Rejuvenation biotechnology encompasses a suite of advanced medical therapies, each of which removes, repairs, replaces, or renders harmless one of the forms of cellular or molecular damage that accumulates in an aging tissue over time and impairs its function. Through the comprehensive abatement of all such aging damage to levels approximating those of younger adults, tissue structure and function can be made more youthful, restoring the health and vigor of aging persons to that of persons years or decades younger. This approach is most prominently under pursuit in the development of cell therapy and tissue engineering, of which the most striking success to date has been the use of fetal and embryonic mesencephalic tissue grafts to replace dopaminergic (DA) neurons lost to the age-related neurodegenerative processes driving Parkinson’s disease
While such grafts have led to striking temporary improvements in the major motion disorder symptoms in many patients, results have been limited, and significant improvements in the protocol are clearly required to realize the potential of cell therapy to help these patients. The grafts are significantly immunogenic, leading to rejection in some cases and necessitating immunosuppression in most patients. The nature of the cell source means that very few patients could ever hope to benefit from treatment, since the supply of fetal midbrain tissue is both inherently limited and subject to politically-imposed restrictions. And the actual benefits to patients have not been as robust as might have been hoped: the magnitude of clinical response has been highly variable, gains have proven impermanent, and ~15% of transplanted patients have developed substantial dyskinesias during the “off” phase of levodopa treatment.
Many of these limitations are attributable to the crude cell sources used in these trials. An important step forward will be to move beyond the use of fetal mesencephalic tissue, and instead derive graft populations of pure DA neurons from pluripotent stem cells, such as embryonic stem cells (ESC), induced pluripotent stem cells (iPS), or somatic cell nuclear transfer (SCNT — “therapeutic cloning”)
A Superior Protocol (for better cells for rejuvenation therapies)
The authors had previously reported a protocol for deriving mesencephalic DA neurons by nudging them through an intermediary stage as midbrain floor plate precursor cells. The floor plate is the developmental topos through which cells are thought to acquire DA neural progenitor characteristics. This entailed a dual inhibition of SMAD signalling in the cells through the simultaneous inhibition of BMP4 using Noggin (an inhibitor of BMP4), and activation of the Lefty/Activin/TGFβ pathway with the drug SB431542, and the approach has subsequently been independently validated by investigators at the MRC Centre for Regenerative Medicine. As part of this new report, two lines each of human ESC and iPS cells were used to derive DA neurons using either a modified version of this new strategy, or the currently-standard protocol of moving such cells through a neural rosette intermediate for DA neuron derivation. The dual SMAD inhibition, floor-plate-intermediate protocol proved superior, generating a higher percentage of tyrosine hydroxylase-expressing (TH+) neurons, which unlike rosette-derived cells expressed markers of the developing mesencephalon and (importantly) led to far lower adventitious generation of serotonergic neurons.
loor-Plate (FP)-Derived Dopaminergic Neuron Grafts from Human ESC Rescue Motion Disorders in 6-OHDA-Lesioned Rats
Success and Safety In Vivo
The investigators next performed in vivo tests of cells derived either from their own modified dual SMAD-inhibition protocol, or using the rosette method.
At four and a half months post-transplant, the fates of cells derived from the two protocols were dramatically different in vivo. In animals (rats) engrafted with DA neurons derived using the standard rosette method, administration of amphetamine led to stereotypic circling motions, caused by the drug’s stimulation of the surviving DA neurons remaining on the unlesioned side of the brain. By contrast, engraftment with cells derived using the floor plate method rescued this behavior.
The most immediate next step in development of this potential therapy is to test the ability of these grafts to rescue the motion disorders of MPTP-lesioned nonhuman primates.
Once these cells have proven their potential in humans, yet further refinement of the protocol can be expected to more fully alleviate the symptoms of PD.
The perfection of such protocols will enable us to move beyond even treatment of clinical PD (parkinsons disease), and into repair of the SNc and other DA neuronal structures lost during prodromal stages of the disease, and ultimately toward alleviating even the more subtle motion dysfunction caused by SNc DA neuronal losses suffered during “normal” brain aging.
Yet further gains will depend on combining this single rejuvenation biotechnology into a wider range of therapies to repair the aging brain.
A key barrier to the use of human pluripotent stem cells to rejuvenate the aging and neurodegenerative brain appears to have been broken. It is now our task to press on, treating Parkinson’s disease and ultimately ending the age-related degeneration of the human brain.
2. A simple blood test can now detect Parkinson’s disease even at the earliest stages (before symptoms appear). The test is possible because scientists found a substance in the blood, called “phosphorylated alpha-synuclein,” which is common in people with Parkinson’s disease, and then developed a way to identify its presence in our blood.