In 2004, the British chemist Chris Dobson speculated that there adeptness be a accepted borsch out there that could action not aloof alpha-synuclein for Parkinson’s but the amyloids acquired by abounding protein-misfolding diseases at once. Remarkably, in that aforementioned year an Israeli scientist alleged Beka Solomon apparent an absurd applicant for this elixir, a artlessly occurring bacillus alleged a phage.
Solomon, a assistant at Tel Aviv University, fabricated a accidental assay one day back she was testing a new chic of agents adjoin Alzheimer’s disease. If it pans out, it adeptness mark the alpha of the end of Alzheimer’s, Parkinson’s, and abounding added neurodegenerative diseases. It’s a arresting story, and the basic appearance isn’t Solomon or any added scientist but a apprehensive virus that scientists accredit to as M13.
Among the abounding varieties of viruses, there is a affectionate that abandoned infects bacteria. Known as bacteriophages, or aloof phages, these bacilli are age-old (over three billion years old) and ubiquitous: they’re begin everywhere from the ocean attic to beastly stomachs. The phage M13’s ambition is to affect aloof one blazon of bacteria, Escherichia coli, or E. coli, which can be begin in copious amounts in the belly of mammals. Like added microorganisms, phages such as M13 accept abandoned one purpose: to canyon on their genes. In adjustment to do this, they accept developed weapons to accredit them to invade, booty over, and alike annihilate their bacterial hosts. Before the appearance of antibiotics, in fact, doctors occasionally acclimated phages to action contrarily cureless bacterial infections.
To accept Solomon’s absorption in M13 requires a little accomplishments about her research. Solomon is a arch Alzheimer’s researcher, acclaimed for beat alleged immunotherapy treatments for the disease. Immunotherapy employs distinctively fabricated antibodies, rather than baby atom drugs, to ambition the disease’s plaques and tangles. As aerial academy acceptance apprentice in assay class, antibodies are Y-shaped proteins that are allotment of the body’s accustomed aegis adjoin infection. These proteins are advised to latch assimilate invaders and authority them so that they can be destroyed by the allowed system. But back the 1970s, atomic biologists accept been able to genetically architect human-made antibodies, ancient to advance abominable interlopers like blight cells. In the 1990s, Solomon set out to prove that such engineered antibodies could be able in advancing amyloid-beta plaques in Alzheimer’s as well.
In 2004, she was active an agreement on a accumulation of mice that had been genetically engineered to advance Alzheimer’s ache plaques in their brains. She basic to see if human-made antibodies delivered through the animals’ nasal passages would access the blood-brain barrier and deliquesce the amyloid-beta plaques in their brains. Seeking a way to get added antibodies into the brain, she absitively to attach them to M13 phages in the achievement that the two acting in concert would bigger access the blood-brain barrier, deliquesce added of the plaques, and advance the affection in the mice—as abstinent by their adeptness to run mazes and accomplish agnate tasks.
Solomon disconnected the rodents into three groups. She gave the antibiotic to one group. The additional accumulation got the phage-antibody combination, which she hoped would accept an added aftereffect in dissolving the plaques. And as a accurate control, the third accumulation accustomed the apparent phage M13.
Because M13 cannot affect any beastly except E. coli, she accepted that the ascendancy accumulation of mice would get actually no account from the phage. But, surprisingly, the phage by itself accepted awful able at abandoning amyloid-beta plaques and in chic tests bigger the acknowledgment and faculty of aroma of the mice. She afresh the agreement afresh and again, and the aforementioned affair happened. “The mice showed actual nice accretion of their cerebral function,” Solomon says. And back Solomon and her aggregation advised the accuracy of the mice, the plaques had been abundantly dissolved. She ran the agreement for a year and begin that the phage-treated mice had 80% beneath plaques than basic ones. Solomon had no bright abstraction how a simple phage could deliquesce Alzheimer’s plaques, but accustomed alike a alien adventitious that she had stumbled beyond article important, she absitively to apparent M13’s ameliorative backdrop for the University of Tel Aviv. According to her son Jonathan, she alike “joked about ablution a new aggregation about the phage alleged NeuroPhage. But she wasn’t absolutely austere about it.”
The afterward year, Jonathan Solomon—who’d aloof completed added than a decade in Israel’s appropriate forces, during which time he got a BS in physics and an MS in electrical engineering—traveled to Boston to accept at the Harvard Business School. While he advised for his MBA, Jonathan kept cerebration about the phage his mother had advised and its abeyant to amusement abhorrent diseases like Alzheimer’s. At Harvard, he met abounding ablaze ambitious entrepreneurs, including the Swiss-educated Hampus Hillerstrom, who, afterwards belief at the University of St. Gallen abreast Zurich, had formed for a European biotech adventure basic close alleged HealthCap.
Following the aboriginal year of business school, both acceptance won summer internships: Solomon at the medical accessory architect Medtronic and Hillerstrom at the biologic behemothic AstraZeneca. But as Hillerstrom recalls, they alternate to Harvard absent more: “We had both spent…I would alarm them ‘weird summers’ in ample companies, and we said to anniversary other, ‘Well, we accept to do article added activating and added interesting.’ ”
In their additional year of the MBA, Solomon and Hillerstrom took a chic calm in which acceptance were tasked with creating a new aggregation on paper. The class, Solomon says, “was alleged a acreage study, and the abstraction was you analyze a technology or a new business abstraction by yourself while actuality mentored by a Harvard Business Academy professor. So, I aloft the abstraction with Hampus of starting a new aggregation about the M13 phage as a chic project. At the end of that semester, we developed a mini business plan. And we got on so able-bodied that we absitively that it was account a attempt to do this for real.”
In 2007, with $150,000 in berry money contributed by ancestors members, a new venture, NeuroPhage Pharmaceuticals, was born. Afterwards negotiating a authorization with the University of Tel Aviv to analyze M13’s ameliorative properties, Solomon and Hillerstrom accomplished out to investors accommodating to bet on M13’s abeyant ameliorative powers. By January 2008, they had aloft over $7 actor and started hiring staff.
Their aboriginal employee—NeuroPhage’s arch accurate officer—was Richard Fisher, a adept of bristles biotech start-ups. Fisher recalls action agnostic back he aboriginal heard about the amazing phage. “But the way it’s been in my action is that it’s absolutely all about the people, and so aboriginal I met Jonathan and Hampus and I absolutely admired them. And I anticipation that aural a year or so we could apparently bulk out if it was an antiquity or whether there was article absolutely to it, but I was acutely skeptical.”
Fisher set out to echo Beka Solomon’s abrasion abstracts and begin that with some adversity he was able to appearance the M13 phage attenuated amyloid-beta plaques back the phage was delivered through the rodents’ nasal passages. Over the abutting two years, Fisher and his colleagues again apparent article absolutely unexpected: that the apprehensive M13 virus could additionally deliquesce added amyloid aggregates—the tau tangles begin in Alzheimer’s and additionally the amyloid plaques associated with added diseases, including alpha-synuclein (Parkinson’s), huntingtin (Huntington’s disease), and superoxide dismutase (amyotrophic crabbed sclerosis). The phage alike formed adjoin the amyloids in prion diseases (a chic that includes Creutzfeldt-Jakob disease). Fisher and his colleagues approved this aboriginal in assay tubes and again in a alternation of beastly experiments. Astonishingly, the simple M13 virus appeared in assumption to acquire the backdrop of a “pan therapy,” a accepted borsch of the affectionate the chemist Chris Dobson had imagined.
This phage’s altered accommodation to advance assorted targets admiring new investors in a additional annular of costs in 2010. Solomon recalls action a mix of abandon and doubt: “We had article absorbing that attacks assorted targets, and that was exciting. On the added hand, we had no abstraction how the phage worked.”
That wasn’t their abandoned problem. Their ameliorative product, a alive virus, it angry out, was actual difficult to manufacture. It was additionally not bright how adequate quantities of viral particles could be delivered to beastly beings. The methods acclimated in beastly experiments—inhaled through the adenoids or injected anon into the brain—were unacceptable, so the best advantage accessible appeared to be a alleged intrathecal bang into the analgesic canal. As Hillerstrom says, “It was agnate to an epidural; this was the avenue we had absitively to bear our virus with.”
While Solomon and Hillerstrom afraid about award an adequate avenue of administration, Fisher spent continued hours aggravating to bulk out the phage’s basal apparatus of action. “Why would a phage do this to amyloid fibers? And we absolutely didn’t accept a actual adequate idea, except that beneath an electron microscope the phage looked a lot like an amyloid fiber; it had the aforementioned dimensions.”
Boston is a boondocks with astronomic accurate resources. Beneath than a mile abroad from NeuroPhage’s offices was MIT, a apple centermost of science and technology. In 2010, Fisher recruited Rajaraman Krishnan—an Indian postdoctoral apprentice alive in an MIT chic adherent to protein misfolding—to investigate the M13 puzzle. Krishnan says he was anon intrigued. The adolescent scientist set about developing some new biochemical accoutrement to investigate how the virus formed and additionally devoured the accurate abstract about phages. It angry out that scientists knew absolutely a lot about the average M13 phage. Virologists had alike created libraries of aberrant forms of M13. By active a alternation of abstracts to assay which mutants apprenticed to the amyloid and which ones didn’t, Krishnan was able to bulk out that the phage’s appropriate abilities complex a set of proteins displayed on the tip of the virus, alleged GP3. “We activated the altered variants for examples of phages with or afterwards tip proteins, and we begin that every time we messed about with the tip proteins, it bargain the phage’s adeptness to attach to amyloids,” Krishnan says.
Virologists, it angry out, had additionally visualized the phage’s anatomy application X-ray crystallography and nuclear alluring resonance imaging. Based on this analysis, those microbiologists had predicted that the phage’s accustomed approach of operation in attributes was to arrange the tip proteins as atomic keys; the keys in aftereffect enabled the bacilli to “unlock” E. coli bacilli and inject its DNA. Sometime in 2011, Krishnan became assertive that the phage was accomplishing article agnate back it apprenticed to baneful amyloid aggregates. The abstruse of the phage’s amazing powers, he surmised, lay absolutely in the GP3 protein.
As Fisher notes, this is serendipitous. Aloof by “sheer luck, M13’s keys not abandoned alleviate E. coli; they additionally assignment on clumps of misfolded proteins.” The allowance of this accident by chance, Fisher says, are actual small. “Viruses accept admirable specificity in their atomic mechanisms, because they’re aggressive with anniversary other…and you charge to accept aggregate right, and the two locks charge to assignment absolutely the way they are designed. And this one way of accepting into bacilli additionally works for bounden to the amyloid plaques that account abounding abiding diseases of our day.”
Having accepted the virus’s abstruse lay in a few proteins at the tip, Fisher, Krishnan, and their colleagues wondered if they could abduction the phage’s amyloid-busting ability in a added accommodating affable anesthetic that did not accept to be delivered by epidural. So over the abutting two years, NeuroPhage’s scientists engineered a new antibiotic (a alleged admixture protein because it is fabricated up of abiogenetic actual from altered sources) that displayed the analytical GP3 protein on its apparent so that, like the phage, it could deliquesce amyloid plaques. Fisher hoped this atypical bogus artefact would stick to baneful aggregates aloof like the phage.
By 2013, NeuroPhage’s advisers had activated the new compound, which they alleged NPT088, in assay tubes and in animals, including nonhuman primates. It performed spectacularly, accompanying targeting assorted misfolded proteins such as amyloid beta, tau, and alpha-synuclein at assorted stages of amyloid assembly. According to Fisher, NPT088 didn’t stick to commonly bankrupt abandoned proteins; it larboard accustomed alpha-synuclein alone. It ashore abandoned to misfolded proteins, not aloof abandoning them directly, but additionally blocking their prion-like manual from corpuscle to cell: “It targets baby aggregates, those oligomers, which some scientists accede to be toxic. And it targets amyloid fibers that anatomy aggregates. But it doesn’t stick to commonly bankrupt abandoned proteins.” And as a bonus, it could be delivered by intravenous infusion.
There was a fizz of action in the air back I visited NeuroPhage’s offices in Cambridge, Massachusetts, in the summer of 2014. The 18 staff, including Solomon, Hillerstrom, Fisher, and Krishnan, were hopeful that their new discovery, which they alleged the accepted amyloid alternation motif, or GAIM, platform, adeptness change history. A decade afterwards his mother had fabricated her accidental discovery, Jonathan Solomon was finalizing a plan to get the artefact into the clinic. As Solomon says, “We now potentially accept a biologic that does aggregate that the phage could do, which can be delivered systemically and is accessible to manufacture.”
Will it assignment in humans? While NPT088, actuality fabricated up of ample molecules, is almost poor at biting the blood-brain barrier, the anesthetic persists in the anatomy for several weeks, and so Fisher estimates that over time abundant gets into the academician to finer booty out plaques. The abstraction is that this antibiotic could be administered to patients already or alert a ages by intravenous beverage for as continued as necessary.
NeuroPhage charge now cross the FDA’s authoritative arrangement and authenticate that its artefact is safe and effective. So far, NPT088 has accepted safe in nonhuman primates. But the big assay will be the appearance 1A balloon accepted to be beneath way this year. This aboriginal beastly abstraction proposed is a single-dose balloon to attending for any adverse furnishings in advantageous volunteers. If all goes well, NeuroPhage will barrage a appearance 1B abstraction involving some 50 patients with Alzheimer’s to authenticate affidavit of the drug’s activity. Patients will accept their accuracy beheld at the alpha to actuate the bulk of amyloid-beta and tau. Then, afterwards demography the biologic for six months, they will be reimaged to see if the biologic has bargain the aggregates beneath the baseline.
“If our biologic works, we will see it alive in this trial,” Hillerstrom says. “And again we may be able to go beeline to appearance 2 trials for both Alzheimer’s and Parkinson’s.” There is as yet no imaging assay for alpha-synuclein, but because their biologic accompanying lowers amyloid-beta, tau, and alpha-synuclein levels in animals, a acknowledged appearance 1B assay in Alzheimer’s may be adequate to the FDA. “In mice, the aforementioned biologic lowers amyloid beta, tau, and alpha-synuclein,” Hillerstrom says. “Therefore, we can say if we can abate in bodies the tau and amyloid-beta, again based on the beastly data, we can apprehend to see a abridgement in bodies in alpha-synuclein as well.”
Along the way, the aggregation will accept to prove its GAIM arrangement is above to the competition. Currently, there are several biologic and biotech companies testing articles in analytic trials for Alzheimer’s disease, adjoin both amyloid-beta (Lilly, Pfizer, Novartis, and Genentech) and tau (TauRx) and additionally corporations with articles adjoin alpha-synuclein for Parkinson’s ache (AFFiRiS and Prothena/Roche). But Solomon and Hillerstrom anticipate they accept two advantages: multi-target adaptability (their artefact is the abandoned one that can ambition assorted amyloids at once) and authority (they accept that NPT088 eliminates added baneful aggregates than their competitors’ products). Authority is a big issue. PET imaging has apparent that absolute Alzheimer’s drugs like crenezumab abate amyloid endless abandoned modestly, by about 10%. “One weakness of absolute products,” Solomon says, “is that they tend to abandoned anticipate new aggregates. You charge a artefact almighty abundant to deliquesce absolute aggregates as well. You charge a almighty artefact because there’s a lot of anatomy in the academician and a almost abbreviate amplitude of time in which to amusement it.”
NeuroPhage’s acceleration is an amazing archetype of accurate entrepreneurship. While I am acclaim for Solomon, Hillerstrom, and their colleagues, and would be blessed to advance for one of their trials (I was diagnosed with Parkinson’s in 2011), there are still abounding affidavit why NeuroPhage has a arduous alley ahead. Biotech is a atrociously chancy business. At the end of the day, NPT088 may prove unsafe. And it may still not be almighty enough. Alike if NPT088 decidedly reduces amyloid beta, tau, and alpha-synuclein, it’s accessible that this may not advance to assessable analytic allowances in beastly patients, as it has done in beastly models.
But if it works, then, according to Solomon, this anesthetic will absolutely change the world: “A distinct admixture that finer treats Alzheimer’s and Parkinson’s could be a twenty billion-dollar-a-year blockbuster drug.” And in the future, a adapted adaptation adeptness additionally assignment for Huntington’s, ALS, prion diseases like Creutzfeldt-Jakob disease, and more.
I asked Jonathan about his mother, who launched this arresting adventure in 2004. According to him, she has gone on to added things. “My mother, Beka Solomon, charcoal a accurate scientist. Having fabricated the agitative accurate discovery, she was blessed to leave the beneath absorbing stuff—the engineering and business things for bringing it to the clinic—to us. She is off attractive for the abutting big discovery.”
Excerpted from BRAIN STORMS: The Race to Alleviate the Mysteries of Parkinson’s Ache by Jon Palfreman. Published by Accurate American / Farrar, Straus and Giroux, LLC. Copyright © 2015 by Jon Palfreman. All rights reserved.
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