June 16, 2021
A link in the chain: Building on his mentor’s work, Martin Safo closes in on sickle cell treatment
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For 30 years, Martin Safo, Ph.D., has worked to find a solution to a complex puzzle: How can chemistry stop human blood cells from twisting and sticking together?
The answer is critical for millions of people with sickle cell disease. Their blood cells fold into bizarre shapes including the sickles that give the disease its name. They clump together, causing excruciating pain, anemia and often an early death.
Now Safo, a professor in the Virginia Commonwealth University School of Pharmacy, thinks he may be close to a treatment. “It is quite exciting,” he said.
His team’s innovative compound has proved effective in initial tests and is showing promising results in preclinical models. If all goes well, Safo and his fellow researchers at the School of Pharmacy plan to start human trials in 2022 for the treatment of sickle cell disease.
“This therapy will improve and save the lives of millions of people,” said Magdalena Morgan, Ph.D., assistant director of VCU Innovation Gateway, which is working to bring it to market. “Innovation Gateway is very proud to be a part of this process.”
VZHE-039, which gets its name from the initials of the researchers and the number of attempts it took to find it, draws on work Safo began in 1991.
Safo was hired as a postdoctoral fellow at the School of Pharmacy by Donald Abraham, the founder of the school’s Institute for Structural Biology, Drug Discovery and Development. Abraham hired Safo as a protein X-ray crystallographer even though Safo had experience only with a similar technique. “He took a chance on me,” Safo said.
At the time, Abraham was studying the use of vanillin, the simple chemical compound that gives vanilla its distinctive flavor, as a way to treat sickle cell disease. Scientists had noticed that in test tubes vanillin somehow prevented blood cells from forming the characteristic twisted shape that gives the disease its name.
Safo acknowledges that at the time he had no special interest in finding treatments for sickle cell. He had received his Ph.D. from the University of Notre Dame in inorganic chemistry. But he felt inspired by Abraham’s passion and pioneering work to apply the insights of structural biology to medical research. And he had family members who suffered from the disease.
With Abraham’s encouragement, Safo became an expert in the highly technical field, using X-rays to reveal the three-dimensional structure of proteins that had been crystallized. He started examining hemoglobin.
Red blood cells in people with the sickle mutation become deformed when their hemoglobin — the part of the blood cell that carries oxygen from the lungs to tissues — drops its oxygen payload. In people with sickle cell, the now-exposed section of hemoglobin with the mutation sticks to other hemoglobin molecules.
The sticky hemoglobin collects into chains of fibrous strands known as polymers that twist and deform the blood cells. Imagine icicles forming inside a water balloon: The growing ice crystals force the balloon to stretch, twist and eventually burst. Similarly, the deformed blood cells clump together or break open.
When they looked closely, Safo and his collaborators realized that vanillin attached to the hemoglobin and formed a sort of scaffold that held the hemoglobin in shape and kept them from twisting and deforming.
But vanillin, so promising in early tests, soon looked like a dead end. The difficulty was that vanillin is a chemical compound called an aromatic aldehyde. Most aromatic aldehydes are toxic, and the human body has evolved ways to destroy them. Vanillin was torn apart by the body’s enzymes long before it could have any therapeutic effect.
Still, the basic idea held promise. Abraham and his team kept looking for similar compounds. Safo found himself deeply interested in the project and continued his work on sickle cell and aldehyde compounds after Abraham retired from VCU in 2007. Safo modified vanillin into other compounds that showed more potent ability to prevent sickling of the red blood cells.
“We went through a few licenses, a few collaborations with pharmaceutical companies and endless conversations with inventors on continuous improvements,” said Innovation Gateway’s Morgan.
About 10 years ago, an unrelated business, Global Blood Therapeutics, demonstrated the power of Safo’s methods. Building on Safo’s published work on the vanillin derivatives, the company produced a compound, voxelotor, that was more potent and more stable than prior versions. Voxelotor was approved to treat sickle cell in 2019.
But voxelotor has a weakness — it does not work in low-oxygen environments. That meant it could not stop blood from sickling in the millions of tiny blood vessels, narrower than a human hair, that weave throughout the body.
Meanwhile, gene therapy researchers were having success after studying the genes of a subset of people with sickle cell who have a second mutation that keeps them from developing any symptoms. These therapies worked by teaching the genes of people who have sickle cell disease to re-create that second mutation. However, gene therapy is both highly technical and prohibitively expensive, making it of limited use as a treatment on a disease that is most prevalent in sub-Saharan Africa.
This therapy will improve and save the lives of millions of people.
Safo went back to the beginning: vanillin. The researchers knew that aromatic aldehydes formed a sort of scaffold that held the hemoglobin in shape. What else could they do?
Safo turned to the technique for which Abraham had first hired him. Using X-ray crystallography, Safo and his team studied the spot where vanillin and their previously studied vanillin derivatives bind to hemoglobin. They realized that these compounds bind to a spot adjacent to a section of hemoglobin known as the F-helix. The F-helix plays a crucial role in locking together the chains of hemoglobin, acting like the couplers that connect train cars and forming those long twisting tendrils.
An idea arose. What if there were a way to keep those locks at the F-helix from coupling in the first place? In a sickle-cell polymer chain, “you have it all intertwined together like a zipper,” Safo said. “If you cut any part, the whole zipper is going to fall apart.”
Safo and his colleagues — including VCU’s Yan Zhang, Ph.D., and Jurgen Venitz, M.D., Ph.D., and Osheiza Abdulmalik, Ph.D., of the Children’s Hospital of Philadelphia — began working to create compounds that would aim to hit the F-helix. The goal was to move it from its locking position and disrupt the formation of polymers.
On their 39th try, they came up with VZHE-039. Like other aromatic aldehyde variations, it prevents the hemoglobin from twisting. Unlike previous compounds, including voxelotor, in blocking the F-helix locking mechanism VZHE-039 keeps the polymer from forming or breaks it apart. This lets the compound work well in low-oxygen areas like capillaries where other aromatic aldehydes lose their therapeutic activity. And while their earlier promising compound survived only up to an hour in the body, Safo said VZHE-039 lasts for several hours — a requirement for a chronic disease.
The compound has been licensed to IllExcor Therapeutics, an incubator associated with the institute where Safo works that is partnering with VCU Innovation Gateway to bring the treatment to market. Clinical trials are tentatively slated to start in 2022 in England.
If the testing is successful, Safo said he can envision using the compound to treat millions around the world — including members of his own family in sub-Saharan Africa.
In May 2021, Safo and the research team received a grant from the National Institutes of Health worth up to $1.7 million to refine the idea and find compounds that bind even more closely to the locking site of hemoglobin polymers.
Safo, who was inducted into the VCU chapter of the National Academy of Inventors in 2018 for his work, points to Abraham, who founded the institute where Safo works and hired him. “He started it all,” Safo said.
Abraham died in April. In a note to fellow faculty after Abraham’s death, Safo wrote simply, “He was a very special person with an incredibly good heart.”
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