How CRISPR/Cas13 severs RNA viruses
Viruses are an unpredictable threat to global health, the economy and society - we have known this at least since the SARS-CoV-2 pandemic. Several million people have died since the beginning of the pandemic. There is still a lack of effective therapeutics against SARS-CoV-2 and emerging variants. The truth is: there are still no therapeutics against many other viruses either. Potentiating viral loads, high mutation rates and limited targets are inherent to viruses, making them true "survival artists" and placing high demands on drug development. The great desire to overcome the pandemic helped new technologies based on mRNA and equally new ways in drug delivery to achieve a rapid breakthrough in vaccine development – contrary to the expectations of many experts.
Similarly, breakthroughs in antiviral drug development are needed. Highly innovative approaches are required to combat viral infections. That is why SPRIND is supporting new technological approaches for breakthrough innovations to combat viral infections with this Challenge.
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Goal of this Challenge: New approaches for the development of antiviral therapeutics
The goal of the Challenge is to expand the repertoire of antiviral therapeutics with breakthrough technologies so that new treatment options will be available in the future and patients can be helped quickly. The Challenge teams are developing approaches for broad-spectrum antivirals and platform technologies for the rapid development of antiviral agents. At the end of the Challenge, the active agent resulting from the solution approach has to be tested in a proof of concept adapted to the development stage.
CRISPR/CAS13
Team CRISPR antivirals use the antiviral defense system CRISPR/Cas13 - perfected by millions of years of evolution by bacteria - to block proliferation and cytopathic effects of RNA viruses such as SARS-CoV-2 through cleavage of their viral genome and mRNA.
iGUARD platform
The iGUARD team develops next-generation RNAi-based molecular therapeutics against respiratory viruses using machine-learning for automated target identification and an optimized vector platform for delivery and preclinical validation in human patient-relevant models.
Virustrap
Team Virustrap uses DNA Origami technology to build nano scale traps for viruses.
MucBoost
Team MucBoost develops an upgrade against pathogens: Boosting the antiviral efficacy of mucus.
Participating in the Challenge pushes the teams to their full potential. We therefore provide intensive and individual support. This includes funding the teams as well as individual support from a Challenge coach, who has significant experience in the Challenge area and has already implemented high-impact innovations.
In the first year of the Challenge, SPRIND funded the teams' work with up to 700,000 euros, in the second year with up to 1.5 million euros, and in the current third year with up to 2.5 million euros each. We provide funding quickly and unbureaucratically, so that the teams can concentrate fully on their innovations.
Thinking one step further: Ideas with the potential for disruptive innovations must be brought to market to benefit patients. That is why SPRIND continues to support projects with potential for breakthrough innovation even after the Challenge has ended.
In October 2023, the expert jury selected the participants for the third and final stage of the 'Broad-Spectrum Antivirals' challenge. Four teams will each receive up to 2.5 million euros over the next twelve months for the further development of their radically new of antiviral therapeutics.
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Science Youtuber Jacob Beautemps introduces the six Challenge teams of stage 2 at Breaking Lab
Revolution in medicine? Jacob Beautemps takes a closer look at CRISPR CAS technology
Our jury of scientists and science entrepreneurs will evaluate all applications and select the teams that have what it takes to implement breakthrough innovations.
Joachim Spatz
Karin Mölling
Detlev Riesner
Nikolaus Rajewsky
Manfred Schubert-Zsilavecz
Holger Reithinger
February 28, 2022
What is an "Innovation Challenge"? What role is played by competition and cooperation? And what are the current SPRIND challenges about? Our host Thomas Ramge asks: Dr. Diane Seimetz, co-founder of Biopharma Excellence and innovation coach, and Dr. Jano Costard, Challenge Officer of the Federal Agency for Disruptive Innovation.
Listen to the episode (in German).
Do you have further questions?
If you have any questions or suggestions, please feel free to contact us at challenge@sprind.org.
Both humans and bacteria have to defend themselves against viruses. This natural antiviral defense system is called CRISPR/Cas. CRISPR/Cas9, in particular, has received a lot of media attention in the last few years because the enzyme can also be used in humans to cut, or cleave, genes—a genetic scissors, so to speak.
“CRISPR/Cas9 has its origins in bacteria where it combats DNA viruses, and it is already being used in a variety of clinical applications, for example for the therapy of hereditary diseases,” explains Prof. Dr. Elisabeth Zeisberg, a medical scientist from the University of Göttingen. But bacteria do not only defend themselves against DNA viruses. Thanks to an enzyme called CRISPR/Cas13, bacteria can also cleave RNA viruses, rendering the viruses harmless.
“CRISPR/Cas9 has its origins in bacteria where it combats DNA viruses, and it is already being used in a variety of clinical applications, for example for the therapy of hereditary diseases,” explains Prof. Dr. Elisabeth Zeisberg, a medical scientist from the University of Göttingen. But bacteria do not only defend themselves against DNA viruses. Thanks to an enzyme called CRISPR/Cas13, bacteria can also cleave RNA viruses, rendering the viruses harmless.
A computer analysis indicates exactly where the RNA should be cut. Zeisberg has established three criteria for identifying the optimal site for cutting RNA: The virus must be affected at a relevant site; if possible, the selected RNA site should not be affected by mutations; and there should be no equivalent in the human genome. “In the case of SARS-CoV-2, we have identified 31 such RNA sites along with their corresponding guide RNAs, and seven of them are optimal in a model system.”
“CRISPR/Cas9 has its origins in bacteria where it combats DNA viruses, and it is already being used in a variety of clinical applications, for example for the therapy of hereditary diseases."
A therapy against RNA viruses was urgently needed at the outbreak of the corona pandemic in 2020. “It was obvious to us that we could use CRISPR/Cas13 as an antiviral therapy for humans, like nature’s gift in a way,” says Zeisberg, founder of Avocet Bio GmbH. In fact, within a very short time, Zeisberg and her team showed that CRISPR/Cas13 reduces the infectivity of cells infected with SARS-CoV-2 by 99 percent. And not only has the proof of concept in the cells been successful, the first animal experiments have also been effective. “Hamsters infected with SARS-CoV-2 show a significant reduction in lung damage,” reports Elisabeth Zeisberg.
For the CRISPR/Cas13 enzyme to cleave viral RNA, it has to be positioned in the right place first, and this is done by so-called guide RNAs, which are small RNA snippets. Guide RNAs direct Cas13 to the target RNA sequence where it then binds to and severs the RNA.
For the CRISPR/Cas13 enzyme to cleave viral RNA, it has to be positioned in the right place first, and this is done by so-called guide RNAs, which are small RNA snippets. Guide RNAs direct Cas13 to the target RNA sequence where it then binds to and severs the RNA.
Already in the midst of the pandemic, Zeisberg and her team confirmed that the selected RNA sites tend not to be affected by mutations. “All the optimal guide RNAs cover 100% of all other previous variants, and mind you, we identified these at a time when only the Wuhan variant of the SARS-CoV-2 virus existed,” says Elisabeth Zeisberg. Optimistically, she adds, “This makes it likely that variants unknown to us today can also be treated effectively in the future.”
Currently, Elisabeth Zeisberg is primarily concerned with how the “packaging material” around the CRISPR/Cas13 is made: “The question is how we get the therapy where we need it—in the case of SARS-CoV-2, in the respiratory tract. That is the focus of our current work, to develop a formulation so that we can develop an effective nasal spray or an effective inhaler.”
Currently, Elisabeth Zeisberg is primarily concerned with how the “packaging material” around the CRISPR/Cas13 is made: “The question is how we get the therapy where we need it—in the case of SARS-CoV-2, in the respiratory tract. That is the focus of our current work, to develop a formulation so that we can develop an effective nasal spray or an effective inhaler.”
In addition to SARS-CoV-2, Zeisberg and her team are also working on treating another disease: rabies. “To this day, if you have not been previously vaccinated, you have to be treated within a very short period of time after contracting the disease, otherwise there is simply no effective treatment. As a result, about 60,000 people die from rabies every year,” says Elisabeth Zeisberg, explaining her motivation.
Zeisberg’s experience with CRISPR technology spans numerous years. As a cardiologist, she uses CRISPR primarily to study organ fibrosis, the defective scarring of organs, including the heart. What fascinates Zeisberg the most about her work is the development of new things and the prospect of making a difference. “But I also enjoy teaching and supporting young scientists,” she adds.
As a mentor, she finds it especially important to be a role model for other women, and as a mother of four, she knows, “Women still have it harder than men when they have children and work full-time. I want to encourage young women to follow their aspirations.”
As a mentor, she finds it especially important to be a role model for other women, and as a mother of four, she knows, “Women still have it harder than men when they have children and work full-time. I want to encourage young women to follow their aspirations.”
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