Nerve Cells restored in Monkeys with Parkinsons like disease

Parkinson’s disease causes the progressive loss of nerve cells that release dopamine, a chemical that helps control body movement. The researchers triggered a similar loss of cells in macaque monkeys, then used human stem cells to replace them.

They hope to have human clinical trials in 2018.

The animals showed significant improvement in their symptoms two years after having precursor dopamine neurons derived from human stem cells transplanted into their brains.

These cells – known as induced pluripotent stem (iPS) cells – are created by genetically reprogramming ordinary adult cells, so that they revert to an embryonic-like state.


Growth and survival of iPS cell-derived dopaminergic neuron progenitors in vivo.

Researcher Prof Jun Takahashi, from Kyoto University, said the work, published in the journal Nature, showed that the artificially created cells were as effective as those created naturally in the brain of the monkeys.

Parkinson’s disease degenerates a specific type of cells in the brain known as dopaminergic (DA) neurons. It has been reported that when symptoms are first detected, a patient will have already lost more than half of his or her DA neurons. Several studies have shown the transplantation of DA neurons made from fetal cells can mitigate the disease. The use of fetal tissues is controversial, however. On the other hand, iPS cells can be made from blood or skin, which is why Professor Takahashi, who is also a neurosurgeon specializing in Parkinson’s disease, plans to use DA neurons made from iPS cells to treat patients.

It is generally assumed that the outcome of a cell therapy will depend on the number of transplanted cells that survive, but Kikuchi found this was not the case. More important than the number of cells was the quality of the cells.

“Each animal received cells prepared from a different iPS cell donor. We found the quality of donor cells had a large effect on the DA neuron survival,” Kikuchi said.

To understand why, he looked for genes that showed different expression levels, finding 11 genes that could mark the quality of the progenitors. One of those genes was Dlk1.

“Dlk1 is one of the predictive markers of cell quality for DA neurons made from embryonic stem cells and transplanted into rat. We found Dlk1 in DA neurons transplanted into monkey. We are investigating Dlk1 to evaluate the quality of the cells for clinical applications.”

In a related study, the same group reports a strategy that improves the survival of the transplanted cells in monkeys. For a transplantation to succeed, the donor and patient must have matching human leukocyte antigens (HLA) to prevent tissue rejection. The equivalent to HLA in monkeys is MHC, or major histocompatibility complex. This study, which can be read in Nature Communications, shows that dopamine neurons derived from MHC-matched monkey iPS cells stimulate far less neuroinflammation when transplanted into monkey brains than did dopamine neurons derived from MHC-unmatched monkey iPS cells.

Matching the antigens of the donor with the patient reduces the amount of immunosuppression drugs.

Nature – Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model

Abstract

Induced pluripotent stem cells (iPS cells) are a promising source for a cell-based therapy to treat Parkinson’s disease (PD), in which midbrain dopaminergic neurons progressively degenerate. However, long-term analysis of human iPS cell-derived dopaminergic neurons in primate PD models has never been performed to our knowledge. Here we show that human iPS cell-derived dopaminergic progenitor cells survived and functioned as midbrain dopaminergic neurons in a primate model of PD (Macaca fascicularis) treated with the neurotoxin MPTP. Score-based and video-recording analyses revealed an increase in spontaneous movement of the monkeys after transplantation. Histological studies showed that the mature dopaminergic neurons extended dense neurites into the host striatum; this effect was consistent regardless of whether the cells were derived from patients with PD or from healthy individuals. Cells sorted by the floor plate marker CORIN did not form any tumours in the brains for at least two years. Finally, magnetic resonance imaging and positron emission tomography were used to monitor the survival, expansion and function of the grafted cells as well as the immune response in the host brain. Thus, this preclinical study using a primate model indicates that human iPS cell-derived dopaminergic progenitors are clinically applicable for the treatment of patients with PD.

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