Posts

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.

The post New Therapy Using Patients’ Own Cells May Halt Parkinson’s Progression, Case Study Suggests appeared first on Parkinson’s News Today.

Engineered Stem Cells Could Be Next Parkinson’s Treatment, Researchers Say

gene editing

Cutting out a portion of or removing a gene linked to Parkinson’s disease protects against the formation of toxic protein clumps within brain cells, scientists have found.

This discovery has the potential to significantly affect the development of next-generation cell-based therapies, which involve injecting healthy cells into brain regions already affected by the disease. Researchers believe the approach may help relieve motor symptoms such as tremor and balance issues.

Findings were published in the study, “Engineering synucleinopathy-resistant human dopaminergic neurons by CRISPR-mediated deletion of the SNCA gene,” in the European Journal of Neuroscience. The work was funded by the U.K. Centre for Mammalian Synthetic Biology, UCB, and The Cure Parkinson’s Trust.

Mutations in the SNCA gene have been found to cause Parkinson’s, a condition characterized by the selective death of midbrain dopamine-producing neurons due to clustering of a protein called alpha-synuclein, also known as Lewy bodies.

Transplantation of dopamine-producing neurons has proved useful in disease management because it can reinnervate Parkinson’s-affected brain regions, restore dopamine levels, and provide symptom relief.

Clinical studies on the transplant of fetal mesencephalic (meaning “of or relating to the midbrain”) tissue into the striatum — a critical area of the brain involved in Parkinson’s — have shown that although some patients saw their motor symptoms improved, others had transplant-induced dyskinesias — abnormal, uncontrolled, and involuntary movement.

Importantly, transplanted tissue (grafts) older than 10 years developed Lewy bodies, which reduced the symptomatic benefit to the patient.

“These clinical observations highlight the need for cell therapies that are resistant to the formation of Lewy bodies. … Such disease-resistant cells will be particularly important for patients with young-onset Parkinson’s or genetic forms of the condition with substantial alpha-synuclein burden,” the researchers wrote.

The team used a gene editing tool known as CRISPR-Cas9. This technique allows scientists to edit parts of the genome by removing, adding, or altering specific sections of the DNA sequence.

Using stem cells, researchers created two distinct cell lines: one with snipped-out portions of the SNCA gene and another without the SNCA gene.

These stem cells were then transformed into dopamine-producing neurons and treated with a chemical agent (recombinant alpha-synuclein pre-formed fibrils) to induce the formation of Parkinson’s-related Lewy bodies.

The team reported that wild-type neurons, or unedited brain cells, were fully susceptible to the formation of toxic aggregates, while engineered cells were significantly resistant to Lewy body formation.

“We know that Parkinson’s disease spreads from neuron [to] neuron, invading healthy cells. This could essentially put a shelf life on the potential of cell replacement therapy. Our exciting discovery has the potential to considerably improve these emerging treatments,” Tilo Kunath, PhD, group leader at the Medical Research Council’s Centre for Regenerative Medicine, University of Edinburgh, and senior author of the study, said in a press release.

By finding a way to “shield” cells from Parkinson’s molecular changes, scientists may have opened the door to the development of cell therapies capable of diverting time’s negative effect on transplanted tissue.

The post Engineered Stem Cells Could Be Next Parkinson’s Treatment, Researchers Say appeared first on Parkinson’s News Today.

Personalized Tissue Implants From Patients’ Own Cells Have Potential to Treat Parkinson’s, Study Suggests

personalized implants

A new, fully personalized tissue implant using a patient’s own materials and cells can regenerate any organ in the body with minimal risk of an immune response, according to researchers who are now exploring the approach as a potential way to treat Parkinson’s disease.

The new technique was reported in the study, “Personalized Hydrogels for Engineering Diverse Fully Autologous Tissue Implants,” published in the journal Advanced Materials.

Engineered tissue implants normally use scaffolding materials such as hydrogels, which provide physical support to cells while also supplying the necessary environment for cellular assembly and function. The materials may be synthetic or natural.

After transplant, these materials may induce an immune response in the host that can lead to rejection of the implanted tissue. As a result, immunosuppressant medications, which inhibit the activation of the immune system, may be necessary throughout the patient’s life even when using DNA-free materials.

Induced pluripotent stem cells (iPSCs), generated from the patient’s own cells, may be used to screen treatment candidates and as personalized cell therapies. These iPSCs are derived from either skin or blood cells that have been reprogrammed back into a stem cell-like state, allowing for the development of an unlimited source of any type of human cell needed for therapeutic purposes.

A gelatinous protein mixture called Matrigel is currently the most used supporting microenvironment for iPSCs. However, because it is derived from the sarcoma tumors of mice, its safety in humans is unknown.

In this study, a team from Tel Aviv University (TAU) collected a small biopsy of a highly vascularized fatty tissue called omentum from healthy human donors or from pigs. This tissue serves as a depot for stem cells.

They separated the cells from the extracellular matrix (ECM) — which provides structural and biochemical support to cells — so that the ECM could be integrated into a temperature-responsive, personalized 3D hydrogel, and the cells could be engineered to become pluripotent, meaning they can give rise to almost all cell types in the body.

Undifferentiated cells were then enclosed within the hydrogel, later generating cardiac muscle cells called cardiomyocytes, neurons of the cerebral cortex, motor neurons (which regulate muscle contraction), endothelial cells (which line the interior of blood vessels), or adipocytes.

After combining the resulting stem cells and the hydrogel, scientists successfully engineered tissue samples and tested potential immune responses first in a laboratory dish and then in vivo, by transferring implants from pigs or mice into a specific mouse strain. Results showed less inflammation when transplants were made within mice.

“With our technology, we can engineer any tissue type, and after transplantation we can efficiently regenerate any diseased or injured organ — a heart after a heart attack, a brain after trauma or with Parkinson’s disease, a spinal cord after injury,” Tal Dvir, PhD, the study’s senior author and a professor at TAU’s Department of Biotechnology, Department of Materials Science and Engineering, said in a press release. “In addition, we can engineer adipogenic (fatty tissue) implants for reconstructive surgeries or cosmetics.”

“This versatile bioengineering approach may assist to regenerate any tissue and organ with a minimal risk for immune rejection,” the researchers wrote in the study.

They are now attempting to regenerate an injured spinal cord and an infarcted heart with spinal cord and cardiac implants, respectively. They are also studying the potential of human dopamine-producing cell implants to treat Parkinson’s in animal models. The gut and the eyes are among other targets for regeneration.

The post Personalized Tissue Implants From Patients’ Own Cells Have Potential to Treat Parkinson’s, Study Suggests appeared first on Parkinson’s News Today.