Progress in α-Synuclein Immunotherapy

The protein α-synuclein is involved in Parkinson's disease in much the same way that β-amyloid is involved in Alzheimer's disease. These particular misfolded proteins accumulate with age to form deposits in everyone's brain tissues, but this is seen to occur to a much greater extent in those suffering from the related neurodegenerative condition. There is a lot of research to suggest that this accumulation of amyloid or synuclein is driving disease pathology and death of brain cells, but equally there is a lot of research to suggest that this is far from a complete picture of all that is going wrong in the failing biochemistry of the aged brain. You'll see a lot more debate on the role of amyloid in Alzheimer's disease because work on α-synuclein has not been a going concern for as many years, while many people are becoming impatient with the lack of meaningful treatments resulting from amyloid-focused research programs. That may or may not result from issues with the theories or the focus on amyloid: just as AIDS researchers had to build the next generation of biotechnologies and knowledge to work with viruses, Alzheimer's researchers have had to build much of the modern basis for understanding and working with the cellular metabolism of the brain along the way. These all remain works in progress.

Regardless, we are entering an age in which it is becoming feasible to substitute action to change the state of a diseased brain in place of painstaking investigations of the unaltered disease process. If it is possible to selectively remove β-amyloid or α-synuclein without greatly altering other biochemistry, for example, then observing the results should go a long way towards settling questions over the role of protein aggregates in age-related neurodegenerative disease. Positive outcomes can then also provide the springboard for developing a therapy based on removal of these misfolded proteins.

Immunotherapy, the use of components of the immune system to achieve therapeutic goals, is one of the most promising of today's new biotechnologies. The immune system has evolved many capabilities that researchers would like to take advantage of in medicine, such as selective destruction of cells and removal of some types of metabolic waste products. Immune cells can in principle be steered towards specific targets, and in recent years some success has been obtained in making this happen for misfolded proteins such as β-amyloid or α-synuclein. Below you'll find a long overview of some present efforts in this direction provided by the folk at the SENS Research Foundation, who have great interest in spurring progress in this field of research. Immunotherapies can in theory do more than just help in treating late stage disease, but might also be tuned to eliminate a range of contributing causes of degenerate aging, such as accumulations of amyloid and senescent cells. Get rid of these and the other unwanted aspects of aged tissue and the process of aging can be slowed, halted, and even turned back given effective enough treatments: it is all just a matter of damage repair.

Bold Leaps Forward for α-Synuclein Immunotherapy

Lewy bodies (LB) and other intracellular α-synuclein (AS) aggregates accumulate in the aging nervous system, and a high burden of such aggregates are hallmark neuropathological signs of Parkinson's disease (PD), Lewy body dementia (LBD), multiple systems atrophy (MSA), and other synucleinopathies. Loss of dopaminergic (DA) neurons in the substantia nigra (SN) to aging processes and toxicity are chiefly responsible for the most overt motor symptoms of PD, and it is on the basis of these symptoms that PD is clinically diagnosed. But prior to the onset of motor symptoms, AS pathology is already present in the peripheral nervous system of aging and especially future PD subjects. It is becoming increasingly clear that LB along with other neuronal protein aggregates are key drivers of "normal" cognitive aging.

In a previous post, we surveyed an exciting new development in rejuvenation biotechnology: the sudden emergence and rapid progress toward the clinic of vaccine- and antibody (Ab)-based immunotherapy to remove α-synuclein aggregates from the aging brain. Therapies applying this paradigm to clear β-amyloid protein (Aβ) plaques and soluble aggregates from patients with Alzheimer's disease (AD) is an extremely active field of research, with multiple active and passive Aβ vaccines currently in human clinical trials.

In the earlier posting, we also surveyed research in applying this same paradigm to α-synuclein (AS) aggregates. Since that post, there have been exciting developments in the progress of the two most advanced of these immunotherapies: PD01A, the AS-targeting active vaccine from Austrian biotechnology startup AFFiRiS AG, developed using its patented "AFFITOME" neo-antigen discovery platform of molecular mimicry; and PRX002, a humanized monoclonal Ab (mAb) under development from Prothena Corp PLC, the successor of aggregate-clearing immunotherapy pioneer Élan Pharmaceuticals. In the ensuing months, the two companies have published detailed, promising animal studies of their immunotherapies, including preclinical efficacy studies in animal models of human synucleinopathies. And both immunotherapies are now advancing through early-stage human clinical trials.

The entry of these two AS-targeting rejuvenation biotechnologies into human clinical testing would seem to mark an inflection point. As recently as two years ago, there was little evidence of any academic or biotech industry interest in pursuing clearance of AS as a therapeutic approach to PD, LBD, or other synucleinopathies of aging: after a promising 2005 report, there had been virtual silence. Today, two AS aggregate-clearing immunotherapies have advanced into human testing, with one using an active vaccine approach and the other a passive mAb infusion strategy. Either or both may prove effective. One might speculate that each of these damage-repair therapeutics may exhibit differential targeting of particular AS species or brain regions, as different clinical synucleinopathies exhibit distinct regional localizations and conformations of AS pathology.

You should read the whole thing, as there are some interesting points made in the concluding sections regarding the ongoing siloing of knowledge in many scientific programs relevant to future human rejuvenation treatments. Medical research is enormously broad as well as deep nowadays, and no one researcher can see more than a sketch of what is going on elsewhere. So it is the tendency of researchers in one field to fail to see the opportunity to combine their narrow focus on treatment with those of other distantly removed research groups. Thus otherwise promising lines of research are dropped because the resulting therapies should be best applied in conjunction with, say, stem cell treatments, or removal of other metabolic wastes, or some other biotechnology.

Comments

I just read through the Michael Rae blog post. He has done a fine job on making it understandable to a lay person such as myself, but the post is still long and dense. It really needs some pictures or visual aids. But on the other hand these take time to produce, and may not reach much of a wider audience.

It would be really interesting to see the effects on a Parkinson's sufferer of removing the α-Synuclein amyloid, removing senescent cells, moving damaged mitochondrial genes to the nucleus via gene therapy, and using iPS stem cells to add back some derived dopaminergic neurons.

Posted by: Jim at December 17th, 2014 2:35 AM

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