Stem Cell Therapy for Parkinson's Disease:

A complete cure for Parkinson's disease requires halting the progression of alpha-synuclein proteins from forming Lewy bodies, the formulation of which is responsible for the destruction of dopamine-generating neurons. In the case of Parkinson's disease, the neurons of concern are located in the substantia nigra region of the brain where these "motor neurons" control muscle movements. For a cure to be successful, one would have to stop the progression of Parkinson's disease, followed by the replacement of the neurons dammaged or killed off to restore full motor control. Stem cell therapies are being developed to address neuron restoration with neurotrophic factors or the growth of new neurons to replace those killed off or damaged by Parkinson's.

There are two varieties of adult stem cells:

1. those found in bone marrow, liver and skin tissue. These stem cells are typically already programmed to become more of the tissue of its origination.
2. Induced Pluripotent Stem Cells (iPSC): which are produced from tissue cells and programmed to revert back from its current developed cell state into an embrionic state and then reprogrammed to develop forward into the desired cell form.

The Induced Pluripotent Stem Cells (iPSC) proposed are developed by converting adult somatic cells (regular human body cells like skin cells) using a procedure developed by Shinya Yamanaka's lab at Kyoto University's Center for iPS Cell Research and Application (CIRA) in Japan (2006). This process provides four specific genes encoding transcription factors to convert somatic cells into pluripotent stem cells which can be converted into any type of human cells, in this case neuron cells. Note that Dr. Shinya Yamanaka won a Nobel Prize in Physiology or Medicine in 2012 for this effort. The iPSCs are then used to develop dopamine-generating neurons which would be grafted into the substantia nigra of the brain, the region affected by Parkinson's disease. Other regions of the basal ganglia area of the brain affected by Parkinson's like the striatum could also have neurons repopulated using this technique.

Also See:

• Transplanted brain cells in monkeys light up personalized therapy - University of Wisconsin–Madison
• Optimizing maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson’s disease (Hiller, B.M., Marmion, D.J., Thompson, C.A. et al., 2022)

The development of neurons from iPSCs typically has a low yield. Work is currently on development of neurons directly from source multipotent progenitor cells and to skip past the pluripotent stage by converting source cells directly to neuron cells.. This methodology is more specific where the source cells are specific to cells that can be turned into neurons (adult neural stem cell multipotent progenitors) rather than using a less specific and more generic path which generates iPSCs which can be transformed into any type of cell. Progenitor cells, like stem cells are those which can differentiate into a specific cell type but are more specific and can only differentiate into their target cell.

Stem Cell Secretome Therapy:

There are stem cell procedures offered today at clinics around the world but they either do nothing or are targeted for other effects besides the regeneration of neurons. Such is the case with the ANOVA Institute for Regenerative Medicine in Frankfurt Germany. The ANOVA approach uses Mesenchymal Stem Cells (MSCs) for their secretome, the regenerative substances that stem cells are secreting. MSCs are typically sourced from bone marrow but in the case of the ANOVA procedure, they are Adipose derived stem cells sourced from body fat under the skin harvested by liposuction. This technique is also in US clinical trials (ref). Note that MSCs are not pluripotent and not neural precursors and the MSCs do not replace lost neurons. Rather, they hope that MSCs secrete proteins that might aid the brain by helping tissue regeneration and to provide ant-inflammatory properties. While this is less risk compared to the re-implantation of stem cells, this is not proven to be an effective cure at this point.

The use of Mesenchymal Stem Cells are also in clinical trials for the treatment of Parkinson's in the US at the University of Texas in Houston (ref)

Stem Cell Neuron Replacement Therapy:

Stem cells have the ability to differentiate into a variety of cell types including dopaminergic motor neurons or their neuronal progenitors. The injection and delivery of replacement cells requires brain surgery to access the putamen where dopamine is produced. Care must be taken so that dopaminergic neurons are not misplaced and generating dopamine in the wrong part of the brain as this will have detrimental consequences. The transplanted cells take two to three years to develop into mature neurons after the surgery.

McLean Hospital (Harvard) and MGH:

A team at McLean Hospital and Massachusetts General Hospital (MGH) took the skin cells, turned them into pluripotent stem cells and then into dopaminergic neurons and then injected about eight million of them into a man's brain. The proceedure used an autologous donation to avoid rejection. The results after a two year checkup were optimistic with improved motor skills. The study was a two million dollar study funded by the patient and the National Institutes of Health.

References:

• New England Journal of Medicine: Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson’s Disease
• A secret experiment revealed: In a medical first, doctors treat Parkinson’s with a novel brain cell transplant - the George Lopez story
• Kwang-Soo Kim, PhD - director of McLean Hospital’s Molecular Neurobiology Laboratory and professor of psychiatry at Harvard Medical School
  • identified defective components of brain cells, the orphan nuclear receptor Nurr1, critical for dopamine neurons and inflammation. Nurr1 is a key modulator of (neuro)inflammation functioning as a transcriptional repressor for neurotoxic cytokine production.
  • Most autologous induced pluripotent stem cells (iPSC) cells have been derived through the use of viral vectors and are not ideal. Dr. Kim’s lab identified novel mechanisms underlying the iPSC reprogramming process through metabolic control, which allowed him to devise more efficient and safer stem cell reprogramming methods.

Also see The Harvard McLean Hospital Neuroregeneration Institute

Personalized Parkinson’s Disease Cell Therapy - Harvard and MGH: Bob Carter MD PhD, Kwang-Soo Kim PhD, Todd Herrington MD PhD, Jeffrey Schweitzer MD PhD

Kyoto University:

Led by Jun Takahashi MD PhD, there is an effort to use Induced Pluripotent Stem Cells (iPSC), expressed into dopaminergic neuron cells, sorted and implanted using "stereotactic implantation bilateral putamen" technology. Dr. Takahashi's team was the first to successfully transplant iPSCs and inhibiting tumor formation which was a common problem with the experimental procedure. About five million cells were transplanted during the three hour surgery by Professor of neurosurgery, Takayuki Kikuchi. After five years the trial has shown to have a greater than 30% improvement using the "Unified Parkinson's Disease Rating Scale" (UPDRS) on a sample of 7 patients.
Details: Video interview with Dr. Takahashi (2018)
Website: Center for IPS Cell Research and Application, Kyoto University

Aspen Neuroscience:

Autologous neuron replacement therapy is being developed by Aspen Neuroscience. While it is currently in the research phase, they are developing two approaches, one for those who possess the inherited "familial" GBA gene (ANPD002) and another for idiopathic "sporadic" Parkinson disease for those who don't have the genetic marker (ANPD001). Aspen is using the patient's own cells converted into Induced Pluripotent Stem Cells (iPSCs) using transient expression of pluripotency-associated transcription factors (Yamanaka Patents).

Video podcast (2021) with professor Jeanne Loring (Aspen founder)

Blue Rock Therapeutics:

Using their induced pluripotent stem cell and gene editing platform, Blue Rock is developing a dopaminergic neuron cell replacement therapy. According to their website they "have pioneered the derivation of dopaminergic neurons that have demonstrated robust preclinical data to restore motor function and increased dopamine release as they mature".
Phase 1 cell therapy trial NCT04802733
Website: Blue Rock Therapeutics - Toronto ON, Cambridge MA, New York NY

ISCO: International StemCell Corporation:

ISCO is developing its ISC-hpNSC treatment for Parkinson's, traumatic brain injury and stroke. The ISC-hpNSC stem cell treatment is hoped to differentiate into dopaminergic neurons as well as express brain-protecting neurotrophic factors. They employ the use of parthenogenic stem cells derived from unfertilized eggs. Now in phase one study (NCT02452723) after preclinical studies in Australia.
Website: International StemCell Corporation Carlsbad, CA

Stem Cell Transplant: Celavie

Offers a stem cell transplant medical treatment HSCfPD for Parkinson's disease.
Clinical trial: NCT02780895

Stem Cell Transplant: Cyto Therapeutics

Offers a stem cell transplant medical treatment ISC-hpNSC for Parkinson's disease.
Clinical trial: NCT02452723

Stem Cell Of America:

Their stem cell treatments use "Fetal Stem Cells" (FSC rather than iPSC generated from one's own tissue) and thus legal issues have lead to treatments which are performed in Mexico. Treatment is designed to restore or repair damaged cells within the brain.
Website: Stem Cell Of America treatment center in Mexico

Stem Cell Therapy Mexico:

Treatment consists of depositing allogeneic mesenchymal stem cells (MSC's) directly into the patient’s body to help repair or replace the dopamine-producing nerve cells. Note that MSCs are not neural precursors and the MSCs do not replace lost neurons. Rather, they hope that MSCs secrete proteins that might aid the brain by helping tissue regeneration and to provide ant-inflammatory properties. While this is less risk compared to the re-implantation of stem cells, this is not proven to be an effective cure at this point.
Website: Stem Cell Therapy Mexico (Tijuana)

Embryonic Stem Cell Neuron Replacement Therapy:

Embryonic stem cells originate from aborted fetuses or fertilized embryos and thus have moral and ethical issues as opposed to "induced" stem cells which originate from the patient and are transformed into stem cells.
Also see: Dopamine Cell Transplantation for Parkinson’s Disease: The Importance of Controlled Clinical Trials (2011)

TransEuro Consortium: Embryonic Stem Cell Transplantation:

Transplantation of dopamine (DA) neuroblasts obtained from fetal ventral mesencephalic (VM) tissue. TransEuro is a European research consortium to develop an efficacious and safe treatment methodology for patients suffering from Parkinson’s disease using fetal cell based treatments.
Website: TransEuro Consortium

Novo Nordisk:

This collaborative effort of the Danish pharmaceutical giant Novo Nordisk, Sweden's Lund University and the University of Copenhagen in Denmark, uses stem cells from surplus fertilized eggs from in-vitro fertilization (IVF) clinics. A series of growth factors are used to generate dopamine-producing nerve cells from stem cells which are then surgically inserted into the brain using techniques developed for inserting deep brain stimulation implants.
Website: Lund University announcement

Stem Cell Research Papers of Interest:

• Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease (Studer et al, 2011)
  "Excellent DA neuron survival, function and lack of neural overgrowth in the three animal models indicate promise for the development of cell-based therapies in Parkinson’s disease."
• The Role of Lmx1a in the Differentiation of Human Embryonic Stem Cells into Midbrain Dopamine Neurons in Culture and After Transplantation into a Parkinson's Disease Model (Lacovitti, Cai et al, 2009)
  "We show here that Lmx1a also plays a pivotal role in the mDA differentiation of human embryonic stem (hES) cells."
• Studies on the Differentiation of Dopaminergic Traits in Human Neural Progenitor Cells In Vitro and In Vivo (Lacovitti, Yang et al, 2007)
  "These findings raise the hope that it may be possible to define conditions in culture that similarly “prime” human progenitors, making them more competent to spontaneously express TH in vivo." Note that TH refers to the dopamine enzyme tyrosine hydroxylase.
  "These differences in brain region and embryonic age could greatly influence developmental potentiality. Indeed, it has been postulated that the brain region from which progenitors are derived may prescribe their range of possible fates."
  "Similarly, only HNPs first treated with an in vitro “priming” protocol that differentiated them into nearly pure neurons were able to express cholinergic traits after engraftment. These findings raise the hope that it may be possible to define conditions in culture that similarly “prime” human progenitors, making them more competent to spontaneously express TH in vivo." HNPs refers to human neural progenitors, the cells capable of dividing and becomming neuronal and glial cells.

• Could possibly reverse the damage caused by Parkinson's.

• No treatments have been developed to halt the progression of Parkinson's. If neurons are regenerated, they may be destroyed again as the disease progresses. The placement of new neurons cells into any part of the brain requires the risk of brain surgery and all associated risks. Also, it may be a while before an approved procedure is available to the public.