Finding the elusive aquaporin modulators
Aquaporins are channel proteins that facilitate the transport of water across cells. The discovery of aquaporins in 1992, for which researcher Peter Agre received the Nobel Prize in Chemistry, opened the door to a new therapeutic approach for treating many health conditions. On one particular start-up’s journey in finding applicable aquaporin modulators, the student has become the master.
Water is one of the substances that are essential for life on Earth and for the survival of all plants and animals. Although the importance of water transport has been recognized since ancient times, the precise mechanism by which water is transported in and out of cells remained elusive until aquaporins were discovered by Peter Agre in 1992. These proteins form pores in the cell membrane to allow water to be transported between cells.
The importance of this fundamental discovery and its potential impacts was acknowledged in 2003, when Agre won the Nobel Prize in Chemistry for “discoveries concerning channels in cell membranes”. However, nearly 30 years after the discovery of aquaporins, the only practical application is in the understanding and treatment of water balance disorders. Despite their pervasive presence in human organs, aquaporins have not featured in any new medical therapies. To understand the mystery surrounding these elusive proteins, Supertrends approached Apoglyx, a Swedish start-up leading the development of aquaporin-based treatments, for a joint interview with Michael Rutzler (CEO and founder of Apoglyx), Søren Nielsen (co-founder and shareholder), and Kristina Nyzell (investor).
Tiny water channels
Søren Nielsen, a professor at the Department of Biomedicine, Aarhus University and the Department of Health Science and Technology, Aalborg University in Denmark, worked very closely with Peter Agre for many years. Both have always believed in the magic of aquaporins. “Aquaporins exist globally in animals, plants, and microbes. These channels are fundamental for life. We are one of the leading groups in identifying different aquaporins and exploring their roles in physiology and medicine. From a biotech perspective, Apoglyx’s approach is to identify inhibitors of aquaporins to exploit their medical importance. This is a new approach, and a very challenging one due to the molecular structure of aquaporins,” Nielsen told Supertrends.
Nielsen is a firm believer in the importance and clinical potential of aquaporins: “It is fundamental. Take the kidney as an example. Aquaporins have a critical role in kidney function and a variety of kidney and cardiovascular diseases. Another example is the brain, where AQP4 has an important role in water transport and in brain edema. It has recently also been shown that aquaporins as glymphatics have additional roles in facilitating brain function. Identifying aquaporins that serve as channels for water transport and in regulation of water balance and water balance disorders was relatively straightforward conceptionally. It is much more difficult to understand the roles of aquaglyceroporins that also serve other functions in addition to water transport. That has turned our focus to AQP7 and AQP9, which play a role in metabolic diseases and sepsis.”
The student has become the master
In 2007, Michael Rutzler met Nielsen at Aarhus University. By then, Rutzler had already done some well-received research on olfactory receptors in insects in identifying potential inhibitors. With the support of many leading scientists like Nielsen, Rutzler now devotes his time to finding aquaporins modulators to treat medical conditions in humans.
“Aquaporins are channels or holes in the cell membrane. They selectively let water and some other small molecules pass. The channels have enormous capacities to let water and other molecules through. That is one reason why it is difficult to find blockers that can stop all these molecules from going through.”
The aquaporin modulators have proven difficult to identify, but Rutzler has successfully identified aquaporin-9 inhibitors and demonstrated promising applications on metabolic diseases and later sepsis.
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection. Despite modern medical advances, it remains a global public health emergency affecting millions of people worldwide and one of the main causes of death across the world. It is also a medical condition for which no effective treatments exist. The COVID-19 crisis has brought this ancient condition into the spotlight again. Developing new treatments for sepsis has always been a difficult task; now, it is even more urgent.
With due caution, Rutzler lays out a possible pathway to success: “In sepsis, the dysfunction of the immune system starts to damage vital organs. The global effects also have an impact on blood circulation. Vital organs, including the brain and kidneys, become impaired. This, in turn, causes further damages to other organs. Through our collaboration with other universities, we found strong evidence that the inhibition of AQP9 demonstrated a protective effect from sepsis in rodent models, especially on heart function. We are hoping to get similar results in humans.” Rutzler and Nyzell are quite excited regarding the promising results of this potential treatment. Nyzell explains in layman’s terms: “Impaired blood flow can cause long-term consequences in vital organ functions. The current COVID-19 debate has been very much focused on keeping patients alive without thinking about long-term complications. I think it is important to look into new ways of treatments from a broader view in sepsis.” And Nielsen adds: “We are working on the role of AQP9 in sepsis and other conditions. Many aisles in finding new efficient treatments have been closed. It is crucial to develop something new based on this preliminary evidence.”
The path to a promising future
In conclusion, Supertrends asked the question that is on everybody’s mind: When will an aquaporin-based treatment be available for sepsis patients?
Starting from humble beginnings in 2012, after Rutzler discovered aquaporin inhibitors, Apoglyx has managed with a small amount of financial support and a great team of scientists to become one of the leaders in developing aquaporin modulators for therapeutic applications. After many years of hard work, Apoglyx now is ready for its breakthrough.
“It also depends on funding. Sepsis is a medical condition, not a disease. Aquaporins and sepsis are under-funded. What Michael and Søren are doing is much more difficult than developing the COVID tracking app,” Nyzell adds, supplying the investor’s perspective.
Apoglyx is planning to submit its Investigational New Drug (IND) application to the FDA and start a Phase 1 clinical trial in 2022; whether alone or potentially in partnerships with larger pharmaceutical companies, it is looking at potentially gaining approval and entering the market in less than ten years.
Before the end of the decade, we may finally be able to lift the veil of mystery that still obscures the path towards aquaporins-based therapies.