We’ve all watched with awe as actor Michael J Fox has struggled mightily, and publicly, with the terrible debilitating impact of Parkinson’s disease. He was diagnosed with the condition in 1991 when he was only 30 years old—unusually early onset for the disease—and announced it publicly in 1998. Fox has gamely continued to act in select roles and voicing characters while funding research and raising awareness of the disease through his foundation.
Fox has managed the symptoms of his disease with the drug combining carbidopa and levodopa, but the deterioration is progressive. Parkinson’s is marked by degeneration of motor function, such as trembling, unsteady walking gait and muscle rigidity or other loss of function. It was first documented in 175 AD and finally categorized as a definable medical issue in 1817 with James Parkinson’s authorship of a paper on the ‘shaking palsy.’
It has been estimated by the Parkinson’s disease foundation that the disease costs about $25 billion per year in the United States alone. About 1,000,000 people in the U.S. have Parkinson’s (with 50,000-60,000 newly-diagnosed cases per year). Its incidence jumps non continuously after about age 40.
Unfortunately for those affected, the treatments available usually have a relatively short effective duration – after which a sort-of ‘crest’ is passed where the disease progression outstrips the ability for current therapies to prevent further decline. Some new research is observing the effects of fetal cell injections in the brain of patients afflicted with Parkinson’s disease to see if there is reversal of the condition.
What does the research show?
An international team led by Roger Barker at the University of Cambridge performed the fetal cell injection into a patient – a male in his 50s. It’s expected to take several years (around five) for this injection treatment to show benefit. Much of this has to do with the time it takes for the fetal brain cells to connect within the patient’s brain and augment neuronal systems that he has lost.
The first time this sort of transplantation of brain cells was performed was in the early 1980s. It was a broad-stroke attempt to treat a severe condition whose underlying pathology was largely not understood. Early trials run in Sweden and the U.S., but they were designed to end after two years. That turned out not be long enough. It appears that for the patients who had significant recovery, it took more than three years for the replacement cells to lead to noticeable effect. Because this was beyond the trial end date, and therefore the experiments were reported (erroneously in some cases) as ineffective.
There are other centers such as the NSCI trying to push this work forward. Barker and his team’s treatment with cell replacement therapy will give another observable trial to see how inserting dopamine neurons can treat the disease state, with the hope of measuring the impact over a longer time period.
Complexities of Parkinson’s
There’s not a simple fix in just improving the dopamine-producing cells in the brain to resolve Parkinson’s disease. The etiology of the disease has an astounding number of biofeedback loops.There are a few causal mechanisms proposed for the disease. Essentially, the part of the brain region called the Substantia Nigra contains the black-pigmented dopamine-producing cells of the brain. Over the course of the disease, all of these cells in the Substantia Nigra are destroyed, and therefore an insufficient quantity of dopamine is produced. This is why the standard treatment for Parkinson’s disease has been supplemental dopamine in the form of the neurotransmitter precursor levodopa (L-DOPA, which is converted to dopamine in the brain) to provide the neurotransmitter feedback effect as part of the complex pathway described above. But the treatment efficacy wanes over time as the disease progresses, and there are potentially serious adverse effects with L-DOPA usage.
There’s also a feature in brain imaging associated with Parkinson’s disease, which are called Lewy bodies. They are comprised of a number of cellular factors, but the substance at the moment receiving most of the research attention within Lewy bodies is α-synuclein. When α-synuclein aggregates improperly, it forms fibrils (α-synuclein fibrils are the basis of the Lewy bodies, see image below). Fragments of α-synuclein are also associated with amyloid plaques in Alzheimer’s disease.
There are also other types of dementia symptoms associated with Lewy bodiesthat are not considered Alzheimer’s disease, and these are termed ‘Lewy body dementias.’ The mechanisms underlying the cause of the aggregation of α-synuclein are still not fully understood. In familial-associated Parkinson’s disease, there is a mutation in the gene which codes for α-synuclein. There are three genetic mutations that have been identified that correspond with the mis-aggregated synuclein (called synucleinopathies); these are A53T, A30P, and E46K. It is these mutations in some cases which may cause these fibrils (amyloid-like aggregations) to form.
Tempered hopes for therapeutic stem cells
Stem cells have been at the center of much buzz and controversy. From treating severe chronic conditions to ‘reversing’ aging skin, it seems there’s no end to the ‘miracles’ they can perform. Of course the truth is somewhat more moderate. At least as far as cosmetics are concerned, they don’t require premarket approval by the FDA, and so the long-term effects are largely unknown, and at this point underwhelming. Most of the marketing boils down to statements about ‘improved appearance’, and not actual proof about real effectiveness (which would require rigorous data for FDA approval).
As for the current Parkinson’s treatment, it uses fetal brain cells implanted to work within the patient’s brain to create feedback connections and produce dopamine. The next avenue for research and applicability in a larger number of patients would be using stem cells to create dopaminergic neurons. This is being explored by using embryonic stem cells as well as what are called induced pluripotent stem cells to make these neurons. These newer methods reduce some of the controversy around using stem cells for medical treatment. Currently, much of the pluripotency is derived by using viruses to regain the cells’ “stemness” by introducing stem cell factors.
But as with pioneering any new research, there is a balance of risk versus benefit; Along with the successes found so far in ‘de-differentiating’ cells back into stem cells, there is also an increased risk of cancer occurring in the altered cells. Continued research is looking into not using viral vectors to deliver the stem factors into cells, with the hope being that future developments will give this control over the cells and their ability to function in many different ways while at the same time not risking an increase in adverse events.
Ben Locwin, Ph.D., MBA, MS is a contributor to the Genetic Literacy Project and is an author of a wide variety of scientific articles for books and magazines. He is also a neuroscience researcher and consultant for a many industries including food and nutrition, pharmaceutical, psychological, and academic. Follow him at @BenLocwin.
http://www.geneticliteracyproject.org/2015/06/08/can-parkinsons-disease-be-cured-by-a-injection-of-fetal-cells-into-the-brain/
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Image via MIT Technology Review.
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Injecting DNA in the brain: What’s the promise of gene therapy for Parkinson’s disease?
Image via MIT Technology Review.
Actor Michael J. Fox has had Parkinson’s disease for many years. It hasn’t kept him from continuing his professional life or from founding a namesake organization to back Parkinson’s research. He has even made the tremors and gait abnormalities characteristic of this common nervous system disorder work for him in his acting career–for example as the foxy, devious lawyer Louis Canning on that delicious TV series, “The Good Wife”.
But even in the rare case when it can be woven into a professional life, living with Parkinson’s disease is not a “fun fact”—although a fun fact is what the E! Entertainment network carelessly called Fox’s Parkinson’s diagnosisduring Sunday night’s livestream of the Golden Globe awards. The tremors and behavioral symptoms and inevitable decline that accompany brain depletion of the neurotransmitter dopamine, the hallmark of Parkinson’s, is the very definition of not fun. Not fun for patients, not fun for their families. There are a great many such people. Parkinson’s is the second most common neurological disorder (after Alzheimer’s); patients are estimated to number about 5 million worldwide.
There are, to be sure, therapies like L-dopa that can work reasonably well to restore normal movement for a few years. But these meds have their own burdens, and ultimately the trajectory is down. So researchers have for a long time hunted for more permanent ways of supplying patients with the dopamine they need for normal movement. Last Friday the British medical journal The Lancet published a study showing some promise for one potential approach: Gene therapy, insertion of therapeutic DNA into the brain. The hope is that gene therapy might be a permanent repair.
The ProSavin approach to curing Parkinson’s disease
This particular therapy, called ProSavin, delivers three genes into the brain region that controls movement. The genes code for enzymes that make dopamine. The point of ProSavin is not to repair the damaged dopamine neurons that are no longer producing the neurotransmitter essential for normal movement and other critical functions. Instead the aim is to reprogram neurons that normally don’t produce dopamine, converting them into neurons that do as a replacement for the constant source of dopamine lost in Parkinson’s disease.
The results of the trial, administered to 15 patients with advanced Parkinson’s disease, were encouraging. Motor function–tremors, speech, rigidity, slow movement–improved in all patients at both 6 months and a year after the surgery that delivered the genes. Side effects were mostly mild. The researchers caution against too much optimism, however. The study was small and they noted that the positive effects fall within the range of positive placebo effects seen in studies of other potential therapies for Parkinson’s disease that involve surgery. The work was funded by OxfordBiomedica, a pharmaceutical company in England.
The long, long road to gene therapy
Few gene therapies are available anywhere and none has yet gotten regulatory agency approval in the US. Susan Young of Tech Review says some may be released for sale in the next few years. She presents a short table listing gene therapies that are in final testing stages in the US. They are aimed at diseases that include prostate cancer, melanoma, artery failure, early blindness, early neurodegeneration, bladder cancer and a hereditary lipid disorder.
Image via MIT Technology Review.
The Lancet paper is the most recent example of the slow and painful rehabilitation of gene therapy that has been increasingly evident in the past year or so. The idea of curing disease by giving patients the genes they need for normal function began in the 1990s with high hopes, but crashed and burned after the death of patient Jesse Gelsinger in a clinical trial in 1999. It seemed like the end of gene therapy. Carl Zimmer described this sorry history and the potential renaissance of gene therapy in Wired last summer.
In principle it seems like a simple idea for curing disease: if a gene in a cell isn’t working, deliver a functioning gene and let it take over. In practice, of course, not so easy, starting with the problem of gene delivery. How the devil do you get the good gene into the cell and then get it to produce the protein the patient needs?
The plan has been to let the good gene ride into the cell on a virus, since what viruses do for a living is slip into cells and take over their genetic machinery. Of course for that you need a virus that will be talented at delivering its foreign gene cargo but won’t endanger the host.
ProSavin’s virus vehicle of choice is a lentivirus, the first time this particular virus has been used in gene therapy for a nervous system disorder. Lentiviruses are not inclined to stimulate the host immune system, they can carry a large payload, and they are efficient at getting into cells. Lentiviruses are retroviruses, a viral family that includes some nasty customers like HIV. But harmless lentiviruses are widely used in research because they’re such a good gene transport system. They’ve been employed as gene-delivery vehicles–researchers call them vectors–in more than 300 clinical trials.
Another trial of gene therapy for Parkinson’s disease
The National Institutes of Health has also funded a US trial of gene therapy for Parkinson’s disease. The NIH trial uses a different approach from ProSavin, and a different virus too. That’s adeno-associated virus (AAV), a more common vector for gene therapy than lentivirus. Zimmer’s piece will fill you in on the history of research on AAVs as gene therapy vectors. There are now more than 300 of them.
The virus in this trial, AAV2, will not be delivering dopamine-producing enzymes like ProSavin. Instead the cargo will be DNA coding for a brain chemical called glial cell line-derived neurotrophic factor (GDNF). GDNF promotes survival of embryonic dopamine-producing neurons in the lab and has also been beneficial in animal models of Parkinson’s. The researchers will be using AAV2 to deliver human GDNF complementary DNA to brain areas involved in preparing for and controlling movement.
This is a Phase 1 trial, one that aims to investigate whether the gene therapy approach is safe. It is now recruiting patients and is scheduled to complete in 2018. If the therapy proves to be safe, there may be a Phase 2 trial to see if it works to ameliorate Parkinson’s symptoms.
In short, even if everything goes perfectly in the studies of GDNF for Parkinson’s disease, this therapy is at least ten years away, probably more. Gene therapy seems to be climbing back from what looked like oblivion, but the climb is slow and arduous. ProSavin, which last Friday was described as looking promising but is still not ready for Parkinson’s patients, has been in the works for 16 years.
Tabitha M. Powledge is a long-time science journalist and a regular contributor to the Genetic Literacy Project. She writes On Science Blogsfor the PLOS Blogs Network. New posts on Fridays.
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