20-Mar-2020 - Harvard University

Building a better botox

Small engineering tweaks to botulinum toxin B could make it more effective and longer-lasting with fewer side effects

Botulinum toxins -- a.k.a. botox -- have a variety of uses in medicine: to treat muscle overactivity in overactive bladder, to correct misalignment of the eyes in strabismus, for neck spasms in cervical dystonia, and more. Two botulinum toxins, types A and B, are FDA-approved and widely used. Although they are safe and effective, the toxins can drift away from the site of injection, reducing efficacy and causing side effects.

New research at Boston Children's Hospital finds that some small engineering tweaks to botox B could make it more effective and longer-lasting with fewer side effects.

A third way for botox B to bind to nerves

Botox works by attaching to nerves near their junction with muscles, using two cell receptors. Once docked, it blocks release of neurotransmitter, paralyzing the muscle.

Min Dong, PhD, at Boston Children's, with lab members Linxiang Yin, PhD, Sicai Zhang, PhD, and Jie Zhang, PhD, had been looking for ways to get botox B to bind to nerve cells more strongly, to keep it in place and avoid side effects. In another member of the botox family, type DC, they identified a potential third means of attachment: a lipid-binding loop capable of penetrating lipid membranes. Through structural modeling studies, they discovered that when particular amino acids are at the tip of the loop, the toxin can indeed use the loop to attach to the nerve-cell surface, in addition to binding to toxin receptors.

They further found that although botox B contains this same lipid-binding loop, it lacks these key amino acids at its tip. So Dong and colleagues added them in through genetic engineering.

As hoped, the introduced changes enhanced the toxin's ability to bind to nerve cells. In a mouse model, the engineered toxin was absorbed by local neurons around the injection site more efficiently than the FDA-approved form of botox B, with less diffusion away from the injection site. This led to more effective local muscle paralysis, longer-lasting local paralysis, and reduced systemic toxicity.

"Based on our mechanistic insight, we created an improved toxin that showed higher therapeutic efficacy, better safety range, and much longer duration," says Dong. "The type A toxin does not have the lipid-binding loop, so we are still working on engineering this lipid-binding capability into type A."

Facts, background information, dossiers
More about Harvard University
  • News

    Separating Drugs with MagLev

    The composition of suspicious powders that may contain illicit drugs can be analyzed using a quick and simple method called magneto-Archimedes levitation (MagLev), according to a new study published in the journal Angewandte Chemie. A team of scientists at Harvard University, USA, has devel ... more

    Combination gene therapy treats multiple age-related diseases

    As we age, our bodies tend to develop diseases like heart failure, kidney failure, diabetes, and obesity, and the presence of any one disease increases the risk of developing others. Traditional drug development targets only one condition per drug, largely ignoring the interconnectedness of ... more

    Biomaterials smarten up with CRISPR

    The CRISPR-Cas system has become the go-to tool for researchers who study genes in an ever-growing list of organisms, and is being used to develop new gene therapies that potentially can correct a defect at a single nucleotide position of the vast reaches of the genome. It is also being har ... more

  • Videos

    A diamond radio receiver

    Researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences have made the world’s smallest radio receiver – built out of an assembly of atomic-scale defects in pink diamonds. This tiny radio — whose building blocks are the size of two atoms — can withstand extrem ... more

    Timing Cancer Treatment

    There may be an ideal waiting period for delivering multiple cancer drugsResearchers led by members of the Department of Systems Biology at Harvard Medical School had been studying how silencing MDMX, an oncogene, affected the dynamics of p53, a natural tumor suppressor, in cancer cells whe ... more

    Chemical Exposures and the Brain: The Flint Water Crisis and More

    The water crisis gripping Flint, Michigan has exposed thousands of children to unsafe lead levels, triggering a federal emergency declaration and national conversation about basic public health protections. Lead can be toxic to the brain, and children can be particularly vulnerable. However ... more