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April 1st, 2015

An alliance for better therapies

Through academic-industry partnership, a familiar toxin may become a lifesaver for patients with neuromuscular disorders

When Min Dong, a biomedical researcher a few years into his career at Harvard, discovered what makes a revered toxin so lethal, it might seem odd that he set about making it more powerful.

Botulinum neurotoxins are among the most lethal toxins known, and humans normally encounter them in a dangerous type of bacterial food poisoning called botulism—or in injectable forms well-known for their effects in aesthetic medicine. Yet these toxins can also be put to life-changing therapeutic use, for the treatment of seriously debilitating muscular tremors and spasms.

Photo by Scott Eisen.

Dong, assistant professor of microbiology and immunobiology at Harvard Medical School (HMS), has created a recombinant version of the botulinum toxin that is better at binding with human neurons than the naturally occurring forms. Designed specifically to improve clinical treatment in humans, its more precise toxicity could—paradoxically—make it a safer treatment.

But the work doesn’t stop there. The creation of this promising botulinum toxin variant has enabled Dong’s laboratory, in collaboration with Harvard’s Office of Technology Development (OTD), to secure three years of valuable research support for the project from an international pharmaceutical company, ensuring that Dong’s discovery is developed further and put to practical use.

“The agreement between Harvard and Ipsen is sustaining cutting-edge biomedical research in a laboratory where the expertise and facilities are unrivaled,” says Isaac Kohlberg, Harvard’s Senior Associate Provost and Chief Technology Development Officer. “It is also improving the likelihood that Dr. Dong’s lab-bench discovery could become a lifesaving drug.”

Precision medicine

In clinical practice, two types of botulinum toxin, type A and type B, are already used as muscle relaxants to treat muscular spasms and tremor in medical conditions including cervical dystonia, blepharospasm, stroke, cerebral palsy, multiple sclerosis, Parkinson’s disease , neurogenic detrusor overactivity and vocal cord dysfunction, as well as pain conditions like chronic migraine. For aesthetic medicine purposes too, of course, botulinum toxin type A is injected into facial muscles to reduce the appearance of frown lines and “crow’s feet.” In all cases, botulinum toxins act from within neural cells, blocking messages from motor neurons to specific muscles.

But there’s a catch. In order to gain access to a neuron, the toxin has to first recognize the cell and then attach to a receptor on the outside of it. If the injected toxin does not find a neuron to bind with, it simply lingers idly. In certain applications, the rate of botulinum toxin uptake can be so low that a large dose is required to achieve a therapeutic effect. The extra, unbound toxin molecules then diffuse to other regions and sometimes cause serious side effects. These free toxin molecules can potentially trigger an immune response, with antibodies attacking the botulinum toxin and robbing it of its therapeutic power.

If the toxin could be engineered to more efficiently target the right human neurons, Dong and other scientists have realized, clinicians could perhaps lower the necessary dose and lessen the risk of side effects.

That’s where Dong’s research has rapidly broken new ground.

Targeted connections

In the space of 10 years, Dong and scientists in other laboratories have identified and characterized the receptors for five major types of botulinum toxin. This fundamental understanding of how the toxin works was essential to the design of a better treatment.

“We had a rough idea about how our findings could offer an improvement over the currently utilized therapeutic toxins, but we did not know how to translate that into a practical product,” Dong recalls.

A technology development presentation led by Michal Preminger, Executive Director of OTD at HMS, revealed a wealth of new resources that the lab could draw upon. “They had the expertise we lacked,” Dong says. “Michal was able to judge both the patentability and the market potential of our findings. They also had well established industry contacts that they could turn to for feedback.”

Dong had already established his laboratory as a leader in botulinum toxin research, but these conversations with other experts provided fresh inspiration, helping him see how his discoveries could be put to clinical use.

“Seeking advice from those industry leaders gave us all a better understanding of the real-world potential and the path forward for this project,” Preminger says.

Soon after, Dong’s research team used their knowledge of botulinum toxin receptors to create an engineered form of the toxin that is far better at binding with human neurons, potentially improving its therapeutic efficacy in patients. Developed further, this new form of recombinant toxin could prove to be a safer treatment, expanding the range of conditions that the toxin can help alleviate.

Harvard’s technology development experts helped Dong file for a patent on the engineered toxin and once again reached out to their contacts—this time, with the goal of entering into a commercial partnership.

“Therapeutic application of botulinum toxins was already a $2-billion industry, and we knew companies that were interested in getting ahead of the rest of the pack,” Preminger recalls. “Before long, we had two interested suitors for Min’s research. The two companies—one larger, one smaller—each had existing botulinum development programs and different strengths to offer a joint effort. Preminger and her colleagues ultimately struck a deal with the larger company, Ipsen the leading pharma biotech in innovative recombinant neurotoxin research. But soon afterward it was also publicly announced that Ipsen had acquired the smaller company, Syntaxin, giving Dong and HMS the best of both worlds.

An ideal outcome

“The industry-funded research collaboration with Ipsen is critical to this project,” says Dong. “It allows me to expand my research group, bringing in new talent to further develop engineered botulinum toxin toward clinical uses. It also offers a great opportunity to interact with scientists at Ipsen, combining the strengths of both academic and industry research. Ultimately, this close collaborative effort should facilitate the technology transfer and development of new therapeutics.”

It is an ideal outcome for Dong’s lab, and it is the type of mutually beneficial collaboration Preminger and her technology development colleagues have negotiated dozens of times since the creation of OTD in 2006.

“We all worked in industry before coming to Harvard,” she says. “We have been at the table when scientific corporations set their strategies for product development and marketing. Our experience helps us navigate the landscape, identify partners who can advance our early technologies toward clinical products, and negotiate arrangements that benefit all parties—ultimately and most importantly, the patients who rely on our innovation.”

“We get very excited when we can help accelerate a discovery toward better diagnosis and treatment of disease,” Preminger adds. “These are inflection points that can change the course of patient care.”

Read about Harvard's recently expanded alliance with Ipsen here.

Tags: Alliances, immunobiology, microbiology, min dong, Therapeutics

Press Contact: Kirsten Mabry | (617) 495-4157