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.
The U.S. has the highest incarceration rate in the world, costing $182 billion per year, partly because its antiquated data systems often fail to identify people who should be released. A tech nonprofit is trying to change that.
Recidiviz has built a platform that connects the different databases, with the goal of identifying people who are already qualified for release but remain behind bars or on supervision. “Think of Recidiviz like Google Maps,” says Jacoby, who worked on Maps when she was at the tech giant. Google Maps takes in data from different sources – satellite images, street maps, local business data — and organizes it into one easy view. “Recidiviz does something similar with criminal justice data,” Jacoby explains, “making it easy to identify people eligible to come home or to move to less intensive levels of supervision.”
People like Jacoby’s uncle. His experience with incarceration is what inspired her passion for criminal justice reform in the first place.
The problems are vast
The U.S. has the highest incarceration rate in the world — 2 million people according to the watchdog group, Prison Policy Initiative — at a cost of $182 billion a year. The numbers could be a lot lower if not for an array of problems including inaccurate sentencing calculations, flawed algorithms and parole violations laws.
Sentencing miscalculations
To determine eligibility for release, the current system requires corrections officers to check 21 different requirements spread across five different databases for each of the 90 to 100 people under their supervision. These manual calculations are time prohibitive, says Jacoby, and fall victim to human error.
In addition, Recidiviz found that policies aimed at helping to reduce the prison population don’t always work correctly. A key example is time off for good behavior laws that allow inmates to earn one day off for every 30 days of good behavior. Some states' data systems are built to calculate time off as one day per month of good behavior, rather than per day. Over the course of a decade-long sentence, Jacoby says these miscalculations can lead to a huge discrepancy in the calculated release data and the actual release date.
Algorithms
Commercial algorithm-based software systems for risk assessment continue to be widely used in the criminal justice system, even though a 2018 study published in Science Advances exposed their limitations. After the study went viral, it took three years for the Justice Department to issue a report on their own flawed algorithms used to reduce the federal prison population as part of the 2018 First Step Act. The program, it was determined, overestimated the risk of putting inmates of color into early-release programs.
Despite its name, Recidiviz does not build these types of algorithms for predicting recidivism, or whether someone will commit another crime after being released from prison. Rather, Jacoby says the company’s "descriptive analytics” approach is specifically intended to weed out incarceration inequalities and avoid algorithmic pitfalls.
Parole violation laws
Research shows that 350,000 people a year — about a quarter of the total prison population — are sent back not because they’ve committed another crime, but because they’ve broken a specific rule of their probation. “Things that wouldn't send you or I to prison, but would send someone on parole,” such as crossing county lines or being in the presence of alcohol when they shouldn’t be, are inflating the prison population, says Jacoby.
It’s personal for the co-founder and CEO
“I grew up with an uncle who went into the prison system,” Jacoby says. At 19, he was sentenced to ten years in prison for a non-violent crime. A few months after being released from jail, he was sent back for a non-violent parole violation.
“For my family, the fact that one in four prison admissions are driven not by a crime but by someone who's broken a rule on probation and parole was really profound because that happened to my uncle,” Jacoby says. The experience led her to begin studying criminal justice in high school, then college. She continued her dive into how the criminal justice system works as part of her Passion Project while at Google, a program that allows employees to spend 20 percent of their time on pro-bono work. Two colleagues whose family members had also been stuck in the system joined her.
As part of the project, Jacoby interviewed hundreds of people involved in the criminal justice system. “Those on the right, those on the left, agreed that bad data was slowing down reform,” she says. Their research brought them to North Dakota where they began to understand the root of the problem. The corrections department is making “huge, consequential decisions every day [without] … the data,” Jacoby says. In a new video by Recidiviz not yet released, Jacoby recounts her exchange with the state’s director of corrections who told her, “‘It’s not that we have the data and we just don’t know how to make it public; we don’t have the information you think we have.'"
A mock-up (with fake data) of the types of dashboards and insights that Recidiviz provides to state governments.
Recidiviz
As a software engineer, Jacoby says the comment made no sense to her — until she witnessed it first-hand. “We spent a lot of time driving around in cars with corrections directors and parole officers watching them use these incredibly taxing, frankly terrible, old data systems,” Jacoby says.
As they weeded through thousands of files — some computerized, some on paper — they unearthed the consequences of bad data: Hundreds of people in prison well past their release date and thousands more whose release from parole was delayed because of minor paperwork issues. They found individuals stuck in parole because they hadn’t checked one last item off their eligibility list — like simply failing to provide their parole officer with a paystub. And, even when parolees advocated for themselves, the archaic system made it difficult for their parole officers to confirm their eligibility, so they remained in the system. Jacoby and her team also unpacked specific policies that drive racial disparities — such as fines and fees.
The Solution
It’s more than a trivial technical challenge to bring the incomplete, fragmented data onto a 21st century data platform. It takes months for Recidiviz to sift through a state’s information systems to connect databases “with the goal of tracking a person all the way through their journey and find out what’s working for 18- to 25-year-old men, what’s working for new mothers,” explains Jacoby in the video.
TED Talk: How bad data traps people in the U.S. justice system
TED Fellow Clementine Jacoby's TED Talk went live on Jan. 13. It describes how we can fix bad data in the criminal justice system, "bringing thousands of people home, reducing costs and improving public safety along the way."
Clementine Jacoby • TED2022
Ojmarrh Mitchell, an associate professor in the School of Criminology and Criminal Justice at Arizona State University, who is not involved with the company, says what Recidiviz is doing is “remarkable.” His perspective goes beyond academic analysis. In his pre-academic years, Mitchell was a probation officer, working within the framework of the “well known, but invisible” information sharing issues that plague criminal justice departments. The flexibility of Recidiviz’s approach is what makes it especially innovative, he says. “They identify the specific gaps in each jurisdiction and tailor a solution for that jurisdiction.”
On the downside, the process used by Recidiviz is “a bit opaque,” Mitchell says, with few details available on how Recidiviz designs its tools and tracks outcomes. By sharing more information about how its actions lead to progress in a given jurisdiction, Recidiviz could help reformers in other places figure out which programs have the best potential to work well.
The eleven states in which Recidiviz is working include California, Colorado, Maine, Michigan, Missouri, Pennsylvania and Tennessee. And a pilot program launched last year in Idaho, if scaled nationally, with could reduce the number of people in the criminal justice system by a quarter of a million people, Jacoby says. As part of the pilot, rather than relying on manual calculations, Recidiviz is equipping leaders and the probation officers with actionable information with a few clicks of an app that Recidiviz built.
Mitchell is disappointed that there’s even the need for Recidiviz. “This is a problem that government agencies have a responsibility to address,” he says. “But they haven’t.” For one company to come along and fill such a large gap is “remarkable.”
