image: Maria Vitória Bentley during her presentation at FAPESP Week London
Credit: Elton Alisson/Agência FAPESP
A technological platform developed by Brazilian researchers could revolutionize the treatment of skin diseases such as psoriasis and vitiligo. The group, affiliated with the NanoGeneSkin laboratory at the University of São Paulo (USP) in Ribeirão Preto, is developing nanoparticles capable of delivering therapeutic RNA molecules directly to skin cells. These nanoparticles can precisely silence the genes responsible for chronic inflammation at the molecular level.
The latest advances in the research were presented during FAPESP Week London, which will run through June 4 at the Science Museum in London.
The research is being conducted under the auspices of the National Institute of Science and Technology (INCT) for Pharmaceutical Nanotechnology, which is funded by FAPESP and the National Council for Scientific and Technological Development (CNPq).
“We began this research 20 years ago, and over that time, we’ve gained experience in obtaining and characterizing lipid nanoparticles to deliver not only drugs, but also interfering RNA [molecules that interact with target genes], with the aim of treating chronic skin diseases such as psoriasis, skin cancer, and vitiligo,” Maria Vitória Bentley, coordinator of NanoGeneSkin and the INCT for Pharmaceutical Nanotechnology, told Agência FAPESP.
Psoriasis affects about 190 million people worldwide, or between 2% and 3% of the global population. Approximately 5 million of those people are in Brazil. Psoriasis is a chronic, immune-mediated, genetic disease caused by an exaggerated response from the body’s immune system with hereditary components. It manifests as severe inflammatory skin lesions caused by excessive production of pro-inflammatory cytokines, which act as alarm signals for the immune system. When present in excess, they cause damage to the body itself. One of the main cytokines is TNF-alpha. Vitiligo, in turn, leads to the destruction of melanocytes, which are the cells responsible for producing melanin, the pigment that gives skin its color. This results in the progressive whitening of areas of the body.
Both conditions share a characteristic that makes them promising targets for RNA therapy: specific genes that are overexpressed, or abnormally active, drive the pathological process. “We understand what the targets are and use a specific complementary RNA to silence the production of that cytokine,” Bentley explained.
Gene silencing
RNA (ribonucleic acid) is a molecule present in all living cells that plays a central role in protein production. DNA broadly functions as the body’s instruction manual, and messenger RNA is the copy of that manual that reaches the cell’s protein factories.
The research group’s core approach is based on using small interfering RNA (siRNA), which are synthetic molecules that act directly on the messenger RNA responsible for producing inflammatory cytokines. The siRNA degrades the messenger RNA before the harmful protein is synthesized. It is like intercepting and destroying the manufacturing order before it reaches the assembly line. The result is a reduction of inflammatory mediators to baseline healthy cell levels without the need for drugs that act throughout the body and tend to cause more side effects.
“It’s precision nanomedicine,” Bentley summarizes. “I have a specific target and a complementary RNA to silence the overexpressed gene in that disease.”
But delivering these molecules to target cells in the skin is no simple task. RNA is chemically fragile and rapidly degraded by enzymes in the body. Furthermore, the skin is an efficient biological barrier designed to prevent the very kind of penetration the researchers need to achieve.
The group developed a solution of liquid crystal nanoparticles, which are structures made of fats (lipids) with a highly ordered internal organization similar to crystals, but with the fluidity characteristic of liquids. This unique architecture allows genetic material to be encapsulated, protecting it from degradation and facilitating its penetration through the skin and uptake by target cells.
Across three lines of research presented by Bentley, the group has demonstrated the effectiveness of these nanoparticles for gene silencing, the enhancement of RNA release within cells by physical methods such as light in a process called photoactivation, and the ability to simultaneously carry multiple RNAs and even conventional anti-inflammatory drugs within a single nanoparticle.
This last strategy is particularly relevant for psoriasis, a disease with a complex inflammatory cascade – that is, a chain reaction involving multiple proteins and cellular signals – and therefore with several possible therapeutic targets. “We have a functional nanoparticle. Since psoriasis is very complex and has multiple targets, our goal is to deliver RNAs to different targets and, at times, also an anti-inflammatory drug,” said the researcher.
The results were validated in cellular models – experiments conducted with cells cultured in a laboratory – and in animals with lesions similar to those of the disease induced experimentally.
Other applications
The group’s scope extends beyond psoriasis. Ongoing research is applying the same platform to vitiligo, an area for which the group already holds a patent involving RNA and nanoparticles, as well as to the healing of chronic wounds. This is another health problem for which there is no fully satisfactory therapeutic solution.
There is also a branch of research that goes beyond skin diseases. This focuses on developing a nanostructure to deliver mRNA, which instructs cells to produce a specific protein. The nanostructure has the potential to be used in vaccines, including an experimental cancer vaccine. This principle made the Pfizer and Moderna COVID-19 vaccines possible. Instead of introducing the virus into the body, only the genetic instructions are introduced so that the body produces a protein characteristic of the infectious agent or tumor. This trains the immune system to recognize and fight it.
In animal models tested by the group, animals immunized with the formulation and subsequently exposed to cancer cells showed tumor regression or no tumor growth. The technology has already attracted the interest of pharmaceutical companies.
“In 2006, the discovery of RNA interference received the Nobel Prize. By 2007, we’d already begun developing those nanoparticles,” Bentley recalls, highlighting the group’s pioneering role on the national stage.
With two patents filed and industrial scaling processes under development, including lyophilization (a technique that removes water from formulations via vacuum freezing to extend shelf life and facilitate commercialization), the group is already thinking beyond scientific proof of concept.
“If it works, how are we going to turn this into a viable product?” Bentley summarizes. This question is guiding the researchers’ next steps. Companies have already expressed interest in licensing the technology, and the group is discussing potential pathways for clinical translation, which is the process of taking a discovery from the lab to the patient.
About São Paulo Research Foundation (FAPESP)
The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at www.fapesp.br/en and visit FAPESP news agency at www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe