A biotech in Cambridge, Mass., is targeting a rare disease called cystinosis with gene therapy. It's been effective for five patients in a clinical trial that's still underway.
Recently, AVROBIO compiled positive clinical data from this first and only gene therapy trial for the disease. The data show the potential of the therapy to genetically modify the patients’ own hematopoietic stem cells—a certain type of cell that’s capable of developing into all different types of blood cells—to express the functional protein they are deficient in. It stabilizes or reduces the impact of cystinosis on multiple tissues with a single dose.
Medical researchers have found that more than 80 different mutations to a gene called CTNS are responsible for causing cystinosis. The most common mutation results in a deficiency of the protein cystinosin. That protein functions as a transporter that regulates a lot metabolic processes in the cells.
“One of the first things we see in patients clinically is an accumulation of a particular amino acid called cystine, which grows toxic cystine crystals in the cells that cause serious complications,” explains Essra Rihda, chief medical officer for AVROBIO. “That happens in the cells across the tissues and organs of the body, so the disease affects many parts of the body.”
Jordan Janz, 23, meets Stephanie Cherqui, the principal investigator of his gene therapy trial, before the trial started in 2019.
Jordan Janz
According to Rihda, although cystinosis can occur in kids and adults, the most severe form of the disease affects infants and makes up about 95 percent of overall cases. Children typically appear healthy at birth, but around six to 18 months, they start to present for medical attention with failure to thrive.
Additionally, infants with cystinosis often urinate frequently, a sign of polyuria, and they are thirsty all the time, since the disease usually starts in the kidneys. Many develop chronic kidney disease that ultimately progresses to the point where the kidney no longer supports the body’s needs. At that stage, dialysis is required and then a transplant. From there the disease spreads to many other organs, including the eyes, muscles, heart, nervous system, etc.
“The gene for cystinosis is expressed in every single tissue we have, and the accumulation of this toxic buildup alters all of the organs of the patient, so little by little all of the organs start to fail,” says Stephanie Cherqui, principal investigator of Cherqui Lab, which is part of UC San Diego’s Department of Pediatrics.
Since the 1950s, a drug called cysteamine showed some therapeutic effect on cystinosis. It was approved by the FDA in 1994 to prevent damage that may be caused by the buildup of cystine crystals in organs. Prior to FDA approval, Cherqui says, children were dying of the disease before they were ten-years-old or after a kidney transplant. By taking oral cysteamine, they can live from 20 to 50 years longer. But it’s a challenging drug because it has to be taken every 6 or 12 hours, and there are serious gastric side effects such as nausea and diarrhea.
“With all of the complications they develop, the typical patient takes 40 to 60 pills a day around the clock,” Cherqui says. “They literally have a suitcase of medications they have to carry everywhere, and all of those medications don’t stop the progression of the disease, and they still die from it.”
Cherqui has been a proponent of gene therapy to treat children’s disorders since studying cystinosis while earning her doctorate in 2002. Today, her lab focuses on developing stem cell and gene therapy strategies for degenerative, hereditary disorders such as cystinosis that affect multiple systems of the body. “Because cystinosis expresses in every tissue in the body, I decided to use the blood-forming stem cells that we have in our bone marrow,” she explains. “These cells can migrate to anywhere in the body where the person has an injury from the disease.”
AVROBIO’s hematopoietic stem cell gene therapy approach collects stem cells from the patient’s bone marrow. They then genetically modify the stem cells to give the patient a copy of the healthy CTNS gene, which the person either doesn’t have or it’s defective.
The patient first undergoes apheresis, a medical procedure in which their blood is passed through an apparatus that separates out the diseased stem cells, and a process called conditioning is used to help eliminate the damaged cells so they can be replaced by the infusion of the patient’s genetically modified stem cells. Once they become engrafted into the patient’s bone marrow, they reproduce into a lot of daughter cells, and all of those daughter cells contain the CTNS gene. Those cells are able to express the healthy, functional, active protein throughout the body to correct the metabolic problem caused by cystinosis.
“What we’re seeing in the adult patients who have been dosed to date is the consistent and sustained engraftment of our genetically modified cells, 17 to 27 months post-gene therapy, so that’s very encouraging and positive,” says Rihda, the chief medical officer at AVROBIO.
When Janz was 11-years-old, his mother got him enrolled in the trial of a new form of cysteamine that would only need to be taken every 12 hours instead of every six. Two years later, she made sure he was the first person on the list for Cherqui’s current stem cell gene therapy trial.
AVROBIO researchers have also confirmed stabilization or improvement in motor coordination and visual perception in the trial participants, suggesting a potential impact on the neuropathology of the disease. Data from five dosed patients show strong safety and tolerability as well as reduced accumulation of cystine crystals in cells across multiple tissues in the first three patients. None of the five patients need to take oral cysteamine.
Janz’s mother, Barb Kulyk, whom he credits with always making him take his medications and keeping him hydrated, had been following Cherqui’s research since his early childhood. When Janz was 11-years-old, she got him enrolled in the trial of a new form of cysteamine that would only need to be taken every 12 hours instead of every six. When he was 17, the FDA approved that drug. Two years later, his mother made sure he was the first person on the list for Cherqui’s current stem cell gene therapy trial. He received his new stem cells on October 7th, 2019, went home in January 2020, and returned to working full time in February.
Jordan Janz, pictured here with his girlfriend, has a new lease on life, plus a new hair color.
Jordan Janz
He notes that his energy level is significantly better, and his mother has noticed much improvement in him and his daily functioning: He rarely vomits or gets nauseous in the morning, and he has more color in his face as well as his hair. Although he could finish his participation at any time, he recently decided to continue in the clinical trial.
Before the trial, Janz was taking 56 pills daily. He is completely off all of those medications and only takes pills to keep his kidneys working. Because of the damage caused by cystinosis over the course of his life, he’s down to about 20 percent kidney function and will eventually need a transplant.
“Some day, though, thanks to Dr. Cherqui’s team and AVROBIO’s work, when I get a new kidney, cystinosis won’t destroy it,” he concludes.
Katalin Karikó, pictured, and Drew Weissman won the Nobel Prize for advances in mRNA research that led to the first Covid vaccines.
The work for which they garnered the illustrious award and its accompanying $1,000,000 cash windfall was completed about two decades ago, wrought through long hours in the lab over many arduous years. But humanity collectively benefited from its life-saving outcome three years ago, when both Moderna and Pfizer/BioNTech’s mRNA vaccines against COVID were found to be safe and highly effective at preventing severe disease. Billions of doses have since been given out to protect humans from the upstart viral scourge.
“I thought of going somewhere else, or doing something else,” said Katalin Karikó. “I also thought maybe I’m not good enough, not smart enough. I tried to imagine: Everything is here, and I just have to do better experiments.”
Unlocking the power of mRNA
Weissman and Karikó unlocked mRNA vaccines for the world back in the early 2000s when they made a key breakthrough. Messenger RNA molecules are essentially instructions for cells’ ribosomes to make specific proteins, so in the 1980s and 1990s, researchers started wondering if sneaking mRNA into the body could trigger cells to manufacture antibodies, enzymes, or growth agents for protecting against infection, treating disease, or repairing tissues. But there was a big problem: injecting this synthetic mRNA triggered a dangerous, inflammatory immune response resulting in the mRNA’s destruction.
While most other researchers chose not to tackle this perplexing problem to instead pursue more lucrative and publishable exploits, Karikó stuck with it. The choice sent her academic career into depressing doldrums. Nobody would fund her work, publications dried up, and after six years as an assistant professor at the University of Pennsylvania, Karikó got demoted. She was going backward.
“I thought of going somewhere else, or doing something else,” Karikó told Stat in 2020. “I also thought maybe I’m not good enough, not smart enough. I tried to imagine: Everything is here, and I just have to do better experiments.”
A tale of tenacity
Collaborating with Drew Weissman, a new professor at the University of Pennsylvania, in the late 1990s helped provide Karikó with the tenacity to continue. Weissman nurtured a goal of developing a vaccine against HIV-1, and saw mRNA as a potential way to do it.
“For the 20 years that we’ve worked together before anybody knew what RNA is, or cared, it was the two of us literally side by side at a bench working together,” Weissman said in an interview with Adam Smith of the Nobel Foundation.
In 2005, the duo made their 2023 Nobel Prize-winning breakthrough, detailing it in a relatively small journal, Immunity. (Their paper was rejected by larger journals, including Science and Nature.) They figured out that chemically modifying the nucleoside bases that make up mRNA allowed the molecule to slip past the body’s immune defenses. Karikó and Weissman followed up that finding by creating mRNA that’s more efficiently translated within cells, greatly boosting protein production. In 2020, scientists at Moderna and BioNTech (where Karikó worked from 2013 to 2022) rushed to craft vaccines against COVID, putting their methods to life-saving use.
The future of vaccines
Buoyed by the resounding success of mRNA vaccines, scientists are now hurriedly researching ways to use mRNA medicine against other infectious diseases, cancer, and genetic disorders. The now ubiquitous efforts stand in stark contrast to Karikó and Weissman’s previously unheralded struggles years ago as they doggedly worked to realize a shared dream that so many others shied away from. Katalin Karikó and Drew Weissman were brave enough to walk a scientific path that very well could have ended in a dead end, and for that, they absolutely deserve their 2023 Nobel Prize.
This article originally appeared on Big Think, home of the brightest minds and biggest ideas of all time.
With conventional fuel cells as their model, researchers learned to use similar chemical reactions to make a fuel from microbes in pee.
Plus, urine contains water, phosphorus, potassium and nitrogen, the key ingredients plants need to grow and survive. Human urine could replace about 25 percent of current nitrogen and phosphorous fertilizers worldwide and could save water for gardens and crops. The average U.S. resident flushes a toilet bowl containing only pee and paper about six to seven times a day, which adds up to about 3,500 gallons of water down per year. Plus cows in the U.S. produce 231 gallons of the stuff each year.
Pee power
A conventional fuel cell uses chemical reactions to produce energy, as electrons move from one electrode to another to power a lightbulb or phone. Ioannis Ieropoulos, a professor and chair of Environmental Engineering at the University of Southampton in England, realized the same type of reaction could be used to make a fuel from microbes in pee.
Bacterial species like Shewanella oneidensis and Pseudomonas aeruginosa can consume carbon and other nutrients in urine and pop out electrons as a result of their digestion. In a microbial fuel cell, one electrode is covered in microbes, immersed in urine and kept away from oxygen. Another electrode is in contact with oxygen. When the microbes feed on nutrients, they produce the electrons that flow through the circuit from one electrod to another to combine with oxygen on the other side. As long as the microbes have fresh pee to chomp on, electrons keep flowing. And after the microbes are done with the pee, it can be used as fertilizer.
These microbes are easily found in wastewater treatment plants, ponds, lakes, rivers or soil. Keeping them alive is the easy part, says Ieropoulos. Once the cells start producing stable power, his group sequences the microbes and keeps using them.
Like many promising technologies, scaling these devices for mass consumption won’t be easy, says Kevin Orner, a civil engineering professor at West Virginia University. But it’s moving in the right direction. Ieropoulos’s device has shrunk from the size of about three packs of cards to a large glue stick. It looks and works much like a AAA battery and produce about the same power. By itself, the device can barely power a light bulb, but when stacked together, they can do much more—just like photovoltaic cells in solar panels. His lab has produced 1760 fuel cells stacked together, and with manufacturing support, there’s no theoretical ceiling, he says.
Although pure urine produces the most power, Ieropoulos’s devices also work with the mixed liquids of the wastewater treatment plants, so they can be retrofit into urban wastewater utilities.
This image shows how the pee-powered system works. Pee feeds bacteria in the stack of fuel cells (1), which give off electrons (2) stored in parallel cylindrical cells (3). These cells are connected to a voltage regulator (4), which smooths out the electrical signal to ensure consistent power to the LED strips lighting the toilet.
Courtesy Ioannis Ieropoulos
Key to the long-term success of any urine reclamation effort, says Orner, is avoiding what he calls “parachute engineering”—when well-meaning scientists solve a problem with novel tech and then abandon it. “The way around that is to have either the need come from the community or to have an organization in a community that is committed to seeing a project operate and maintained,” he says.
Success with urine reclamation also depends on the economy. “If energy prices are low, it may not make sense to recover energy,” says Orner. “But right now, fertilizer prices worldwide are generally pretty high, so it may make sense to recover fertilizer and nutrients.” There are obstacles, too, such as few incentives for builders to incorporate urine recycling into new construction. And any hiccups like leaks or waste seepage will cost builders money and reputation. Right now, Orner says, the risks are just too high.
Despite the challenges, Ieropoulos envisions a future in which urine is passed through microbial fuel cells at wastewater treatment plants, retrofitted septic tanks, and building basements, and is then delivered to businesses to use as agricultural fertilizers. Although pure urine produces the most power, Ieropoulos’s devices also work with the mixed liquids of the wastewater treatment plants, so they can be retrofitted into urban wastewater utilities where they can make electricity from the effluent. And unlike solar cells, which are a common target of theft in some areas, nobody wants to steal a bunch of pee.
When Ieropoulos’s team returned to wrap up their pilot project 18 months later, the school’s director begged them to leave the fuel cells in place—because they made a major difference in students’ lives. “We replaced it with a substantial photovoltaic panel,” says Ieropoulos, They couldn’t leave the units forever, he explained, because of intellectual property reasons—their funders worried about theft of both the technology and the idea. But the photovoltaic replacement could be stolen, too, leaving the girls in the dark.
The story repeated itself at another school, in Nairobi, Kenya, as well as in an informal settlement in Durban, South Africa. Each time, Ieropoulos vowed to return. Though the pandemic has delayed his promise, he is resolute about continuing his work—it is a moral and legal obligation. “We've made a commitment to ourselves and to the pupils,” he says. “That's why we need to go back.”
Urine as fertilizer
Modern day industrial systems perpetuate the broken cycle of nutrients. When plants grow, they use up nutrients the soil. We eat the plans and excrete some of the nutrients we pass them into rivers and oceans. As a result, farmers must keep fertilizing the fields while our waste keeps fertilizing the waterways, where the algae, overfertilized with nitrogen, phosphorous and other nutrients grows out of control, sucking up oxygen that other marine species need to live. Few global communities remain untouched by the related challenges this broken chain create: insufficient clean water, food, and energy, and too much human and animal waste.
The Rich Earth Institute in Vermont runs a community-wide urine nutrient recovery program, which collects urine from homes and businesses, transports it for processing, and then supplies it as fertilizer to local farms.
One solution to this broken cycle is reclaiming urine and returning it back to the land. The Rich Earth Institute in Vermont is one of several organizations around the world working to divert and save urine for agricultural use. “The urine produced by an adult in one day contains enough fertilizer to grow all the wheat in one loaf of bread,” states their website.
Notably, while urine is not entirely sterile, it tends to harbor fewer pathogens than feces. That’s largely because urine has less organic matter and therefore less food for pathogens to feed on, but also because the urinary tract and the bladder have built-in antimicrobial defenses that kill many germs. In fact, the Rich Earth Institute says it’s safe to put your own urine onto crops grown for home consumption. Nonetheless, you’ll want to dilute it first because pee usually has too much nitrogen and can cause “fertilizer burn” if applied straight without dilution. Other projects to turn urine into fertilizer are in progress in Niger, South Africa, Kenya, Ethiopia, Sweden, Switzerland, The Netherlands, Australia, and France.
Eleven years ago, the Institute started a program that collects urine from homes and businesses, transports it for processing, and then supplies it as fertilizer to local farms. By 2021, the program included 180 donors producing over 12,000 gallons of urine each year. This urine is helping to fertilize hay fields at four partnering farms. Orner, the West Virginia professor, sees it as a success story. “They've shown how you can do this right--implementing it at a community level scale."