- A team of researchers recently developed a novel way of delivering nucleic acid-based medicines using a method similar to an ancient cupping technique.
- Their experiments indicate that the technique makes vaccine delivery more effective by several orders of magnitude.
- The cupping technique is currently undergoing clinical trials to deliver a COVID-19 vaccine.
Nucleic acids are present in all living cells, most notably as DNA and RNA.
Treatments and vaccines that use nucleic acids work by inhibiting, adding, replacing, or editing DNA and RNA in host cells.
How well these treatments and vaccines work depends on how well they can be delivered to the host’s cells. If directly injected into tissue, for example, most nucleic acids will rapidly degrade unless protected.
The Pfizer-BioNTech and Moderna COVID-19 vaccines are both nucleic acid-based medicines. Nucleic acids in these vaccines are enclosed and protected by lipid nanoparticles that deliver them across the host cell membrane.
Although they are effective, drugs delivered in this way are vulnerable to
One delivery method for nucleic acid-based medicines is
While somewhat effective, these electrical impulses can cause muscle contractions, tissue damage, and pain, and they may not be suitable for people who use implantable electrical devices such as defibrillators or pacemakers.
Using this method also requires substantial training, and equipment costs may make it inaccessible to regions and populations with fewer resources.
Creating a method for delivering nucleic acid-based medicines that overcomes unwanted side effects and cost barriers while still being effective could increase the accessibility of vaccines to areas with limited resources.
Recently, researchers from Rutgers, the State University of New Jersey in Piscataway, and GeneOne Life Science in Seoul, South Korea, developed a method based on an ancient cupping technique to deliver nucleic acid-based medicines.
“Development of enhanced delivery technologies plays an instrumental role in bringing nucleic acid-based biologics to broad use and clinical relevance, and worldwide vaccine distribution is just one example,” said senior study author Prof. Hao Lin.
“We have demonstrated an alternative, safe, and effective transfection platform that yields high levels of transgene expression.”
“The advantages also include device cost effectiveness, […] manufacturing scalability, and minimal requirements for user training,” he added.
“Because of the inherent advantages of DNA, not least of which is avoiding cold-chain requirements of other vaccines, this technology facilitates vaccination programs into remote regions of the world where resources are limited,” he added.
The study now appears in the journal Science Advances.
Although evidence of its health benefits is
To test the method, the researchers gathered two groups of rats and injected both with DNA in the upper layers of their skin. One group received the “suction cup treatment” on their injection site, whereas the other group did not.
The researchers monitored the activity of the DNA with fluorescence microscopy. They found that gene expression from the vaccine was detectable at 4 hours post-vaccination. In the rats who also underwent cupping, however, gene expression was detectable at 1 hour post-vaccination.
At 24 hours post-injection, the researchers saw that gene expression was detectable eight times deeper under the skin among the rats who underwent cupping than among those who received DNA injections alone.
To investigate whether or not this technology could work to deliver potential COVID-19 vaccines, the researchers next injected the rats with a synthetic SARS-CoV-2 DNA candidate vaccine.
They split the rats into three groups:
- The first group received two injections of the vaccine candidate without suction on days 0 and 14.
- The second group received one vaccine, followed by dermal suction on day 0.
- The third group received two vaccinations and dermal suction on days 0 and 14.
The researchers collected blood samples from the rats on days 0 and 14, before vaccination, and again on day 29.
They found that the rats who received cupping after the vaccine had a significantly stronger immune response than those who received the vaccine alone.
The researchers also found that immune responses in the rats who received a single vaccine followed by suction were not statistically different from those who received two vaccines followed by suction.
They also note that the rats who underwent suction had no evidence of tissue damage or lymphocyte infiltration in their injected areas.
The researchers say that the underlying mechanisms for suction-enhanced delivery are not clear. They hypothesize, however, that it may work via the CG pathway. This plays a role in determining which molecules travel through membranes and enter cells.
The researchers explain that it will be challenging to confirm the underlying mechanisms of cupping due to the complexity of the processes involved and a lack of availability of drugs used for testing.
Nevertheless, the researchers say that even without mechanistic understanding, it is still possible to improve the method.
“Currently, the procedure is two-step: an injection followed by suction,” Dr. Lin told Medical News Today.
“We are working on a combination device/method to render one-step application — that is, injection and suction in a single step by a single device,” he continued. “Furthermore, we are trying to reduce suction time even further to increase patient and staff acceptance.”
When asked whether this method could work for COVID-19 vaccines, Dr. Lin said, “Theoretically, this may be possible, but we cannot answer without testing since, except for DNA vaccines, COVID-19 vaccines are delivered into the muscle, whereas this device delivers [the] vaccine to the upper layers of the skin.”
“The [suction] device is being tested currently in phase 1 and phase 2 clinical trials of a COVID-19 vaccine. The documentation to enable filing with regulatory agencies for general and widespread clinical use is being readied,” he said.
In response to the same question, Dr. Karl McCullagh — who is a lecturer and principal investigator at the Department of Physiology at the National University of Ireland, Galway, and was not involved in the study — said: “Potentially yes. However, one gaping difference between rodent rat skin and human skin is the attachment of a thin skeletal muscle layer called the panniculus carnosus (PC). Rat dermis has the PC muscle, which is absent in human skin. For that reason alone, the procedure would need to be trialed on human skin to see if the efficiency is the same, less, or enhanced.”
“Current, DNA-based COVID-19 vaccines use an adenovirus (a common flu-like virus) to carry the DNA into cells, and the sometimes reported side-effects are likely due to the mounting of an immune response against the adenovirus. Medicinal approval bodies are always concerned with DNA-based treatments running the risk of genome insertional mutagenesis,” he added.
“Therefore, adapting the reported technique for the delivery of mRNA-based vaccines into dermal tissues would be very interesting to experiment with and again look at the efficacy of immune resistance to COVID-19 infection. The technique could be easily envisioned for delivery of DNA-based vaccines, but the instability of mRNA-based vaccines may require an adaptation of the protocol,” he explained.
The researchers conclude that cupping is a promising method for nucleic acid-based medicine delivery. However, further research is necessary to see whether it could work to deliver COVID-19 vaccines to humans.
“The suction device has numerous advantages relative to other devices for DNA vaccine delivery. First, it is very inexpensive and easy to use, requiring minimal training,” Dr. Lin told MNT. “Secondly, the device is run from a battery that is easily rechargeable.”
“Third,” he continued, “is the high degree of patient acceptance, as the device will help deliver DNA vaccines without pain or discomfort.”
“And fourth, unlike the significant setup times with other devices, this only requires changing out a cap and then pressing the power button; the machine will turn off in a few seconds.”
“This, coupled with the many advantages of DNA as a vaccine type — the greatest advantages being the ability to completely avoid the need for freezers from the clinician’s perspective, and low side effects and discomfort from the patient’s perspective — makes this an ideal vaccine platform for resource-limited and remote regions.”
– Dr. McCullagh
“[This vaccination method] is very attractive for multiple reasons. The development of an enhanced nonviral method of delivering DNA to cells/tissues without much tissue disruption or damage is much needed for human clinical use,” said Dr. McCullagh. “Nonviral gene delivery is notoriously weak compared with the super-efficient viral gene delivery methods […], one of which involves encapsulating the DNA or RNA in lipid vesicles of differing chemistries (exploited for recent COVID-19 mRNA vaccine success) and facilitates entry into the cells.”
“However, the less extra chemistry to facilitate the movement of nucleic acids across the plasma membrane lipid bilayer will lessen the chance for secondary side effects. The simple use of negative pressure over a small tissue surface area would lend itself very well to vaccination programs and medical treatment of superficial or skin surface-linked diseases, such as melanomas, etc.,” he added.
“[A limitation to this research] is that much of the reported data showing high efficiency of gene transfection has been generated in experiments where only the relatively small GFP-expressing plasmids have been used. The efficiency of transfection reduces with larger genes and plasmids. Therefore, plasmids encoding different COVID antigen genes of varying sizes would need to be examined and efficiency reported before initiating human trials,” he concluded.