Cell therapies for Parkinson's disease have been under development for a very long time indeed, decades at this point. The condition is characterized by aggregation of α-synuclein and loss of the small but critical population of dopamine-generating neurons in the brain. The latter is the proximate of cause of the loss of motor control and depression observed in patients. These cells are particularly sensitive to the combination of toxic α-synuclein biochemistry, mitochondrial dysfunction, chronic inflammation, and other contributing factors that manifest in this condition - and in aging in general. The motivation for a cell therapy approach to Parkinson's disease is the replacement of these lost cells, and thus restoration of the supply of dopamine in the brain.
Cell therapy has proven challenging to implement sufficiently well for widespread use in the case of Parkinson's disease. Early attempts used fetal cells, while later attempts produced neurons from embryonic stem cells and then induced pluripotent stem cells. A recent small trial used cell reprogramming to generate neurons for transplantation from a patient's own cells. This is the end goal, a therapy with patient-matched cells that are generated to order and have minimal risk of rejection. Things move very slowly in this part of the field, however, as demonstrated by the animal study discussed in today's research materials. This project has been ongoing for a decade in order to produce results in non-human primates, wile it has been more than thirty years since the first fetal cell transplants were carried out in human trials for Parkinson's disease.
Individualized brain cell grafts reverse Parkinson's symptoms in monkeys
Parkinson's disease damages neurons in the brain that produce dopamine, a brain chemical that transmits signals between nerve cells. The disrupted signals make it progressively harder to coordinate muscles for even simple movements and cause rigidity, slowness, and tremors that are the disease's hallmark symptoms. Patients - especially those in earlier stages of Parkinson's - are typically treated with drugs like L-DOPA to increase dopamine production.
Scientists have tried with some success to treat later-stage Parkinson's in patients by implanting cells from fetal tissue, but research and outcomes were limited by the availability of useful cells and interference from patients' immune systems. Researchers have instead spent years learning how to dial donor cells from a patient back into a stem cell state, in which they have the power to grow into nearly any kind of cell in the body, and then redirect that development to create neurons. "The idea is very simple. When you have stem cells, you can generate the right type of target cells in a consistent manner. And when they come from the individual you want to graft them into, the body recognizes and welcomes them as their own."
The application was less simple. More than a decade in the works, the new study began in earnest with a dozen rhesus monkeys several years ago. A neurotoxin was administered - a common practice for inducing Parkinson's-like damage for research - and researchers evaluated the monkeys monthly to assess the progression of symptoms. During the course of the Parkinson's study, the researchers injected millions of dopamine-producing neurons and supporting cells into each monkey's brain in an area called the striatum, which is depleted of dopamine as a consequence of the ravaging effects of Parkinson's in neurons. Half the monkeys received a graft made from their own induced pluripotent stem cells (called an autologous transplant). Half received cells from other monkeys (an allogenic transplant). And that made all the difference.
Within six months, the monkeys that got grafts of their own cells were making significant improvements. Within a year, their dopamine levels had doubled and tripled. The monkeys who received allogenic cells showed no such lasting boost in dopamine or improvement in muscle strength or control, and the physical differences in the brains were stark. The axons - the extensions of nerve cells that reach out to carry electrical impulses to other cells - of the autologous grafts were long and intermingled with the surrounding tissue.
Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys
Degeneration of dopamine (DA) neurons in the midbrain underlies the pathogenesis of Parkinson's disease (PD). Supplement of DA via L-DOPA alleviates motor symptoms but does not prevent the progressive loss of DA neurons. A large body of experimental studies, including those in nonhuman primates, demonstrates that transplantation of fetal mesencephalic tissues improves motor symptoms in animals, which culminated in open-label and double-blinded clinical trials of fetal tissue transplantation for PD. Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues.
Generation of induced pluripotent stem cells enables standardized and autologous transplantation therapy for PD. However, its efficacy, especially in primates, remains unclear. Here we show that over a 2-year period without immunosuppression, PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs. These behavioral improvements were accompanied by robust grafts with extensive DA neuron axon growth as well as strong DA activity in positron emission tomography (PET). Mathematical modeling reveals correlations between the number of surviving DA neurons with PET signal intensity and behavior recovery regardless autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number.
View the full article at FightAging
