This ‘miracle poison’ could lead to new treatments for various diseases, scientists say

CAMBRIDGE, Mass. — When people hear about botulinum toxin, they usually think of a treatment for wrinkles or a deadly chemical. Scientists at Harvard University note this “miracle poison” can also help with chronic migraines and neurological conditions like muscle spasms. Now, they say you may soon be able to add treating a host of life-threatening conditions to that list. Their study finds scientists can evolve this toxin so it targets specific proteins in the body which cause anything from neuro-regeneration to chronic inflammation.

“In theory, there is a really high ceiling for the number and type of conditions where you could intervene,” says study first author Travis Blum in a university release.

The breakthrough is the culmination of a partnership between Min Dong of Harvard Medical School and David Liu from the Broad Institute. Together, the team achieved two major feats. First, they reprogrammed proteases — enzymes which either activate or deactivate proteins — to modify entirely new protein targets. Next, they reprogrammed these enzymes to avoid engaging their original protein targets in the body.

The research also addressed what Blum calls the “classical challenge in biology;” which is designing treatments that can enter the human cell. Unlike other large proteins, the proteases coming from botulinum toxin can actually enter nerve cells. This makes them very appealing to scientists looking to create new medical therapeutics.

What can proteases do for human patients?

Using advanced scientific equipment for evolving proteins, researchers say they can create tailor-made substances to target one specific protein causing problems in the body.

“Such a capability could make ‘editing the proteome’ feasible in ways that complement the recent development of technologies to edit the genome,” says Liu.

Current gene-editing techniques usually focus on treating chronic diseases like sickle cell anemia which develop due to some pre-existing genetic error. If you correct the genetic flaw, the symptoms tend to fade away. For other illnesses however, such as brain and nerve damage resulting from a stroke, there is no genetic error to fix.

Study authors say this is where proteases come in handy. The proteins help improve the body’s own abilities to heal injuries like nerve damage in as few as one treatment. Unlike viral antibodies which only fight foreign substances in the body, proteases can attach themselves a wide variety of proteins. On top of destroying harmful targets, proteases can even reactivate dormant proteins which help the body function.

“Despite these important features, proteases have not been widely adopted as human therapeutics, primarily because of the lack of a technology to generate proteases that cleave protein targets of our choosing,” Liu notes.

The right tool for the right job

To carry out this new step in gene-editing, the study notes that the team had the help of PACE, or phage-assisted continuous evolution. The invention from the Liu lab rapidly evolves proteins which have valuable features for patients.

PACE can advance dozens of generations of proteins each day with little effort. Using the new technology, researchers taught “promiscuous” proteases — which usually target several proteins — to be more selective and only cut certain targets. From there, the team worked on teaching proteases to target proteins completely outside of their normal biological wheelhouse.

“At the outset, we didn’t know if it was even feasible to take this unique class of proteases and evolve them or teach them to cleave something new because that had never been done before,” Blum explains.

The results revealed that proteases from botulinum toxin could indeed be reprogrammed to target various malfunctioning proteins in the body. Four proteases from three families of the “miracle poison” successfully cut protein targets with a high level of specificity.

More work to do before botulinum is tackling diseases

Study authors note there is still plenty of work to do to make proteases capable of fighting diseases. One of the biggest hurdles is that proteins are not an ideal weapon against diseases because of their short lifespan in the body. The human immune system recognizes these new proteins as alien substances and attacks them.

Typical proteins last for just hours or sometimes days in the cells. Although normal botulinum toxin can last up to three months in the cells, the new proteases will likely have a shorter lifespan, which cuts down their effectiveness.

“We’re still trying to understand the system’s limitations, but in an ideal world,” Blum adds, “we can think about using these toxins to theoretically cleave any protein of interest.”

To side-step this issue, researchers are also looking at evolving mammal proteases. The team believes the human immune system is less likely to attack proteins which look similar to the ones it already knows.

The study appears in the journal Science.

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