go a long way towards determining if CRT for PD will be a viable therapeutic option for people living with this condition. (Click here for more)

 

Gene Therapy

 

Here is an excerpt from my interview with Prof. Gao Guangping, Director of the Horae Gene Therapy Center and Viral Vector Core at the University of Massachusetts Medical School, discussing some of the challenges and recent breakthroughs in gene therapy techniques.

“The first challenge in gene therapy is getting the transgene (an external therapeutic gene delivered into another organism) into enough cells, at high enough levels to be effective without toxicity. AAVs (adeno-associated viruses) do this better than other viral vectors (tools used to deliver genetic material into cells) or other chemical delivery mechanisms, they are also not toxic to humans, and they can last for many years. AAVs will change the paradigm of disease treatment by allowing us to safely and effectively deliver genes that can help people fight disease.

Gene therapy is much more complicated than conventional drug development, it is a systematic engineering process. This process has greatly improved over the years in terms of drug design, manufacturing, method of delivery, and understanding appropriate dosage. At the time of previous attempts we did not have a good enough understanding of the system needed to effectively deliver gene therapy.”

 

Neurogenesis

 

Here is an excerpt from my interview with Prof. David Sulzer, Professor at Columbia University Medical Center, discussing a possible pharmacological solution that could restore neuronal growth.

“Even in advanced PD there is still a lot of dopamine neurons left, they are just in different parts of the brain. So the idea is, could we get these neurons to grow to the parts of the brain where dopamine is reduced in people with PD? We found that some of the binding sights use a weird amino acid called D-serine that could do the trick. D-serine has been used for years in health food stores and we are trying to move forward with a trial to test if D-serine could restore neuronal growth. This is exciting because in contrast to neuroprotective therapies, neurorestorative therapies would be much easier to measure and detect efficacy. It won’t be a cure, but in combination with neuroprotective treatments, these kind of neurorestorative therapies could significantly improve quality of life for people with PD.”

 

Better L-Dopa Delivery

 

A more steady supply of levodopa would go a long way towards addressing some of the biggest problems that people with Parkinson’s disease face. Improved delivery methods are coming along, one of the most promising strategies is via subcutaneous infusion through either a pump or a patch. Two are currently in clinical trial, one from Abbvie and another from Neuroderm.

 

 

Know of any that I missed? Add it in the comments below or send it to me here.

 

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The Search for a Cure

 

Part 1: Back to the Future 

Part 2: Coping with Biology

Part 3: A Crash Course in Drug Development

Part 4: Today’s Most Promising Drug Targets

Coming up in this series...(tentative schedule)

Part 6: Obstacles to Overcome

Part 7: The Bigger Problems

Part 8: Technology to the Rescue

Part 9: The Promise of Precision Medicine

Part 10: The Role of Patients

Part 11: Where Hope Springs 

Part 12: The End of PD – Not with a bang, but a whimper