Gene Therapy: The Good, The Bad & The Promised Land : By Dr. De Leon

Gene Therapy: The Good, The Bad & The Promised Land : By Dr. De Leon

Science has yet to isolate the Godiva chocolate or Prada gene, but that does not mean your weakness for pricey swag isn’t in your DNA.” Jeffrey Kluger
Parkinson’s disease (PD) since it was first described by Dr. James Parkinson’s over a century ago has remained a big enigma for neurologist and neuroscientist…in the 1960’s with the discovery of neurotransmitters quickly came the development of L-dopa which was hoped to be the cure for Parkinson’s given the simplistic view which consisted of a disease being caused by pure loss of “dopamine” in the substancia nigra – black substance of the brain within the basal ganglia. Therefore, it was believed that if we simply replaced this one chemical symptoms would be halted and restored completely. Although, the discovery of the now gold standard treatment of Parkinson’s better known as Sinemet(L-dopa/carbidopa)has revolutionized the care of PD. Yet, we all know it has posed more challenges as well. The next big treatment was in the early 1990’s with the invention of DBS surgery which improved the quality of life of millions of patients afflicted with this illness. But, the cure has continued to alluded us.
So, the future of Parkinson’s like so many other neurological illnesses now lies in trying to prevent or alter the cells before they become ill or have other normal cells take over the function of dying or abnormally functioning cells.
One way scientists have attempted to do this is though Gene therapy.
These have been underway since a decade ago. Since then there have been 9 gene therapy trials.

First of all, gene therapy is a method by which a piece of nucleic acid is introduced into a cell of interest using a “vector” (a carrier or transportation system usually a virus that has been altered so it won’t cause disease). This is usually accomplished through injection of the vector into the brain via brain surgery in the case of PD.
Gene therapy falls into 2 major domains: 1. Aimed at slowing the progression of the disease. (most are in this category)
2. Aimed at improving symptoms of PD by enhancing the effects of levodopa (allowing patients to better tolerate).

One such therapy was the study of gene for AAV- neurturin also known as CERE 120, a tropic factor that aids neurons to stay alive, healthy and thriving. Ceregene just closed in (April) which had closed about a year ago for failing to met endpoint results. Although, because some patients had reported subjective improvement in motor symptoms Fox trials took over briefly but closed once again after failing to show statistical objective significant improvement. However, it is important to distinguish between poor performance of this and any other particular gene therapy trial and the potential benefit of gene therapy as a whole!

Another gene that was studied was one that produced an enzyme known as aromatic amino acid decarboxylase (AADC) which turned levodopa the precursor of active dopamine into active neuronal messenger dopamine. First a small pilot study involving infusion of amino acid decarboxylase (AADC) was conducted then a larger study was under way. In this study they used an MRI scan to guide delivery of infused genes which they hoped would optimize distribution into target area.

Another study involved the gene for glutamic acid decarboxylase (GAD) an enzyme involved in the synthesis of GABA. This study was sponsored by company Neurologix, Inc. The study was a double blind, controlled trial involving gene therapy delivering an inhibitory gene-glutamic acid decarboxylase or GAD which makes GABA…this study closed down in 2012. The company reported closing due to financial problems although the study participants who received the active treatment known as NLX-P191 revealed statistically significant improvement in off- medication motor scores compared with those who received a sham surgery.

We also witnessed the study where patients received an infusion of genes packed into an adeno-associated virus (AAV). The genes were designed to manufacture glial cell derived neurotrophic factor (GDNF) which promote survival of dopamine producing neurons (both in animals and in vitro). 24 patients have received this form. Trials showed mixed results. Investigators have since learned that the problem might not have been in the molecule itself but in the delivery system. Since 2004, scientist have ascertain that for GDNF to be effective it must be delivered continuously into the brain- it is very hard to deliver throughout all desired regions of the brain other than the immediate target area- does not spread easily. Various trials used differing pumps and catheters for delivery thus explaining some of the varying results seen in patients. Today, there is still possibility of studying different dosing regiments and delivery systems targeted more towards early PD. In contrast to gene therapy which is surgical and once implanted it is out of the hands of the surgeon and investigator, the GNDF approach allows the treating physician to maintain control over its delivery system so if side effects were experienced system could be shut off. There is hope of restarting this type of research therapy anew.

All of these studies showed initial promising results but have been terminated due to failure to show any evidence of being able to alter course or symptoms of illness statistically significantly.

Since then the world of Parkinson’s gene therapy has been hit with many setbacks and failures. Two major companies have closed trials after realizing that the benefits did not outweigh the risks nor the costs of development. The national Institute of Health (NIH) has joined researchers in various academic centers across the nation to test yet another gene therapy approach in Parkinson’s.

The latest development and future promise is coming from overseas from an early-phase clinical trial called ProSavin. This is a Parkinson’s therapy which combines 3 different enzyme genes imperative in the production of dopamine. The research led by Dr. S. Palfi from France injected the genes in to 15 subjects brains with advance PD ages ranging from 48-65. These patients had dyskenesias in response to l-dopa. The first 3 received a smaller dose once found to be safe the next 6 got a higer dose and the following 6 an even higher dose through a technique of inserting large quantities of gene into basal ganglia to try to coax brain cells to produce a continues supply of dopamine. So far results, have revealed after 12 months of follow up no serious side effects other than increased dyskenesias which alleviated with reduction of their own levodopa dose. The UPDRS scores (which is the means of measuring the motor symptoms of Parkinson’s) has improved about 12 points off levodopa at 6 and 12 months. – So far, it has shown to be safe in its technique but not very dramatic so far. This study falls upon the category of aiming to help the symptoms of the disease just like DBS. I still worry about long term effect of disrupting brain equilibrium by inducing constant dopamine production you are bound to alter the homeostasis and cause other chemicals to either down regulate or up regulate to compensate for such increase…what then? At this moment the effects seen are not very impressive can get same or better results from DBS which has been tried and true and can be controlled externally if does not work can be shut down without significant harm to individual risk of insertion are about the same and maybe even better for DBS because widely studied and perfected for over 20 years.
The one question we all have to ask ourselves when participating in any trial especially when trials fail and we are left with broken dreams and disappointments, who are we doing this for?
Are we trying to please our doctors? Are we trying to help future generations of Parkinson’s Patients? Or are we doing it for ourselves?
Whatever the reason, there is no right or wrong answer. I find it is usually all of the above.
I do get very upset when patients sign up for studies of this (requiring surgical interventions) nature especially when they have sacrificed so much and a trial fails and their physicians DO NOT offer other treatments even though they clearly need them because they want to keep following them- I thing this borderlines in almost unethical! However if the patient agrees … but sometimes , I feel patients feel coerced or want to please their doctors… of course we as scientist want to keep the science pure and keep following patients forever uninterrupted without any other intervention that would mock up or obscure the findings. However, if you are not doing well and NEED other treatments or surgeries YOU ARE within YOUR RIGHTS to ASK even if not offered – if that doctor refuses –I recommend you seek care elsewhere. (Okay, I said my peace…).

We as physicians and researchers need to keep our Hippocratic Oath ever present..” First & Above all do no harm.” If we abide by this simple rule …our patients would be better off in the long run.

For more information visit New Gene Therapy May Improve Parkinson’s Motor Symptoms, June 09, 2014
Emborg. M. M.D., Ph.D., A New Generation of Anti-Parkinson Treatments: Are we There YET?
Parkinson’s Disease Foundation Comments on Failed Trial of Experimental Treatment for Parkinson’s, Science News, April 19, 2013
Talan, Jamie. In Open-Label Trial Gene Therapy Found Safe and Well-Tolerated in Advance Parkinson’s, Neurology Today, February, 20, 2014, Vol. 14. Issue 4,pages 1, 13-15


Dr. M. De Leon is a movement disorder specialist on sabbatical, PPAC member and research advocate for PDF (Parkinson’s Disease Foundation); Texas State Assistant Director for PAN (Parkinson’s Action Network). You can learn more about her work at you can also learn more about Parkinson’s disease at or at;,

All materials here forth are property of Defeatparkinsons without express written consent, these materials only may be used for viewers personal & non-commercial uses which do not harm the reputation of Defeatparkinsons organization or Dr.De Leon provided you do not remove any copyrights. To request permission to reproduce release of any part or whole of content, please contact me at

Categories: parkinson's disease, parkinsons dementia, parkinsons health and beauty tips, research, research in parkinson's diseaseTags: , ,

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