A simple blood stem cell transplant is showing tremendous promise in treating a wide range of metabolic, blood and immune disorders such as thalassemia and some leukodystrophies.
These are considered rare diseases – meaning there are fewer than 200,000 people with them in the US – so there is often little funding available to develop new therapies to help people suffering from them. So, researchers at UPMC Children’s Hospital of Pittsburgh set out to develop a therapy that could help several different disorders without having to craft individual approaches for each condition.
The team used blood stem cells from donated umbilical cords and placentas. In a news article, study senior author Dr. Paul Szabolcs, said they then used a combination of chemotherapy and immunotherapy to prepare the patients for the transplant and increase the chance of success.
“We approached the topic with the mindset to design a regimen that carefully balances low-intensity chemo (bringing safety) with sufficiently effective immunotherapy to blast away the patients’ immune system, therefore preventing rejection. Rejection has been a common failure when other centers explored the reduced-intensity conditioning (RIC) approach with cord blood. We are the first to prove the RIC is able to give reliable results in long-term engraftment.”
Szabolcs says another advantage to their approach was that it meant there didn’t need to be a perfect immune system match of donor and recipient.
“That’s huge for ethnic minorities. The probability of a perfect match is very low, but with a cord blood graft, we have a chance to overcome this discrepancy over the course of a couple months and then taper immunosuppressants away.”
Altogether 44 children were treated this way. After undergoing the preparation, they had the blood stem cells transfused into them and, once those cells had integrated into the body they got a second, smaller, transfusion a few weeks later to help kick start their immune system.
Most of the complications from the infusions were mild, and while around 5 percent of children died from viral infection due to the immune suppression this was much lower than in earlier studies. Another encouraging sign was that none of the children suffered severe Graft vs Host disease which can be fatal.
Thirty of the children in the trial suffered from metabolic disorders, meaning their bodies were unable to remove dangerous toxins, and this led to developmental delays in their brains. One year after the treatment all 30 children had normal enzyme levels and their neurological decline had stopped. Some of the children even showed improvements and gained new skills.
Most of the children with metabolic disorders had leukodystrophies. These are usually fatal within a few years of diagnosis. Even with a cord blood transplant the three-year survival rate is only 60 percent. In this trial more than 90 percent of children with leukodystrophies were alive after three years.
Dr. Szabolcs says this approach has a lot of advantages over existing approaches, including cost.
“There has been a lot of emphasis placed on cool new technologies that might address these diseases, but — even if they prove effective — those aren’t available to most centers. The regimen we developed is more robust, readily applicable and will remain significantly less expensive.”
Frances Saldana is one of the most remarkable women I know. She has lost all three of her children to Huntington’s disease (HD) – a nasty, fatal disease that steadily destroys the nerve cells in the brain – but still retains a fighting spirit and a commitment to finding a cure for HD. She is the President Emeritus for HD-Care, an organization dedicated to raising awareness about HD, and finding money for research to cure it. She recently wrote a Mother’s Day blog for HD-Care about the similarities between HD and COVID-19. As May is National Huntington’s Disease Awareness Month we wanted to share her blog with you.
COVID-19 has consumed our entire lives, and for many, our livelihoods. This is a pandemic like we have never experienced in our lifetime, bringing out in many families fear, financial devastation, disabilities, isolation, suffering, and worst of all, loss of life. But through all this, the pandemic has uncovered emotions in many who rose to the occasion – a fight and stamina beyond human belief.
As a family member who has lost all of my children to Huntington’s disease, it makes me so sad to watch and hear about the suffering that people all over the world are currently experiencing with COVID-19. This devastation is nothing new to Huntington’s disease families. Although Huntington’s disease (HD) is not contagious, it is genetic, and much of the uncertainty and fears that families are experiencing are so similar to what HD families experience….in slow motion, with unanswered questions such as:
Who in my family is carrying the mutant HD gene? (Who in my family is carrying the coronavirus?)
Who in my family will inherit the mutant HD gene? (Who will get infected by the COVID-19?)
Will my loved on live long enough to benefit from a treatment for HD? (Will there be a vaccination soon if my loved one is infected by COVID-19?)
How long will my HD family member live? (Will my affected COVID-19 loved one survive after being placed on a ventilator?)
Is my HD family member going to die? (Will my COVID-19 family member die?)
In watching some of the footage of COVID-19 patients on TV and learning about the symptoms, it appears that those with a severe case of the virus go through similar symptoms as HD patients who are in the late and end-of-life stages: pneumonia, sepsis, pain, and suffering, to name a few, although for HD families, the journey goes on for years or even decades, and then carries on to the next generation, and not one HD patient will survive the disease. Not yet!
Scientists are working furiously all over the world to find a treatment for COVID-19. The same goes for scientists focused on Huntington’s disease research. Without their brilliant work we would have no hope. Without funding there would be no science. I have been saying for the last 20 years that we will have a treatment for Huntington’s disease in the next couple of years, but with actual facts and successful clinical trials, there is finally a light at the end of the tunnel and we have much to be thankful for. I feel it in my heart that a treatment will be found for both COVID-19 and Huntington’s disease very soon.
The month of May happens to be National Huntington’s Disease Awareness Month. Mother’s Day also falls in the month of May. Huntington’s disease “Warrior Moms” are exemplary women, and I have been blessed to have known a few. Driven by love for their children, they’ve worn many hats as caregivers, volunteers, and HD community leaders in organizations such as HD-CARE, HDSA, WeHaveAFace, Help4HD, HD Support &Care Network, and many others.
The mothers have often also been forced to take on the role of breadwinners when the father of the family has unexpectedly become debilitated from HD. In spite of carrying a heavy cross, HD Warrior Moms persevere, and they do it with endless love, often taking care of HD family members from one generation to the next. They are the front-line workers in the HD community, tirelessly protecting their families and at the same time doing all they can to provide a meaningful quality of life.
Many HD Warrior moms have lost their children in spite of their fierce fight to save them, but they keep their memory alive, never losing hope for a treatment that will end the pain, suffering, and loss of life. Many HD Warrior Moms have lost the fight themselves, not from HD, but from a broken heart. These are the HD Warrior Moms.
When you have worked with a group of people over many years the relationship becomes more than just a business venture, it becomes personal. That’s certainly the case with jCyte, a company founded by Drs. Henry Klassen and Jing Yang, aimed at finding a cure for a rare form of vision loss called retinitis pigmentosa. CIRM has been supporting this work since it’s early days and so on Friday, the news that jCyte has entered into a partnership with global ophthalmology company Santen was definitely a cause for celebration.
The partnership could be worth up to $252 million and includes an immediate payment of $62 million. The agreement also connects jCyte to Santen’s global business and medical network, something that could prove invaluable in bringing their jCell therapy to patients outside the US.
Here in the US, jCyte is getting ready to start a Phase 2 clinical trial – which CIRM is funding – that could prove pivotal in helping it get approval from the US Food and Drug Administration.
As Dr. Maria Millan, CIRM’s President and CEO says, we have been fortunate to watch this company steadily progress from having a promising idea to developing a life-changing therapy.
“This is exciting news for everyone at jCyte. They have worked so hard over many years to develop their therapy and this partnership is a reflection of just how much they have achieved. For us at CIRM it’s particularly encouraging. We have supported this work from its early stages through clinical trials. The people who have benefited from the therapy, people like Rosie Barrero, are not just patients to us, they have become friends. The people who run the company, Dr. Henry Klassen, Dr. Jing Yang and CEO Paul Bresge, are so committed and so passionate about their work that they have overcome many obstacles to bring them here, an RMAT designation from the Food and Drug Administration, and a deal that will help them advance their work even further and faster. That is what CIRM is about, following the science and the mission.”
Paul Bresge, jCyte’s CEO says they couldn’t have done it without CIRM’s early and continued investment.
“jCyte is extremely grateful to CIRM, which was established to support innovative regenerative medicine programs and research such as ours. CIRM supported our early preclinical data all the way through our late stage clinical trials. This critical funding gave us the unique ability and flexibility to put patients first in each and every decision that we made along the way. In addition to the funding, the guidance that we have received from the CIRM team has been invaluable. jCell would not be possible without the early support from CIRM, our team at jCyte, and patients with degenerative retinal diseases are extremely appreciative for your support.”
Here is Rosie Barrero talking about the impact jCell has had on her life and the life of her family.
Like many kids, let’s face it, many adults too, Ronav “Ronnie” Kashyap is getting a little bored stuck inside all day during the coronavirus pandemic. This video, shot by his dad Pawash, shows Ronnie trying to amuse himself by pretending to be hard at work.
In Ronnie’s case he was rushed to UC San Francisco shortly after his birth when a newborn screening test showed he had SCID. He spent the next several months there, in isolation with his parents, preparing for the test. Doctors took his own blood stem cells and, in the lab, corrected the genetic mutation that causes SCID. The cells were then re-infused into Ronnie where they created a new blood supply and repaired his immune system.
How good is his immune system today? Last year his parents, Upasana and Pawash, were concerned about taking Ronnie to a crowded shopping mall for fear he might catch a cold. Their doctor reassured them that he would be fine. So, they went. The doctor was right, Ronnie was fine. However, Upasana and Pawash both caught colds!
Just a few weeks ago Ronnie started pre-school. He loves it. He loves having other kids to play with and his parents love it because it helps him burn off some energy. But they also love it because it showed Ronnie is now leading a normal life, one where they don’t have to worry about everything he does, every person he comes into contact with.
Sounds a bit like how the rest of us are living right now doesn’t it. And the fears that Ronnie’s parents had, that even a casual contact with a friend, a family member or stranger, might prove life-threatening, are ones many of us are experiencing now.
When Ronnie was born he faced long odds. At the time there were only a handful of scientists working to find treatments for SCID. But they succeeded. Now, Ronnie, and all the other children who have been helped by this therapy are living proof that good science can overcome daunting odds to find treatments, and even cures, for the most life-threatening of conditions.
Today there are thousands, probably tens of thousands of scientists around the world searching for treatments and cures for COVID-19. And they will succeed.
Till then the rest of us will have to be like Ronnie. Stay at home, stay safe, and enjoy the luxury of being bored.
Orphan drug designation is a special status given by the Food and Drug Administration (FDA) for potential treatments of rare diseases that affect fewer than 200,000 in the U.S. This type of status can significantly help advance treatments for rare diseases by providing financial incentives in the form of tax credits towards the cost of clinical trials and prescription drug user fee waivers.
Fortunately for us, a stem cell-gene therapy approach used in a CIRM-funded clinical trial for Cystinosis has just received orphan drug designation. The trial is being conducted by Dr. Stephanie Cherqui at UC San Diego, which is an academic collaborator for AVROBIO, Inc.
Cystinosis is a rare disease that primarily affects children and young adults, and leads to premature death, usually in early adulthood. Patients inherit defective copies of a gene called CTNS, which results in abnormal accumulation of an amino acid called cystine in all cells of the body. This buildup of cystine can lead to multi-organ failure, with some of earliest and most pronounced effects on the kidneys, eyes, thyroid, muscle, and pancreas. Many patients suffer end-stage kidney failure and severe vision defects in childhood, and as they get older, they are at increased risk for heart disease, diabetes, bone defects, and neuromuscular defects.
Dr. Cherqui’s clinical trial uses a gene therapy approach to modify a patient’s own blood stem cells with a functional version of the defective CTNS gene. The goal of this treatment is to reintroduce the corrected stem cells into the patient to give rise to blood cells that will reduce cystine buildup in affected tissues.
In an earlier blog, we shared a story by UCSD news that featured Jordan Janz, the first patient to participate in this trial, as well as the challenges promising approaches like this one face in terms of getting financial support. Our hope is that in addition to the funding we have provided, this special designation gives additional support to what appears to be a very promising treatment for a very rare disease.
You can read the official press release from AVROBIO, Inc. related to the orphan drug designation status here.
Each year, around 24,000 women in the US lose a pregnancy. One reason for this unfortunate occurrence are metabolic disorders, one of which is known as Sly syndrome and is caused by a single genetic mutation. In Sly syndrome, the body’s cells lack an enzyme necessary for proper cell function. Many fetuses with this condition die before birth but those that survive are treated with regular injections of the lacking enzyme. Unfortunately, patients can eventually develop an immune response to these injections and it cannot enter the brain after birth.
However, a team of researchers at UCSF are looking at exploring a potential treatment that could be delivered in-utero. In a CIRM supported study, Dr. Tippi Mackenzie and Dr. Quoc-Hung Nguyen transplanted blood-forming stem cells from normal mice into fetal mice carrying the genetic mutation for Sly syndrome. The researchers were most interested to see whether these cells could reach the brain, and whether they would change into cells called microglia, immune cells that originate from blood-forming stem cells. In a normally developing fetus, once matured, microglia produce and store the necessary enzyme, as well as regulate the immune environment of the brain.
The researchers found that the stem cells were able to engraft in the brain, liver, kidney, and other organs. Furthermore, these stem cells were able to eventually turn into the appropriate cell type needed to produce the enzyme in each of the organs.
In a press release, Dr. Mackenzie talks about the impact that this potential treatment could have.
“This group of vulnerable patients has been relatively ignored in the fetal surgery world. We know these patients could potentially benefit from a number of medical therapies. So this is our first foray into treating one of those diseases.”
In the same press release, Dr. Nguyen talks about the impact of the results from this study.
“These exciting findings are just the tip of the iceberg. They open up a whole new approach to treating a range of diseases. At the same time, there’s also a lot of work to do to optimize the treatment for humans.”
The next step for Dr. Mackenzie is to apply to the U.S. Food and Drug Administration to launch a clinical trial of enzyme replacement therapy that will ultimately enroll patients with Sly syndrome and related metabolic disorders.
This approach is similar to a CIRM funded trial conducted by Dr. Mackenzie that involves a blood stem cell transplant in utero.
The full results to this study were published in Science Translational Medicine.
This past Thursday the governing Board of the California Institute for Regenerative Medicine (CIRM) were presented with an update on CIRM’s clinical portfolio, which to date includes 60 clinical trials in various areas including kidney failure, cancer, and other rare diseases. The full President’s Report gives an update on 15 of these trials, in addition to our landmark Cure Sickle Cell Initiative with the NIH and our various educational programs.
Although we won’t be diving into extensive detail for all of these trials, we wanted to highlight several key updates made in this presentation to demonstrate how our clinical portfolio is maturing, with many of these trials moving towards registration. Classically, registration trials are large Phase 3 trials. Notably, some of the highlighted CIRM trials are small Phase 2 or earlier trials that seek to gain enough safety and efficacy data to support final FDA marketing approval. This is a trend with regenerative medicine programs where trial sizes are often small due to the fact that the affected populations are so small with some of these rare diseases. Despite this, the approaches could allow a so called “large effect size,” meaning the signal of clinical benefit per patient is strong enough to give a read of whether the therapy is working or not. CIRM programs often address rare unmet needs and utilize this approach.
For example, Orchard Therapeutics, which is conducting a phase 2 clinical trial for ADA Severe Combined Immunodeficiency (ADA-SCID), a rare immune disorder caused by a genetic mutation, has shown a long-term recovery of the immune system in 20 patients two years post treatment. Orchard plans to submit a Biologics License Application (BLA) sometime in 2020, which is the key step necessary to obtain final approval from the Food and Drug Administration (FDA) for a therapy.
“We are thrilled to see encouraging results for this genetically modified cell therapy approach and a path forward for FDA approval,” says Maria T. Millan, MD, President and CEO of CIRM. “CIRM is proud of the role it has played in this program. We funded the program while it was at UCLA and it is now in partnership with Orchard Therapeutics as it takes the program through this final phase toward FDA marketing approval. Success in this program is a game changer for patients with ADA-SCID who had no other options and who had no bone marrow transplant donors. It also opens up possibilities for future approaches for this dieaseas as well as the other 6,000 genetic diseases that currently have no treatment.”
The trial uses a gene therapy approach that takes the patient’s own blood stem cells, introduces a functional version of the ADA gene, and reintroduces these corrected blood stem cells back into the patient. From blood tests, one can readily detect whether the approach is successful from the presence of ADA and from the presence of immune cells that were not previously present. To date, it has been awarded approximately $19 million in CIRM funding. Additionally, it has received FDA Breakthrough Therapy as well as Orphan Drug Designations, both of which are designed to accelerate the development of the treatment.
Another trial that was highlighted is Rocket Pharmaceutical’s clinical trial for Leukocyte Adhesion Deficiency-1 (LAD-1), a rare and fatal pediatric disease that affects the body’s ability to combat infections. They have just released initial results from their first patient. This is also a gene therapy approach using the patient’s own blood stem cells. The notable aspect of this trial is that the investigators designed this small phase 1 trial of nine patients to be “registration enabling.” This means that, if they find compelling data, they intend to bring the experience and data from this trial to the FDA to seek agreement on what would be required to get final marketing approval in order to get this treatment to patients with severe unmet medical needs in the most timely way possible.
Preliminary results demonstrate early evidence of safety and potential efficacy. There were visible improvements in multiple disease-related skin lesions after receiving the therapy. They are collecting more data on more patients. To date, it has received $6.6 million in CIRM funding.
As a unique immuno-oncology approach (using the body’s immune system to battle cancer), CIRM is funding Forty Seven Inc. to conduct a clinical trial for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), both of which are forms of cancer. They have received Fast Track and Orphan Drug designation from the FDA.
The trial is using an antibody blocking CD47, a “don’t eat me” signal, which allows the body’s own immune cells to seek and destroy cancerous stem cells. This is combined with chemotherapy to render the cancer stem cells more susceptible to immune destruction. This trial has received $5 million in CIRM funding thus far.
Other registration phase trials in the CIRM portfolio include the following Phase 3 trials:
Brainstorm Cell Therapeutics, for a fatal debilitating neurodegenerative disease, Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease). That company has completed enrollment and expects top line results in the final quarter of 2020.
Humacyte, which is testing bioengineered de-cellularized vessels that are implanted to create vascular access that is repopulated by the patients own stem cells to make it more like native vessel. The company is conducting two Phase 3 trials to compare this bioengineered vessel to synthetic grafts and to the patients’ own vessels for use in hemodialysis, a “life line” for patients with end stage renal disease. Humacyte was the first US FDA Cell Therapy program to receive the Regenerative Medicine Advanced Technologies (RMAT) in March 2017. To date, these trials have been awarded $24 million in CIRM funding.
Medeor Therapeutics has received $11.2M in CIRM funding to conduct a Phase 3 trial in combined blood stem cell and kidney transplantation to induce immunologic tolerance so that the blood stem cells teach the patient’s immune system to recognize the transplanted kidney as its own. The goal is to remove the need for chronic immunosuppressive medications, that have its own complications. If successful, transplant recipients would not need to “trade one chronic condition for another.”
CIRM funds a lot of research and all of it has life-saving potential. But every once in a while you come across a story about someone benefiting from CIRM-supported research that highlights why the work we do is so important. This story is about a brilliant researcher at UC San Diego developing a treatment for a really rare disease, one that was unlikely to get funding from a big pharmaceutical company because it offered little chance for a return on its investment. At CIRM we don’t have to worry about things like that. Stories like this are our return on investment.
Our thanks to our colleagues at UCSD News for allowing us to run this piece in full.
By Heather Buschman, PhD
Born with a rare disease called cystinosis, 20-year-old Jordan Janz arrived at a crossroads: continue life as-is, toward a future most likely leading to kidney failure and an early death or become the first patient in the world to undergo a new gene-and-stem cell therapy developed over more than a decade by UC San Diego School of Medicine researchers
For the majority of Jordan Janz’s 20 years of life, most neighbors in his tiny Canadian town never knew he was sick. Janz snowboarded, hunted and fished. He hung with friends, often playing ice hockey video games. He worked in shipping and receiving for a company that makes oil pumps.
But there were times when Janz was younger that he vomited up to 13 times each day. He received a growth hormone injection every day for six years. He needed to swallow 56 pills every day just to manage his symptoms. And the medication required around-the-clock administration, which meant his mother or another family member had to get up with him every night.
“I was tired for school every day,” Janz said. “I was held back in second grade because I missed so much school. And because the medication had a bad odor to it, when I did go to school kids would ask, ‘What’s that smell?’ It was hard.”
Janz was born with cystinosis, a rare metabolic disorder that’s detected in approximately one in 100,000 live births worldwide. People with cystinosis inherit a mutation in the gene that encodes a protein called cystinosin. Cystinosin normally helps cells transport the amino acid cystine. Because cells in people with cystinosis don’t produce the cystinosin protein, cystine accumulates. Over the years, cystine crystals build up and begin to damage tissues and organs, from the kidneys and liver to muscles, eyes and brain. Numerous symptoms and adverse consequences result.
These days, Janz manages his condition. There’s a time-release version of the symptom-relieving medication now that allows him to go 12 hours between doses, allowing for a good night’s sleep. But there’s no stopping the relentless accumulation of cystine crystals, no cure for cystinosis.
In October 2019, Janz became the first patient to receive treatment as part of a Phase I/II clinical trial to test the safety and efficacy of a unique gene therapy approach to treating cystinosis. The treatment was developed over more than a decade of research by Stephanie Cherqui, PhD, associate professor of pediatrics, and her team at University of California San Diego School of Medicine.
“The day they started looking for people for the trial, my mom picked up the phone, found a number for Dr. Cherqui, called her and put my name in as a candidate,” Janz said.
Janz’s mom, Barb Kulyk, has long followed Cherqui’s work. Like many parents of children with cystinosis, Kulyk has attended conferences, read up on research and met many other families, doctors and scientists working on the condition. Kulyk says she trusts Cherqui completely. But she was understandably nervous for her son to be the first person ever to undergo a completely new therapy.
“It’s like giving birth,” she said shortly before Janz received his gene therapy. “You’re really looking forward to the outcome, but dreading the process.”
Cherqui’s gene therapy approach involves genetical modifying the patient’s own stem cells. To do this, her team obtained hematopoietic stem cells from Janz’s bone marrow. These stem cells are the precursors to all blood cells, including both red blood cells and immune cells. The scientists then re-engineered Janz’s stem cells in a lab using gene therapy techniques to introduce a normal version of the cystinosin gene. Lastly, they reinfused Janz with his own now-cystinosin-producing cells. The approach is akin to a bone marrow transplant — the patient is both donor and recipient.
“A bone marrow transplant can be very risky, especially when you take hematopoietic stem cells from a another person. In that case, there’s always the chance the donor’s immune cells will attack the recipient’s organs, so-called graft-versus-host disease,” Cherqui explained. “It’s a great advantage to use the patient’s own stem cells.”
As is the case for other bone marrow transplants, Janz’s gene-modified stem cells are expected to embed themselves in his bone marrow, where they should divide and differentiate to all types of blood cells. Those cells are then expected to circulate throughout his body and embed in his tissues and organs, where they should produce the normal cystinosin protein. Based on Cherqui’s preclinical data, she expects the cystinosin protein will be transferred to the surrounding diseased cells. At that point, Janz’s cells should finally be able to appropriately transport cystine for disposal — potentially alleviating his symptoms.
Before receiving his modified stem cells, Janz had to undergo chemotherapy to make space in his bone marrow for the new cells. Not unexpectedly, Janz experienced a handful of temporary chemotherapy-associated side-effects, including immune suppression, hair loss and fatigue. He also had mucositis, an inflammation of mucous membranes lining the digestive tract, which meant he couldn’t talk or eat much for a few days.
Now, only three months after his transfusion of engineered stem cells, Cherqui reports that Janz is making a good recovery, though it’s still too early to see a decrease in his cystinosis-related symptoms.
“I’ve been sleeping at least 10 hours a day for the last few weeks,” Janz said. “It’s crazy, but I know my body is just working hard to, I guess, create a new ‘me.’ So it’s no wonder I’m tired. But I’m feeling okay overall.
“One of the hardest parts for me is being inactive for so long. I’m not used to doing nothing all day. But I’m taking an online course while I wait for my immune system to rebuild. And I’m getting pretty good at video games.”
Like all Phase I/II clinical trials, the current study is designed to first test the safety and tolerability of the new treatment. Janz knows the treatment might not necessarily help him.
“When we started this trial, my mom explained it like this: ‘We have a tornado at the front door and a tsunami at the back door, and we have to pick one to go through. Neither will be any fun and we don’t know what’s going to happen, but you have to believe you will make it and go.
“So we weighed the pros and cons and, basically, if I don’t do this trial now, when I’m older I might not be healthy and strong enough for it. So I decided to go for it because, even if there are consequences from the chemotherapy, if it works I could live 20 years longer than I’m supposed to and be healthy for the rest of my life. That’s worth it.”
Besides the possible benefit to himself, Janz also sees his participation in the clinical trial as a way to contribute to the tight-knit community of families with children who have cystinosis.
“I’m willing to do if it helps the kids,” he said. “Somebody has to do it. I don’t have the money to donate to scientific conferences and stuff like that, but I can do this trial.”
If the treatment continues to meet certain criteria for safety and efficacy for Janz and one other participant after three months, two more adult participants will be enrolled. Three months after that, if the treatment continues to be safe and effective, the trial might enroll two adolescent participants. To participate in the clinical trial, individuals must meet specific eligibility requirements.
Later in the trial, Cherqui and team will begin measuring how well the treatment actually works. The specific objectives include assessing the degree to which gene-modified stem cells establish themselves in bone marrow, how they affect cystine levels and cystine crystal counts in blood and tissues.
“This trial is the first to use gene-modified hematopoietic stem cell gene therapy to treat a multi-organ degenerative disorder for which the protein is anchored in the membrane of the lysosomes, as opposed to secreted enzymes,” Cherqui said. “We were amazed when we tested this approach in the mouse model of cystinosis — autologous stem cell transplantation reversed the disease. The tissues remained healthy, even the kidneys and the eyes.”
Trial participants are closely monitored for the first 100 days after treatment, then tested again at six, nine, 12, 18 and 24 months post-gene therapy for a variety of factors, including vital signs, cystine levels in a number of organs, kidney function, hormone function and physical well-being.
“If successful in clinical trials, this approach could provide a one-time, lifelong therapy that may prevent the need for kidney transplantation and long-term complications caused by cystine buildup,” Cherqui said.
For the trial participants, all of the pre-treatment tests, the treatment itself, and monitoring afterward means a lot of travel to and long stays in San Diego.
It’s tough on Kulyk and Janz. They have to fly in from Alberta, Canada and stay in a San Diego hotel for weeks at a time. Kulyk has two older adult children, as well as a 12-year-old and a seven-year-old at home.
“I’ve missed a lot of things with my other kids, but none of them seem to hold any grudges,” she said. “They seem to be totally fine and accepting. They’re like, ‘We’re fine, mom. You go and take care of Jordan.’”
Janz is looking forward to getting back home to his friends, his dog and his job, which provided him with paid leave while he received treatment and recovers.
For Cherqui, the search for a cystinosis cure is more than just a scientific exercise. Cherqui began working on cystinosis as a graduate student more than 20 years ago. At the time, she said, it was simply a model in which to study genetics and gene therapy.
“When you read about cystinosis, it’s just words. You don’t put a face to it. But after I met all the families, met the kids, and now that I’ve seen many of them grow up, and some of them die of the disease — now it’s a personal fight, and they are my family too.”
Patients with cystinosis typically experience kidney failure in their 20s, requiring kidney dialysis or transplantation for survival. For those born with cystinosis who make it into adulthood, the average lifespan is approximately 28 years old.
“I’m optimistic about this trial because it’s something we’ve worked so hard for and now it’s actually happening, and these families have so much hope for a better treatment,” Cherqui said. “After all the years of painstaking laboratory research, we now need to move into the clinic. If this works, it will be wonderful. If it doesn’t, we will all be disappointed but a least we’ll be able to say we tried.”
Nancy Stack, who founded the Cystinosis Research Foundation after her own daughter, Natalie, was diagnosed with the disease, calls Cherqui “the rock star of our community.”
“She cares deeply about the patients and is always available to talk, to explain her work and to give us hope,” Stack said. “She said years ago that she would never give up until she found the cure — and now we are closer to a cure than ever before.” (Read more about Natalie here.)
In addition to cystinosis, Cherqui says this type of gene therapy approach could also lead to treatment advancements for other multi-organ degenerative disorders, such as Friedreich’s ataxia and Danon disease, as well as other kidney, genetic and systemic diseases similar to cystinosis.
While they wait for the long-term results of the treatment, Kulyk is cautiously hopeful.
“Moms are used to being able to fix everything for their children — kiss boo-boos make them better, make cupcakes for school, whip up Halloween costumes out of scraps, pull a coveted toy out of thin air when it has been sold out for months.
“But we have not been able to fix this, to take it away. I not only want this disease gone for my child, I want cystinosis to be nothing more than a memory for all the children and adults living with it. I know that even if and when Jordan is cured, there will still be so much work to do, in terms of regulatory approvals and insurance coverage.
“Having hope for your child’s disease to be cured is a slippery slope. We have all been there, held hope in our hands and had to let go. But, I find myself in a familiar place, holding onto hope again and this time I am not letting go.”
For more information about the Phase I/II clinical trial for cystinosis and to learn how to enroll, call 1-844-317-7836 or email firstname.lastname@example.org.
Cherqui’s research has been funded by the Cystinosis Research Foundation, California Institute for Regenerative Medicine (CIRM), and National Institutes of Health. She receives additional support from the Sanford Stem Cell Clinical Center and CIRM-funded Alpha Stem Cell Clinic at UC San Diego Health, and AVROBIO.
A few years ago, Brenden Whittaker was running out of time. Brenden was born with a rare condition called x-linked chronic granulomatous disease or XCGD. It meant he lacked a critical part of his immune system that protects against bacterial or fungal infections.
Over 22 years Brenden was in and out of the hospital hundreds of times. Twice he almost died. When antibiotics failed to clear up persistent infections surgeons had to remove parts of his lungs and liver.
Brenden felt he was running out of options. Then he signed up for a clinical trial (funded by CIRM) that would use his own stem cells to correct the problem. More than four years later Brenden is doing just fine.
And he’s not the only one. A new study, published in the journal Nature Medicine, shows that six other patients in the clinical trial are now in remission and have stopped taking any other medications.
Don Kohn, the lead researcher on the team from UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, says that in the past the only “cure” for people with CGD was a bone marrow transplant, but that was rarely an option for most patients. In a news release he said finding a perfect match for a transplant was difficult, and even then, patients had to take powerful anti-rejection medications to stop their body rejecting the transplant. So, they developed another approach, using genetically re-engineered stem cells from the patient themselves.
“With this gene therapy, you can use a patient’s own stem cells instead of donor cells for a transplant. This means the cells are perfectly matched to the patient and it should be a much safer transplant, without the risks of rejection.”
The team removed blood stem cells from the patients and, in the lab, corrected the genetic mutation that caused CGD. They then returned those cells to the patients which, because they are stem cells, multiplied and created a new blood supply – one free of CGD – and repaired the immune system.
Brenden was the first of five patients treated in the US. Another four were treated in Europe. All were between the ages of 2 and 27 (CGD patients often die in their 20’s because of the impact of repeated infections).
Two patients died because of previously incurred infections
Six of the seven surviving patients have discontinued previous treatments
Four new patients have since been treated and are currently free of infections
Dr. Kohn said the results are really encouraging: “None of the patients had complications that you might normally see from donor cells and the results were as good as you’d get from a donor transplant — or better.”
The next step is for the researchers to work with the US Food and Drug Administration to get permission to carry out a larger trial, with the eventual goal of getting approval to make it available to all patients who need it.
Regular readers of our blog will remember that Don Kohn also pioneered a similar approach in treating, and curing, children battling another rare immune disorder, severe combined immunodeficiency or SCID. You can read about that here.
As for Brenden, he is now in college and has his sights set on medical school. In 2016 we profiled him in our Annual Report and ran a long interview with him on the blog where he talked about the joys of mowing the lawn and learning to live without a deadly disease stalking him.
The briefing is a traditional kick-off event to mark JP Morgan week in the City, a time when hotel rooms go for $1,000 a night and just reserving a table in the lobby for meetings can set you back hundreds of dollars. Fortunately, the ARM briefing is free. And worth every penny.
987 companies world wide – most of those in the US
1,000 + clinical trials
$9.8 billion in revenue/investments
Saying “for many of these patients these therapies don’t just bring improvements, they bring dramatic improvements” Lambert pointed out that when those 1,000 clinical trials are fully enrolled it will mean 60,000 patients getting stem cell and gene therapies. She says it’s estimated that in the coming years around half a million patients in the US alone will get one of those therapies.
More and more of the clinical trials are at advanced stages:
100 Phase 3
591 Phase 2
381 Phase 1
The biggest sector for clinical trials is cancer, but there are also substantial numbers for central nervous system therapies, muscular skeletal and even rare diseases.
Lambert said there are two key issues facing the field in the coming year. One is improving the industry’s manufacturing capability to ensure we are able to produce the cells needed to treat large numbers of patients. As evidence she cited the fact that Pfizer and Novartis are investing hundreds of millions of dollars in in-house manufacturing facilities.
The second key issue is reimbursement, so that companies can get paid for delivering those treatments to patients. “There is appetite and interest in this from people around the world, but right now most conversations about reimbursement are taking place one at a time. We haven’t yet evolved to the point where we have standard models to help get products to market and help them be commercially successful.”
The forecast for the year ahead? “Sunny with some clouds. 2019 was a year of significant growth and we enter 2020 with hopes of continued expansion, as we look to grow the impact on patients.”