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New Therapy Using Patients’ Own Cells May Halt Parkinson’s Progression, Case Study Suggests

transplanting cells

A new therapeutic approach in which patient-derived dopamine-producing neurons are transplanted into the brain may halt Parkinson’s disease progression, a case report suggests.

The approach uses patient-derived induced pluripotent stem cells (iPSCs),  which are cells collected from the skin or blood that researchers can reprogram in a lab dish to revert them back to a stem cell-like state that has the capacity to then differentiate into almost any cell type.

“Because the cells come from the patient, they are readily available and can be reprogrammed in such a way that they are not rejected on implantation. This represents a milestone in ‘personalized medicine’ for Parkinson’s,” Kwang-Soo Kim, PhD, said in a news story. Kim is co-senior author of the study and director of the Molecular Neurobiology Laboratory at McLean Hospital in Massachusetts.

Two-year data following the first of two interventions suggest the therapy resulted in at least a stabilization of the patient’s motor function and an improved quality of life. However, clinical studies with longer follow-up periods are needed to confirm the therapeutic potential of this approach in Parkinson’s patients, the researchers noted.

The case study, “Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson’s Disease,” was published in the New England Journal of Medicine.

Parkinson’s is characterized by the gradual loss of dopamine-producing (dopaminergic) neurons in the substantia nigra, a region of the brain responsible for movement control. The death of dopaminergic neuron results in lower dopamine levels, affecting the regulation of muscle movement and coordination.

While the potential use of tissue transplants to replace the lost dopaminergic neurons in Parkinson’s patients has been studied since the 1980s, the creation of iPSCs offered the hope to transplant precursors of dopaminergic neurons into a patient’s brain.

In 2018, a team of researchers in Japan reported the implantation of precursors of dopaminergic neurons into the brain of a Parkinson’s patient. Six other patients were expected to receive this experimental therapy that used iPSCs developed from skin cells of an anonymous donor. Researchers plan to collect all safety and effectiveness data by the end of this year.

When implanting cells derived from other individuals, patients need to receive immunosuppressive therapies (for an undetermined period of time) to prevent the development of immune responses against the implanted cells. However, the use of a patient’s own cells would make the need for immunosuppression unnecessary.

Now, a team of researchers at the McLean Hospital and Massachusetts General Hospital (MGH) reported the case of a 69-year-old man treated with a similar approach using the patient’s own iPSCs.

The man had a 10-year history of progressive Parkinson’s disease with no signs of dyskinesia (abnormal involuntary movements that characterize advanced Parkinson’s). He was treated with extended release carbidopalevodopa tablets, Neupro patches (by UCB), and Azilect (by Teva Pharmaceuticals).

He reported poor control of his symptoms, with three hours of “off”-periods — when the medications’ effects wear off and symptoms worsen before a new dose can be taken. Higher levodopa doses caused him lightheadedness associated with a drop in blood pressure when changing to a standing position (orthostatic hypotension).

The researchers used the man’s skin cells to create iPSCs and develop them into precursors of dopaminergic neurons, which were tested extensively, including a mouse model used in human-derived transplant studies.

Using these data, Kim applied to the U.S. Food and Drug Administration (FDA) for a single-patient, investigational new drug application and also received approval from the hospital board to implant the cells into the patient’s brain.

The man underwent two surgeries, in 2017 and 2018 (separated by six months) at the Weill Cornell Medical Center in New York, and at MGH.

At each surgery, four million cells were delivered into the putamen, a large brain structure involved in movement control that is filled with dopamine receptors and receives signals from the substantia nigra. The first intervention targeted the putamen on the left hemisphere of the brain, while the second targeted the one on the right hemisphere.

The cells were delivered using a new minimally invasive neurosurgical implantation procedure developed by Jeffrey Schweitzer, MD, PhD, the study’s lead author, a Parkinson’s specialized neurosurgeon, in collaboration with other neurosurgeons at MGH and Weill Cornell. Schweitzer is director of the Neurosurgical Neurodegenerative Cell Therapy program at MGH.

The patient’s motor function was assessed through the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III and quality of life with the 39-item Parkinson’s Questionnaire.

Two years after the first intervention, imaging tests showed that the transplanted cells were alive and working correctly as dopaminergic neurons, highlighting the technical success of this personalized cell-replacement approach.

There were no reports of side effects or immune reactions against the cells (without the need for immunosuppressive therapy), or signs that the cells caused any unwanted growth or tumors.

Notably, there was at least a stabilization in the man’s motor function, with MDS-UPDRS scores varying over time, but never reaching the initial values, and he reported improvements in his day-to-day activities and quality of life.

The man reported less than one hour of “off” period per day and the levodopa equivalent daily dose was lowered by 6%, “a reduction of uncertain clinical importance,” the researchers wrote.

“This strategy highlights the emerging power of using one’s own cells to try and reverse a condition — Parkinson’s disease — that has been very challenging to treat. I am very pleased by the extensive collaboration across multiple institutions, scientists, physicians, and surgeons that came together to make this a possibility,” said Bob Carter, MD, PhD, another co-senior author of the study and MGH’s chief of Neurosurgery.

Despite these apparently positive results, the researchers emphasized this is just a first step in this therapy’s development.

“These results reflect the experience of one individual patient and a formal clinical trial will be required to determine if the therapy is effective,” said Schweitzer.

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As My Losses from Parkinson’s Accelerate, It’s Time to Fight Back

fight

Don’t forget you’re human. It’s OK to have a meltdown, just don’t unpack and live there. Cry it out and then refocus on where you are headed.” —Unknown

I tend to have meltdowns more frequently these days.

Why is this happening?

My losses from this disease seem to be accelerating. Following are some examples:

  • In boxing class, I sometimes struggle with the punching choreography and can’t seem to coordinate my hands to do the actions required.
  • When reaching to place items on a high shelf, I lose my balance and fall backward.
  • My speed bag workouts are slowing down, and I lose my rhythm more often.
  • I am clumsier and tend to knock things over.
  • Typing on a computer keyboard is an exercise in futility. Sometimes my finger holds pressure on a key too much, and at other times, not enough. I can’t tell anymore.

I suspect that you can relate to my experiences only if you also have Parkinson’s disease (PD). While these setbacks may seem inconsequential, when they occur with increased frequency, it becomes frightening and overwhelming.

I must be mindful of what I do now more than ever. Falling and injuring myself a few weeks ago shocked me to the reality and seriousness of this disease. I find myself cursing at PD and yelling expletives at the top of my lungs in my house when my body fails me. My pet bunny doesn’t know what to make of this. I think the poor guy thinks I am yelling at him.

When my body does not move the way my mind is telling it to, my frustration levels accelerate. This may also be a harbinger of things to come.

Fighting back. (Photo by Michelle Del Giorno)

Running on empty

Some research indicates that over 50 percent (and as much as 60-70 percent) of dopamine-producing neurons are dead by the time Parkinson’s symptoms first appear. I have no doubt that the disease is aging me before my time. A 90-year-old friend is starting to experience symptoms that are due to aging — the same signs that I have at age 66 because of PD.

My neurologist has suggested that sometimes I need to take a step back, refocus, and not be too hard on myself. He knows me well.

I must fight back — and not give in!

At any given moment, you have the power to say: This is not how the story is going to end.” Christine Mason Miller

***

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

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Agomelatine Worsens Motor Function, Neuron Loss in Parkinson’s Rate Study

agomelatine

A common depression treatment called agomelatine worsens Parkinson’s-related loss of dopamine-producing neurons, motor dysfunction, and protein oxidation, according to research in rats.

The study with that finding, “Effects of Agomelatine in Rotenone-induced Parkinson’s Disease in Rats,” was published in the journal Neuroscience Letters.

Neuroinflammation, oxidative stress, loss of dopamine-producing neurons in a brain area called substantia nigra, and degeneration of nerve fibers in a connected region known as the striatum, all underlie Parkinson’s disease.

Despite positive results in preclinical studies, work in patients with Parkinson’s has revealed that treatment with the hormone melatonin, which has anti-oxidant and anti-inflammatory properties, failed to ease motor dysfunction.

Agomelatine, developed by Servier for depression and also used to treat sleep disturbances in Parkinson’s patients, is an agonist for both melatonin-1 and melatonin-2 receptors, and also a 5-HT2C serotonin receptor blocker.

An agonist is a molecule that binds to and stimulates a receptor. The 5-HT2C serotonin receptor,  a potential therapeutic target in Parkinson’s disease, is present on the surface of different brain cells and binds to serotonin — a chemical produced by nerve cells that can act as a natural mood stabilizer.

Scientists at Ondokuz Mayıs University, in Turkey, used a rotenone-induced Parkinson’s rat model  to assess the effect of chronic treatment with agomelatine on behavioral, molecular, and tissue-related parameters.

Damage in dopamine-producing neurons was evaluated 10 days after delivery of rotenone, an agrochemical, into the left substantia nigra and the ventral tegmental area, which is part of the brain’s reward system. Stimulation of this system, also controlling motivated behavior, induces the release of dopamine.

Agomelatine (40 mg/kg) was administered over 18 days in a separate group of rats. This dose had suggested anti-oxidant and neuroprotective properties in prior studies. Tests of motor coordination and activity (rotarod and pole test) were conducted 24 hours after the last dose.

In the rotarod test rats are placed on a rotating rod and investigators count the number of times they fall. In the pole test the animals are head up on top of a vertical rod and the scientists measure the time it takes them to descend to their home cage. Of note, the pole test is a common way to study bradykinesia, or slowness of movement.

The results revealed that treatment with agomelatine worsened (increased) the number of rotations induced by apomorphine, a dopamine agonist that inhibits dopamine-producing neurons in the substantia nigra. Agomelatine also worsened rats’ motor function in both tests.

As for molecular analyses, agomelatine caused a pronounced increase in the levels of the advanced oxidation protein product (AOPP) — a marker of oxidative stress — compared to animals given rotenone only and control rodents. In contrast, levels of malondialdehyde — a product of lipid (fat) oxidative damage — were unchanged.

Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or reactive oxygen species, are harmful to cells and are associated with a number of diseases, including Parkinson’s disease.

Agomelatine also increased the levels of the protein caspase-3 — a marker of apoptosis, which refers to programmed cell death, as opposed to death caused by injury — but not of the enzyme PARP-1, whose activation has been associated with DNA damage and neurodegeneration in Parkinson’s.

The data further showed that agomelatine aggravated the rotenone-induced decrease in dopamine-producing neurons and higher cell volume in the striatum.

“Our findings in the current study showed that decreased rotarod performance and impaired motor coordination most likely happened due to the induced loss of dopamine-containing neurons,” researchers wrote.

“Although we investigated the effects of the agomelatine in the manner of ameliorating the rotenone toxicity in animals, agomelatine exacerbates rotenone-induced toxicity which mimics Parkinson’s disease pathology [symptoms],” they concluded.

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For First Time, Precursors of Dopamine Neurons Implanted in Brain of Parkinson’s Patient

Parkinson's stem cells

Precursors of dopamine-producing cells were implanted into the brain of a Parkinson’s patient for the first time. The patient in Japan is the first of seven to receive this experimental therapy.

The approach uses induced pluripotent stem cells (iPSCs), which are developed by reprogramming cells collected from the skin or blood of adults so that they revert to a stem cell-like state and are able to differentiate into almost any cell type.

Scientists at Kyoto University can transform iPSCs into precursors of dopamine-producing neurons. In Parkinson’s, progressive loss of these neurons in a brain area called substantia nigra, and reduced dopamine release in a connected region called striatum, lead to the characteristic motor symptoms.

Last month, neurosurgeon Takayuki Kikuchi implanted 2.4 million dopamine precursor cells into the brain of a Parkinson’s patient in his 50s. The team implanted the cells into 12 centers of dopamine activity over three hours. Stem cell researcher Jun Takahashi and colleagues derived the dopamine precursor cells from iPSCs originally developed from skin cells of an anonymous donor.

“The patient is doing well and there have been no major adverse reactions so far,” Takahashi said in a Nature press release, written by David Cyranoski. The man will be observed over six months. If he does not develop complications, an additional 2.4 million dopamine precursor cells will be implanted into his brain.

Six more Parkinson’s patients are expected to receive this stem cell therapy, which will allow researchers to collect safety and efficacy data by the end of 2020. According to Takahashi, the treatment could reach the market as early as 2023 under Japan’s fast-track approval system for regenerative medicines. “Of course it depends on how good the results are,” he said.

In 2017, Takahashi and his team showed that dopamine-producing neurons transplanted into the brains of monkeys enabled them to move spontaneously over two years. Also, the transplanted cells did not lead to abnormal and jerky movements (dyskinesia), did not develop into tumors — a key concern with iPSCs-based treatments — and did not trigger an immune response not treatable with an immunosuppressive therapy.

In 2014, a Japanese woman in her 70s became the first patient to receive retinal cells derived from iPSCs to treat an eye condition called age-related macular degeneration.

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