Neuroprotection by Modified-Macrophages in a Parkinson’s Model System

“Somewhere, something incredible is waiting to be known.” Carl Sagan

“You never change things by fighting the existing reality.  To change something, build a new model that makes the existing model obsolete.” R. Buckminster Fuller

Précis: Scientists at the University of North Carolina at Chapel Hill are using an innovative approach to treat Parkinson’s in a model animal system (I realize this is my University, but it’s still very cool science). Dr. Elena Batrakova’s research is focused on engineering macrophages (a key host defense cell) for delivery to and therapy in the brain.  This “Trojan Horse” therapeutic system has been used for treating Parkinson’s in an animal model (go here: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106867).

What is a Trojan Horse therapeutic system?  From Greek mythology:The Trojan Horse is a tale from the Trojan War about the subterfuge that the Greeks used to enter the city of Troy and win the war. In the canonical version, after a fruitless 10-year siege, the Greeks constructed a huge wooden horse, and hid a select force of men inside.” (https://en.wikipedia.org/wiki/Trojan_Horse).  From  modern neuroscience and molecular engineering: The Trojan Horse therapeutic system is to use a naturally occurring cell (macrophage) that fools the body (to get into and past the blood brain barrier) into accepting the cell as self. After being accepted as self, it allows the material housed inside the macrophage to be released directly at the site of injury (mid-brain region called substantia nigra that has dopamine producing cells). The drawing below illustrates the science of this study and the depiction of the Trojan Horse.

Macrophages+Parkinsons.160208

“Everything is theoretically impossible, until it is done.” Robert A. Heinlein

What are macrophages (in this study they are the Trojan horse)? Bone marrow makes many different cell types including red blood cells, white blood cells (WBC), and platelets. Macrophages are derived from the WBC named monocyte. Monocytes released from the bone marrow circulate in the bloodstream for a couple of days and leave and go to the various organs and tissues where they mature and become macrophages.  Macrophages are incredibly versatile and important cells in our host defense system; including a role as a sentinel, a role as a  General in a bunker giving out orders to all the other soldiers, and even a role functioning as a garbage collector. Let me explain. Macrophages live in our tissues and they stand guard ready to attack invading microorganisms.  Macrophages generate many different substances (growth factors and  cytokines)  that recruit and activate WBC’s both to enhance the attack against invading microorganisms  and to initiate the immune system.  Macrophages also help out by cleanup debris and cellular waste products. Macrophages can be activated when  exposed to different kinds of inflammatory cytokines and they become what are called M1 and M2 macrophages.  M1 macrophages have a role being pro-inflammatory while M2 macrophages have a role being regenerative.

“The good thing about science is that it’s true whether or not you believe in it.” Neil deGrasse Tyson

What is GDNF (in this study it is the Greek soldiers)? GDNF  stands for glial cell-line derived neurotrophic factor  (neurotrophic substances regulate the growth, survival, and differentiation of nerve cells/nervous tissue).  There is evidence in the scientific literature of the positive impact of neurotrophic factors in experimental treatment of Parkinson’s. The idea behind using GDNF is to promote survival of dopamine producing neurons and also to reduce inflammation in the mid-brain area. One of the major obstacles to this research area in general has been delivering the neurotrophic factor through the blood brain barrier and to the damaged tissue. The study here gets around this by using the macrophage as the carrier to deliver GDNF, the neurotrophic factor, directly to the brain.

“Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less.” Marie Curie

Is this research similar to regenerative medicine?  Ultimately, if this science translates from bench-to-bedside, it satisfies elements of what is called regenerative medicine.  By definition, “regenerative medicine is a branch of translational research in tissue engineering and molecular biology which deals with the ‘process of replacing, engineering or regenerating human cells, tissues or organs to restore or establish normal function.'” (https://www.google.com/search?q=personalized+medicine&ie=utf-8&oe=utf-8#q=regenerative+medicine+definition).  The approach used in this study was first, to use the macrophage as the protective cell carrier and as the decoy in the Trojan horse model. And second, to express GDNF in the macrophage and have the macrophages deliver the neurotrophic factor directly to the brain. This idea is partially based on the hypothesis that macrophages would migrate toward areas of inflammation; there is substantial evidence linking inflammation in the mid-brain region to someone with Parkinson’s.

“Wonder is the seed of knowledge” Francis Bacon

 Was there good news using GDNF-expressing macrophages in the experimental mouse model of Parkinson’s?   There were several notable positive results from the study, including: 1)  macrophages were able to be transfected with GDNF; 2)  macrophages were activated to the M2 regenerative state; 3) injecting GDNF-expressing macrophages into the Parkinson’s disease mouse showed significant  improvement in both neuroinflammation and  neurodegeneration; 4) behavioral studies confirmed the neuroprotective effect in the mouse model; and 5) these results indicate successful   delivery of GDNF by macrophages, release of GDNF into the affected area, and transfer of the neurotrophic factor to the appropriate targeted neurons.

“The scientist is not a person who gives the right answers, he’s one who asks the right questions.” Claude Lévi-Strauss

Of ‘Mice and Men’, what do the results mean for the future treatment of Parkinson’s?  The results of this paper are both elegant and straightforward.  Their overall goal is to use cell-mediated delivery of therapeutic substances that either stop or slow progression of Parkinson’s. Doing this successfully in a mouse model is one thing; however, getting it translated into a human study is another. We must remain positive that scientists of this caliber continue to get their research funded, continue to train scientists in the neurodegenerative field, and continue to publish their results.  We must remain persistent in managing our own disorder because there are several important studies going on right now; and some of them could reverse and/or slow down the progression of Parkinson’s.  Is this really possible? Time will tell whether this study translates from mice to men.  Finally, I am hopeful that in the near-future a strategy will emerge to slow/halt the progression of Parkinson’s; allowing our return to normalcy.

“The important thing is to not stop questioning. Curiosity has its own reason for existence. One cannot help but be in awe when he contemplates the mysteries of eternity, of life, of the marvelous structure of reality. It is enough if one tries merely to comprehend a little of this mystery each day. Albert Einstein —”Old Man’s Advice to Youth: ‘Never Lose a Holy Curiosity.'” LIFE Magazine (2 May 1955) p. 64”

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