At the recent 2022 Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction Winter Meeting, Min Dong, PhD, presented a talk on the latest frontiers in therapeutic toxins for urologic conditions. In speaking with Urology Times®, he discusses the main points of this presentation along with the potential impact of onabotulinumtoxinA (Botox) therapies on future urologic treatment. Dong is an associate professor of urology at Harvard Medical School in Cambridge, Massachusetts.
Please summarize the main points of your presentation.
I mainly introduced the latest research going on in my laboratory on 2 aspects. The first part of my talk is on engineering of botulinum neurotoxins aiming to generate a new generation of therapeutic toxins that will improve the efficacy of [current] Botox [therapies]. The second part of my talk [focused] on this newly developed technology from my lab for treating botulinum neurotoxin intoxication. We call it [a] “Botox reversal agent,” in a sense. So, this is the best in activated toxins, [which use a] detoxified botulinum neurotoxin molecule as a drug carrier, and then use it to send neutralizing antibodies into motor nerve terminals as a way to neutralize botulinum neurotoxins that already entered the motor nerve terminals. That worked out very well in mice models and achieved a fairly quick reversal of muscle paralysis induced by Botox. I’m very excited to introduce that to the field.
What research is on the horizon for onabotulinumtoxinA?
Botox has been a wonderful drug for many, many years. It works very well for many medical indications. In the past 10, 20 years, the basic research on Botox has accumulated more and more knowledge about those toxins—how they work, what are the receptors, the mechanism for them to work within the nerve terminals, and the receptor distributions in different types of neurons. So, all of this basic research, at this point, allows us and others to start to think about how [we can] improve the toxins. How can we make the toxin work better in clinic for different indications? For instance, for urological indications. The toxin works like magic. For paralyzing skeletal muscles, it’s almost perfect. But, for many other indications, there is space for further improvement. For instance, for urological indications, there [is] space for improvement for those toxins. This is something that we are working on, and this is something that other labs are interested in working on. There are a couple of companies that are working on this direction as well, using a different approach. My lab, particularly, is taking the approach of modulating the protein sequence of the toxin through different approaches as a way to improve their biochemical pharmacological properties in that way.
One of the focuses in [my] lab is the receptors, based on our recent study of understanding the toxin receptors expressed in bladder tissues, which is actually different from the ones expressed at traditional neuromuscular junction. That allows us to think about ways to create toxins that [are] tailor-made for bladder applications, rather than skeletal muscle applications. We hope to see the advantage in terms of both better efficacy so you can achieve a better outcome with a lower dose, as well as better safety because it has much less activity or less toxicity on skeletal muscles. So, those are our goals. But there are also other aspects of innovation, particularly in formulation of the toxins. There are groups and companies that are working on using different ways of formulating toxins—[inserting] additives into the formulations that can facilitate toxin action, [or using a] liquid formulation instead of a powder form. This is another area for lots of innovation. There are also exploratory efforts on different ways of delivering toxins, using electric pumps [or] using other methods to reduce the frequency of injection. But everybody’s goal is the same: to make this drug work better for [clinicians] and for patients.
What is the take-home message for the practicing urologist?
Botox has been wonderful [and] has been a great tool for urologists. For [the] basic scientist community, we are working on further improve[ments to] those tools and drugs. Hopefully, within the next few years, we’ll see updated versions, [improving] the versions that can be utilized to benefit patients. For us, [the] scientists, I think it’s important for us to have communication with clinicians because we have to learn the research direction from clinical needs. That’s really something that guides us to do protein engineering [of] toxins or improving toxin efficacy or other aspects of toxins based on the clinical needs. We are not just changing toxins for the sake of changing toxins; we are changing toxins to satisfy the needs from the clinical community, and it’s always very important for us to learn [those needs from the clinicians].
Is there anything else you feel our audience should know about this topic?
We are open to collaboration, and as basic scientists, we always welcome input and feedback from clinical communities who are actually using Botox on actual patients and getting feedback. So, we work in the lab using animal models, which is still quite different from, seeing responses in human patients and seeing the areas that need to be improved in human patients. So, I think [we should] keep that communication open. It is very important for our basic science community.
1. Dong M. New frontiers in therapeutic toxins for urologic disease. Presented at the 2022 Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction (SUFU) Winter Meeting; February 22-26, 2021; San Diego, California.