Bacteriophages, or simply phages, are viruses that infect bacteria. This article covers the lengthy process of turning a serendipitous discovery, that a particular phage can dissolve the amyloids and other aggregates involved in neurodegenerative conditions, into a drug candidate. It demonstrates well why medical development takes a long time, more than a decade so far in this case even prior to entering the regulatory process. Each step in the process can take years to work through, funding is ever a problem, and there are frequent delays and dead ends.
In 2004, researchers were running an experiment on a group of mice that had been genetically engineered to develop Alzheimer's disease plaques in their brains. They wanted to see if human-made antibodies delivered through the animals' nasal passages would penetrate the blood-brain barrier and dissolve the amyloid-beta plaques in their brains. Seeking a way to get more antibodies into the brain, she decided to attach them to M13 phages in the hope that the two acting in concert would better penetrate the blood-brain barrier. As a scientific control, one group received the plain phage M13. Because M13 cannot infect any organism except E. coli, it was expected that the control group of mice would get absolutely no benefit from the phage. But, surprisingly, the phage by itself proved highly effective at dissolving amyloid-beta plaques and in laboratory tests improved the cognition and sense of smell of the mice.
In 2007, with $150,000 in seed money, a new venture, NeuroPhage Pharmaceuticals, was born. After negotiating a license to explore M13's therapeutic properties, the founders reached out to investors willing to bet on M13's potential therapeutic powers. By January 2008, they had raised over $7 million and started hiring staff. Over the next two years, researchers then discovered something totally unexpected: that the humble M13 virus could also dissolve other amyloid aggregates - the tau tangles found in Alzheimer's and also the amyloid plaques associated with other diseases, including alpha-synuclein (Parkinson's), huntingtin (Huntington's disease), and superoxide dismutase (amyotrophic lateral sclerosis). This was demonstrated first in test tubes and then in a series of animal experiments. This phage's unique capacity to attack multiple targets attracted new investors in a second round of financing in 2010.
Their therapeutic product, a live virus, it turned out, was very difficult to manufacture. It was also not clear how sufficient quantities of viral particles could be delivered to human beings. In 2010, researchers were able to figure out that the phage's special abilities involved a set of proteins displayed on the tip of the virus, called GP3. The phage's normal mode of operation in nature was to deploy the tip proteins as molecular keys; the keys in effect enabled the parasite to "unlock" bacteria and inject its DNA. Sometime in 2011, the researchers became convinced that the phage was doing something similar when it bound to toxic amyloid aggregates.
Over the next two years, NeuroPhage's scientists engineered a new antibody (a so-called fusion protein because it is made up of genetic material from different sources) that displayed the critical GP3 protein on its surface so that, like the phage, it could dissolve amyloid plaques. By 2013, NeuroPhage's researchers had tested the new compound, which they called NPT088, in test tubes and in animals, including nonhuman primates. It performed spectacularly, simultaneously targeting multiple misfolded proteins such as amyloid beta, tau, and alpha-synuclein at various stages of amyloid assembly. According to Fisher, NPT088 didn't stick to normally folded individual proteins; it left normal alpha-synuclein alone. It stuck only to misfolded proteins, not just dissolving them directly, but also blocking their prion-like transmission from cell to cell.
There was a buzz of excitement in the air at NeuroPhage's offices in the summer of 2014. The 18 staff were hopeful that their new discovery, which they called the general amyloid interaction motif, or GAIM, platform, might change history. Will it work in humans? While NPT088, being made up of large molecules, is relatively poor at penetrating the blood-brain barrier, the medicine persists in the body for several weeks, and so the researchers estimates that over time enough gets into the brain to effectively take out plaques. The concept is that this antibody could be administered to patients once or twice a month by intravenous infusion for as long as necessary. NeuroPhage must now navigate the FDA's regulatory system and demonstrate that its product is safe and effective. So far, NPT088 has proved safe in nonhuman primates. But the big test will be the phase 1A trial expected to be under way this year. This first human study proposed is a single-dose trial to look for any adverse effects in healthy volunteers. If all goes well, NeuroPhage will launch a phase 1B study involving some 50 patients with Alzheimer's to demonstrate proof of the drug's activity.