Asthma & Nanoparticles
The Power of Tiny Gold Particles to Improve Asthma Treatments
From chemistry to modern physics, the past century and a half of science has taught us that things look a lot different on the smallest scales. “If you take a big piece of gold,” Khalid Salaita, PhD, associate professor of chemistry recently told me, “it’s yellow, it’s characteristically shiny. If you produce a ten-nanometer gold particle, it has a striking wine red, ruby red color. That’s because it interacts with light in a different way. The melting point of gold is roughly 900 degrees Celsius, but if you shrink it to the scale of nanoparticles, that melting temperature shifts.” The novel properties of nanoparticles have found applications in anything from sunblock to toothpaste to solar energy. Now, Salaita and a team of Emory researchers have exploited their miniscule size as a delivery mechanism for a new asthma therapeutic.
Asthma is a chronic condition characterized by airway inflammation and mucus production that ranges in severity across patients. As Cherry Wongtrakool, MD, associate professor of pulmonary medicine, who served as a primary collaborator on the project, recently explained to me, “Asthma is very heterogeneous and a lot of it is driven by symptoms. What has evolved in the last few years is what we call “endo-typing.” Based on the type of inflammation that drives your asthma, you fit into an endotype.”
“For us and our technology, we’re very interested in the T2 or TH2 endotype,” she continued. This endotype is characterized by the over expression of a particular protein, GATA-3, which helps program the development of immune cells, T cells in particular. These T cells start in a naïve state and when GATA-3 binds to their nucleus, they transform into type 2 helper T cells, also known as TH2. TH2 is responsible for the production of inflammatory particles known as cytokines. An overactive production of TH2 leads to the overproduction of cytokines, thus creating the inflammation characteristic of asthma.
“The asthma therapeutic is a ten-nanometer gold particle that is coated with 100 copies of DNA,” Salaita explained. “What’s special about the DNA is that it destroys a gene that encodes for the GATA-3 protein.” In the context of asthma inflammation, Salaita refers to GATA-3 as the “master switch.” Instead of targeting cytokines or inflammation symptoms like other medications do, this therapeutic goes straight for the source and diminishes GATA-3 expression. “We’re focused on type 2 inflammation because it’s the most common,” Wongtrakool elaborated, “though by plurality, rather than majority.” The therapeutic is inhaled through a nebulizer, something that most severe asthmatics already own, and the gold nanoparticles are transported directly to the lungs.
As is often the case in medical research, the Salaita Lab had to model their results using mice. “The biggest challenge with lung delivery in a mouse is that you cannot train a mouse to take the drug or inhale on demand,” Salaita joked. This complicated the process of monitoring dose responses and developing an optimal dose, as getting consistent dosing in the first place was tricky. Furthermore, Wongtrakool explained that, “Mice don’t develop asthma like we do.” To remedy this, “We gave mice a house dust mite antigen,” she recounted. House dust mite is known to cause asthma in humans. Thus, Wongtrakool indicated, “If you sensitize mice to house dust mite, they develop an asthma-like phenotype with characteristics similar to what humans have.”
The mouse trials showed promising results and having now established the safety and efficacy of the therapeutic, Salaita hopes to soon commence clinical trials on humans. Approval would mark a significant advance in the treatment of severe asthma cases, as Salaita expressed that while “current treatment strategies for mild and intermediate asthma are reasonable … when you get to severe asthma cases, that’s either when you go to the ER or you get put on oral steroids.”
Oral steroids have long been an option for severe asthma patients, but their chronic use results in a slew of complications, including weight gain, osteoporosis, and diabetes. This stems from their systemic effect – they help manage asthma but impact the whole body in the process. As the DNA-coated nanoparticles are inhaled, they target the lungs directly. This means that the immune system and GATA-3 expression are unaffected in the rest of the body, which is important since cytokines are crucial for fighting off infection.
Targeted drug delivery additionally reduces dosage size, and since the therapeutic is administered by a nebulizer, it doesn’t require a visit to the doctor’s office. Nanoparticle therapy claims many benefits against its competitors, but it comes with its own uncertainties. As Dr. Salaita explained, “The DNA is safe. But, what does a ten-nanometer gold particle do?” Gold is considered the safest and most inert metal and it is often ingested in the form of edible gold leaf, but its interaction with bodily tissue like the lungs is still not fully understood.
“We did a six-month study to find out where the gold goes. There’s a very small amount of accumulation in the liver and the spleen. But with daily dosing for six months, only a dose worth is accumulated in the lungs, so it’s excreted for the most part,” Salaita assured me.
The market need for severe asthma therapeutics is indisputable. And, the nanoparticle platform is undoubtedly exciting. Sarah Wilkening, OTT’s case manager for the technology, indicated that “There haven’t been any nanoparticles, to my knowledge, that have been approved for the delivery of drugs yet, though there have been clinical trials for safety and efficacy.”
Wongtrakool finds the therapeutic ripe with possibility for this reason – “We’ve developed a platform that can theoretically be applied to a lot of different endotypes within asthma. If it’s successful with T2, we can modify it to address other endotypes that don’t respond well to steroids. Steroids are bad, but at least they work. For some of these patients, steroids are not effective, so they really struggle with how to manage or treat their disease.” Modifying the DNA that is wedded to the nanoparticle could provide treatments for the TH17 endotype, or even other lung diseases.
“Especially when it comes to institutions doing research, a lot of things are ahead of the curve and ahead of their own market,” Wilkening elaborated. “Sometimes we’ll get an invention and we won’t understand entirely what the market is because it hasn’t been created yet.” This reasoning is particularly applicable here. While the technology is a vital offering for asthma patients, our understanding of its possibilities has only begun. Of course, translating this therapeutic to other diseases will require hard work, time, and extensive research. But then again, all that is gold doesn’t glitter.
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