Killer turned savior

Insights into Huntington’s protein lead to major discovery for vaccine adjuvants

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CANTON, Mass.—In a breakthrough that Cure Lab Inc. founder and CEO Alex Shneider says "exemplifies how discoveries and inventions can come from the least expected areas," a protein sequence important in the development of Huntington's disease has shown promise as one of the first members of a new generation of vaccine adjuvants.

The search for better antigens for use in vaccines has been one of the most pressing medical and public health necessities, Shneider notes, and the biotech industry invests heavily in this research today. But he points out that antigens only generate a limited immune response if administered alone without adjuvants, which are strong facilitators of the immune response.

Next-gen adjuvants are critical, he says, because molecular biology is driving a paradigm shift in which companies focus ever more on recombinant vaccines that enable the human body to produce antigens, instead of introducing those antigens exogenously.

"This new level of vaccine development requires a new level of both antigens and adjuvants, and what we have here is a new class of intramolecular adjuvants," Shneider explains.

In the search for efficient, non-toxic adjuvants, scientists at Cure Lab had focused on recent breakthroughs in understanding the neurodegenerative disorder Huntington's disease, which results from mutations in the protein huntingtin, which in turn contains a sequence of polyglutamine residues (polyQ). Increased glutamines in the polyQ segment in neurons induces protein self-aggregation, or formation of big protein "chunks," eventually causing neuronal dysfunction.
Research had shown, though, that attachment of a prolonged polyQ segment to almost any protein promotes its aggregation.

Shneider noticed that small aggregates formed by an antigen fused to a polyQ tail resembled the droplets conventional adjuvants formed with antigenic peptides exposed on their surface. He then hypothesized that these polyQ containing aggregates were easily taken up by antigen-presenting cells, as is the case with adjuvant droplets.

Another piece of the puzzle was provided by Michael Sherman, a professor at Boston University Medical School and a scientific consultant at Cure Lab, who found polyQ aggregates are destroyed in cells by a special degradation system called autophagy.

"So, attachment of a polyQ tail should specifically target the antigen to autophagy, which in turn should facilitate the response. Thus, polyQ would serve as a molecular adjuvant," Shneider says.

He also notes that there are two branches to the immune system, one responsible for developing antibodies against bacteria, viruses and toxins freely circulating in the organism, and the other aimed at eliminating virus-infected or cancer cells.

A recent Cure Lab paper published in the journal Vaccine indicates that the new polyQ-based adjuvant efficiently enhances both branches of the immune response to a poor model antigen. Importantly, the adjuvant caused no apparent toxicity in mice, but Shneider admits many questions remain to be answered, and the adjuvant properties of the polyQ tail will have to be tested for each individual antigen of importance.

"I have confidence though, that this work can be the start of a whole new era in vaccine development: molecular adjuvants," Shneider says. "And it starts from such an unlikely source. Prior to our work, there has been no example in the history of science where vaccinology and immunology would benefit directly from insights into the biochemistry of a neurodegenerative disorder."

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