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.
Silkworm silk is fragile, which limits its uses, but a few extra genes can help.
Today, biomimetics is everywhere. Shark-inspired swimming trunks, gecko-inspired adhesives, and lotus-inspired water-repellents are all taken from observing the natural world. After millions of years of evolution, nature has quite a few tricks up its sleeve. They are tricks we can learn from. And now, thanks to some spider DNA and clever genetic engineering, we have another one to add to the list.
The elusive spider silk
We’ve known for a long time that spider silk is remarkable, in ways that synthetic fibers can’t emulate. Nylon is incredibly strong (it can support a lot of force), and Kevlar is incredibly tough (it can absorb a lot of force). But neither is both strong and tough. In all artificial polymeric fibers, strength and toughness are mutually exclusive, and so we pick the material best for the job and make do.
Spider silk, a natural polymeric fiber, breaks this rule. It is somehow both strong and tough. No surprise, then, that spider silk is a source of much study.The problem, though, is that spiders are incredibly hard to cultivate — let alone farm. If you put them together, they will attack and kill each other until only one or a few survive. If you put 100 spiders in an enclosed space, they will go about an aggressive, arachnocidal Hunger Games. You need to give each its own space and boundaries, and a spider hotel is hard and costly. Silkworms, on the other hand, are peaceful and productive. They’ll hang around all day to make the silk that has been used in textiles for centuries. But silkworm silk is fragile. It has very limited use.
The elusive – and lucrative – trick, then, would be to genetically engineer a silkworm to produce spider-quality silk. So far, efforts have been fruitless. That is, until now.
We can have silkworms creating silk six times as tough as Kevlar and ten times as strong as nylon.
Spider-silkworms
Junpeng Mi and his colleagues working at Donghua University, China, used CRISPR gene-editing technology to recode the silk-creating properties of a silkworm. First, they took genes from Araneus ventricosus, an East Asian orb-weaving spider known for its strong silk. Then they placed these complex genes – genes that involve more than 100 amino acids – into silkworm egg cells. (This description fails to capture how time-consuming, technical, and laborious this was; it’s a procedure that requires hundreds of thousands of microinjections.)
This had all been done before, and this had failed before. Where Mi and his team succeeded was using a concept called “localization.” Localization involves narrowing in on a very specific location in a genome. For this experiment, the team from Donghua University developed a “minimal basic structure model” of silkworm silk, which guided the genetic modifications. They wanted to make sure they had the exactly right transgenic spider silk proteins. Mi said that combining localization with this basic structure model “represents a significant departure from previous research.” And, judging only from the results, he might be right. Their “fibers exhibited impressive tensile strength (1,299 MPa) and toughness (319 MJ/m3), surpassing Kevlar’s toughness 6-fold.”
A world of super-materials
Mi’s research represents the bursting of a barrier. It opens up hugely important avenues for future biomimetic materials. As Mi puts it, “This groundbreaking achievement effectively resolves the scientific, technical, and engineering challenges that have hindered the commercialization of spider silk, positioning it as a viable alternative to commercially synthesized fibers like nylon and contributing to the advancement of ecological civilization.”
Around 60 percent of our clothing is made from synthetic fibers like nylon, polyester, and acrylic. These plastics are useful, but often bad for the environment. They shed into our waterways and sometimes damage wildlife. The production of these fibers is a source of greenhouse gas emissions. Now, we have a “sustainable, eco-friendly high-strength and ultra-tough alternative.” We can have silkworms creating silk six times as tough as Kevlar and ten times as strong as nylon.
We shouldn’t get carried away. This isn’t going to transform the textiles industry overnight. Gene-edited silkworms are still only going to produce a comparatively small amount of silk – even if farmed in the millions. But, as Mi himself concedes, this is only the beginning. If Mi’s localization and structure-model techniques are as remarkable as they seem, then this opens up the door to a great many supermaterials.
Nature continues to inspire. We had the bird, the gecko, and the shark. Now we have the spider-silkworm. What new secrets will we unravel in the future? And in what exciting ways will it change the world?
This article originally appeared on Freethink, home of the brightest minds and biggest ideas of all time.
