Human Trials of Therapies that Aim to Clear α-synuclein from the Aging Brain

A major theme in rejuvenation biotechnology is periodical removal of metabolic waste. The accumulation of various altered proteins into solid deposits that are not found in young tissues is a form of damage. The presence of this waste at best alters cellular behavior in undesirable ways, and at worst causes harm and cell death. This is a root cause of aging, and thus the ability to safely remove the buildup of waste, once achieved, will be a form of rejuvenation. There are many forms of unwanted waste proteins found in old tissues: the amyloid-β and tau best known for their appearance in Alzheimer's disease; the transthyretin amyloid of senile systemic amyloidosis; the many constituents of lipofusin, including the A2E that contributes to cell death in retinal degeneration; the glucosepane cross-links that make bone become brittle and arteries stiffen; and the topic for today, the α-synuclein implicated in Parkinson's disease and other synucleinopathies.

The research community is slowly making inroads into the development of clearance therapies. The most funding has gone into Alzheimer's and amyloid-β, but there is more interest now in tau and α-synuclein than there was in the past. The SENS Research Foundation has done a great deal to pick up the slack where other forms of waste were being ignored: they funded the work that lead to A2E clearance development at Ichor Therapeutics, for example, have worked on breaking down 7KC, one of the compounds implicated in atherosclerosis, and are currently coordinating a research effort aimed at the production of drug candidates to remove glucosepane cross-links. So far, however, only amyloid clearance can claim a large number of initiatives with significant funding that reached the stage of clinical trials. Still, progress is underway and funding is growing in the matter of α-synuclein, as this essay from the SENS Research Foundation notes.

Human Trials of Two New Rejuvenation Biotechnologies Targeting Alpha-Synuclein

Parkinson's disease (PD) is diagnosed on the basis of what are called "motor symptoms" of the disease. This group of symptoms is caused by the progressive loss of dopamine-generating neurons in an area of the brain called the substantia nigra pars compacta (SNc). But there's another group of PD symptoms, termed the "non-motor symptoms" (NMS) of PD, that gets far less attention, even though NMS begin to manifest earlier in the disease, are harder to treat with current therapies, and include some of the most crippling features of living with the later stages of PD.

Whereas PD motor symptoms are driven by loss of dopamine-producing neurons, many of the nonmotor symptoms are instead linked to the accumulation of Lewy bodies and other malformed clumps and fibrils of the protein alpha-synuclein (AS) inside and between neurons. The various forms of aggregated AS first appear in neurons in the periphery of the body (that is, outside of the brain and spinal cord), and then invade the brain, starting from the base of the skull and slowly spreading their way forward across the brain over the course of the disease.

Because most NMS are not driven primarily by loss of dopamine signaling, dopamine-boosting treatments are completely ineffective in controlling most of them. Yet there's now hope: a race amongst several biotech companies to develop rejuvenation biotechnologies to clear AS aggregates out of the aging and early PD brain. These companies are taking what, in SENS terminology, is the amyloSENS approach, developing and testing antibodies that recognize and bind to malformed AS, allowing them to interdict the toxic proteins as they spread from one neuron to the next, and possibly also capturing some of the aggregates inside existing neurons and facilitating their degradation. By sweeping away AS aggregates before they get a chance to spread, AS immunotherapies have the potential to hold the nonmotor symptoms of PD at bay, slowing the overall progress of the disease, and - when combined with mature cell therapy - eventually preventing the disease altogether, and potentially even reversing it.

When we last reported news from Prothena Corp PLC, the founder had recently presented the results of studies using their AS-targeting antibodies at SENS Research Foundation's Rejuvenation Biotechnology 2014 conference. Scientists at Prothena had confirmed that several of their candidate antibodies were able to clear AS pathology out of the brains and spinal cords of mouse models of PD and related disorders, substantially shielding them against the PD-like motor and cognitive impairments suffered by their untreated cousins. They also revealed some very early information specific to PRX002, the humanized version of the most promising antibody tested in the mouse studies, which was then slated to enter into early-stage human trials.

Now we can report on the first published results of those trials, and on early information coming out of an additional trial that has not yet been formally published. For their first basic safety and pharmacokinetics trial, Prothena scientists recruited 40 healthy people without PD to receive either placebo injections or or one of 5 doses of PRX002, ranging from 1 to 30 mg/kg. An hour after dosing, the lowest dose of the antibody led to a reduction of AS in the circulation of more than 30%, with the highest doses reducing it by up to 96%; 24 hours later, levels remained similarly suppressed in the higher-dose groups.

We learned more about the potential of PRX002 from a sneak peak at the interim results from an ongoing Phase 1b clinical trial of of PRX002 in PD patients. This was a larger (80 subjects) trial that for the first time involved volunteers suffering PD - most with the early stages of the disease. The effects of the first dose of PRX002 on serum AS in PD patients were similar to what was seen in young, healthy people in the first trial: up to a 97% decline in the ratio of free to total AS at the highest dose, with the ratio remaining strongly suppressed for at least four hours. But now for the first time, they could see the longer-term effects of each dose. A month after receiving their first dose, just before taking their second shot, subjects' free-to-bound AS ratios had only partially returned to where they had been before receiving their first dose. No serious adverse reactions to PRX002 were observed in trial participants. There was no improvement in symptoms or other signs of disease progression, but no firm conclusion can be drawn from this due to the short duration of the trial period.

Biotech pioneer Biogen has been rather quiet about their work on their AS-targeting antibody BIIB054 - unlike their widely-heralded Aducanumab, another amyloSENS-style immunotherapy, which has generated enormous excitement for what seems to be the clearest-cut effect on both beta-amyloid and problems with cognitive function in people with Alzheimer's disease. They initiated their Phase 1 BIIB054 trial in 2015, and reported promising early results of its use in an animal model of Parkinson's back in the summer of 2016, but have never published the results, issued press releases, or held conference calls to share their findings with the wider public. But all the while, BIIB054 has been jumping one hurdle after another, and the company is powering ahead.

BIIB054 initially emerged as a strong candidate anti-AS imunotherapy. In further testing, BIIB054 selectively bound aggregated AS in tissue samples from people with PD and with Dementia with Lewy Bodies (DLB - a related disease of AS-driven neurological aging), while leaving native AS alone. The company's scientists also report that when they then injected preformed AS fibrils into the brains of mice, BIIB054 slowed the self-templating spread of AS pathology across the brain, and held much of the ensuing motor dysfunction at bay. Based on these results, Biogen advanced BIIB054 into a Phase 1 clinical trial in 2015. 48 healthy people without PD, aged 40-65, were given a single dose of BIIB054 at one of six doses across a very wide range, and followed up for the next 16 weeks using multiple clinical and laboratory assessments, as well as MRI and electrocardiogram data. The results reported so far are similar to the PRX002 results as far as they go, but are clearly at an earlier stage.

Overall this is an exciting moment. Multiple amyloSENS rejuvenation biotechnologies have now emerged from the rejuvenation biotechnology ecosystem, targeting the removal of aggregated alpha-synuclein from the brain and being tested in early-to-mid-stage human clinical trials. Each uses a different approach to targeting these malformed proteins, and is supported by data in animal models - and the early human evidence looks favorable, if very preliminary. And there are more in the pipeline, including candidate AS immunotherapies from Proclara, NeuroPore, and BioArctic Neuroscience. All this suggests that multiple developments are converging toward groundbreaking progress in this area.

Comments

Related to this, the Michael J. Fox Foundation has already spent over $700 M on Parkinson's research and AFAIK they follow the SENS approach. I wonder how much SENS 1.0 development in humans (not mice) will finally cost.

Posted by: Antonio at August 24th, 2017 7:11 PM

MJ Fox are supporting the very promising GAIM system by Proclara which I have been following for the last 3 years. GAIM supports a repair based approach to aging by removing amyloids and is one of the most promising so far.

Posted by: Steve Hill at August 25th, 2017 5:21 AM

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