An experimental gene therapy with a hairy twist

In October 2019, 20-year-old Jordan Janz became the first person in the world to receive an experimental therapy for cystinosis. Cystinosis is a rare genetic disorder characterized by the accumulation of an amino acid called cystine in different tissues and organs of the body including the kidneys, eyes, muscles, liver, pancreas, and brain. This accumulation of cystine ultimately leads to multi-organ failure, eventually causing premature death in early adulthood. On average, cystinosis patients live to 28.5 years old. By that calculation, Janz didn’t have a lot of time.

The treatment was grueling but worth it. The experimental gene therapy funded by the California Institute for Regenerative Medicine seemed to work and Janz began to feel better. There was, however, an unexpected change. Janz’s almost white, blonde hair had settled into a darker tone. Of all the things the gene therapy was expected to alter such as the severity of his cystinosis symptoms hair color was not one of them. Eventually, the same phenomenon played out in other people: So far in the gene-therapy trial, four of the five patients all of whom are white have gotten darker hair.

The outcome, while surprising to researchers, didn’t seem to be a sign of something going awry, instead they determined that it might be a very visible sign of the gene therapy working.

The sudden hair-color changes were surprising to Stephanie Cherqui, a stem-cell scientist at UC San Diego and the principal investigator of the gene-therapy trial. However, it didn’t seem to be a sign of something going awry, instead Cherqui and her colleagues determined that it might be a very visible sign of the gene therapy working.

But exactly how did genetically modifying Janz’s (and other participants’) blood cells change his hair color? In this instance, scientists chose to genetically tweak blood stem cells because they have a special ability: Some eventually become white blood cells, which then travel to all different parts of the body.

Janz’s new white blood cells were genetically modified to express the gene that is mutated in cystinosis, called CTNS. Once they traveled to his eyes, skin, and gut, the white blood cells began pumping out the missing protein encoded by the gene. Cells in the area began taking up the protein and clearing away long accumulated cystine crystals. In Janz, the anti-cystine proteins from his modified blood cells must have reached the hair follicles in his skin. There, they cleared out the excess cystine that was blocking normal melanin production, and his hair got darker.

Hair color is one way in which patients in the clinical trial are teaching scientists about the full scope of the CTNS gene. The investigators have since added hair biopsies to the trial in order to track the color changes in a more systematic fashion.

Read the full article on The Atlantic.

Creating a ‘bespoke’ approach to rare diseases

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Up until recently the word “bespoke” meant just one thing to me, a hand-made suit, customized and fitted to you. There’s a street in London, Saville Row, that specializes in these suits. They’re gorgeous. They’re also very expensive and so I thought I’d never have a bespoke anything.

I was wrong. Because CIRM is now part of a bespoke arrangement. It has nothing to do with suits, it’s far more important than that. This bespoke group is aiming to create tailor-made gene therapies for rare diseases.

It’s called the Bespoke Gene Therapy Consortium (BGTC). Before we go any further I should warn you there’s a lot of acronyms heading your way. The BGTC is part of the Accelerating Medicines Partnership® (AMP®) program. This is a public-private partnership between the National Institutes of Health (NIH), the U.S. Food and Drug Administration (FDA), and multiple public and private organizations, such as CIRM.

The program is managed by the Foundation for the NIH (FNIH) and it aims to develop platforms and standards that will speed the development and delivery of customized or ‘bespoke’ gene therapies that could treat the millions of people affected by rare diseases.

Why is it necessary? Well, it’s estimated that there are around 7,000 rare diseases and these affect between 25-30 million Americans. Some of these diseases affect only a few hundred, or even a few dozen people. With so few people they almost always struggle to raise the funds needed to do research to find an effective therapy. However, many of these rare diseases are linked to a mutation or defect in a single gene, which means they could potentially be treated by highly customizable, “bespoke” gene therapy approaches.

Right now, individual disease programs tend to try individual approaches to developing a treatment. That’s time consuming and expensive. The newly formed BGTC believes that if we create a standardized approach, we could develop a template that can be widely used to develop bespoke gene therapies quickly, more efficiently and less expensively for a wide array of rare diseases.

“At CIRM we have funded several projects using gene therapy to help treat, and even cure, people with rare diseases such as severe combined immunodeficiency,” says Dr. Maria T. Millan, the President and CEO of CIRM. “But even an agency with our resources can only do so much. This agreement with the Bespoke Gene Therapy Consortium will enable us to be part of a bigger partnership, one that can advance the field, overcome obstacles and lead to breakthroughs for many rare diseases.”

With gene therapy the goal is to identify the genetic defect that is causing the disease and then deliver a normal copy of the gene to the right tissues and organs in the body, replacing or correcting the mutation that caused the problem. But what is the best way to deliver that gene? 

The BGTC’s is focusing on using an adeno-associated virus (AAV) as a delivery vehicle. This approach has already proven effective in Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), and spinal muscular atrophy. The consortium will test several different approaches using AAV gene therapies starting with basic research and supporting those all the way to clinical trials. The knowledge gained from this collaborative approach, including developing ways to manufacture these AAVs and creating a standard regulatory approach, will help build a template that can then be used for other rare diseases to copy.

As part of the consortium CIRM will identify specific rare disease gene therapy research programs in California that are eligible to be part of the AMP BGTC. CIRM funding can then support the IND-enabling research, manufacturing and clinical trial activities of these programs.

“This knowledge network/consortium model fits in perfectly with our mission of accelerating transformative regenerative medicine treatments to a diverse California and world,” says Dr. Millan. “It is impossible for small, often isolated, groups of patients around the world to fund research that will help them. But pooling our resources, our skills and knowledge with the consortium means the work we support here may ultimately benefit people everywhere.”

UCLA gene therapy offers children with LAD-1 a new chance at living a normal life

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Photo courtesy of Tamara Hogue/UCLA Broad Stem Cell Research Center

Leukocyte adhesion deficiency type 1 (LAD-1) is a rare pediatric disorder that causes the immune system to malfunction, resulting in recurrent, often severe, bacterial and fungal infections as well as delayed wound healing. This is because of a missing protein that would normally enable white blood cells to stick to blood vessel walls- a crucial step that is needed before moving outside the vessel walls and into tissues to fight infections. If left undiagnosed and untreated, LAD-1 is fatal and most children with the disorder will die before the age of 2.

When Marley Gaskins was finally diagnosed with LAD-1 at age 8 (an extraordinary feat on its own) she had already spent countless hours hospitalized and required round the clock attention and care. The only possible cure was a risky bone marrow transplant from a matched donor, a procedure so rarely performed that there is no data to determine the survival rate.

In search of a better treatment option, Marley’s family came across a clinical trial for children with LAD-1 led by Dr. Donald Kohn, MD, a researcher in the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. 

The novel clinical trial, sponsored by Rocket Pharmaceuticals and CIRM, uses gene therapy in a treatment that works by harvesting the defective blood-making stem cells, correcting the mutation in a lab, and then transplanting the properly functioning cells back into the child’s body. The process eliminates the potential rejection risks of a bone marrow transplant because the corrected cells are the patient’s own.

For Marley’s family, the decision was a no-brainer. “I didn’t hesitate in letting her be a participant in the trial,” Marley’s mother, Tamara Hogue explains, “because I knew in my heart that this would give her a chance at having a normal life.”

In 2019, 9-year-old Marley became the first LAD-1 patient ever to receive the stem cell gene therapy. In the following year, five more children received the gene therapy at UCLA, including three siblings. And Last week, Dr. Kohn reported at the American Society of Hematology Annual Meeting and Exposition that all the children “remain healthy and disease-free”. 

More than two years out of treatment, Marley’s life and daily activities are no longer constricted by the frequent and severe infections that kept her returning to the hospital for months at a time. Instead, she enjoys being an average 12-year-old: going camping, getting her ears pierced, and most importantly, attending what she calls “big school” in the coming year. For patients and families alike, the gene therapy’s success has been like a rebirth. Doctors expect that the one-time therapy will keep LAD-1 patients healthy for life.

Celebrating a young life that almost wasn’t

Often on the Stem Cellar we feature CIRM-funded work that is helping advance the field, unlocking some of the secrets of stem cells and how best to use them to develop promising therapies. But every once in a while it’s good to remind ourselves that this work, while it may often seem slow, is already saving lives.

Meet Ja’Ceon Golden. He was one of the first patients treated at U.C. San Francisco, in partnership with St. Jude Children’s Hospital in Memphis, as part of a CIRM-funded study to treat a rare but fatal disorder called Severe Combined Immunodeficiency (SCID). Ja’Ceon was born without a functioning immune system, so even a simple cold could have been fatal.

At UCSF a team led by Dr. Mort Cowan, took blood stem cells from Ja’Ceon and sent them to St. Jude where another team corrected the genetic mutation that causes SCID. The cells were then returned to UCSF and re-infused into Ja’Ceon.  

Over the next few months those blood stem cells grew in number and eventually helped heal his immune system.

He recently came back to UCSF for more tests, just to make sure everything is OK. With him, as she has been since his birth, was his aunt and guardian Dannie Hawkins. She says Ja’Ceon is doing just fine, that he has just started pre-K, is about to turn five years old and in January will be five years post-therapy. Effectively, Ja’Ceon is cured.

SCID is a rare disease, there are only around 70 cases in the US every year, but CIRM funding has helped produce cures for around 60 kids so far. A recent study in the New England Journal of Medicine showed that a UCLA approach cured 95 percent of the children treated.

The numbers are impressive. But not nearly as impressive, or as persuasive of the power of regenerative medicine, as Ja’Ceon and Dannie’s smiles.

Ja’Ceon on his first day at pre-K. He loved it.

CIRM funded trial may pave way for gene therapy to treat different diseases

Image Description: Jordan Janz (left) and Dr. Stephanie Cherqui (right)

According to the  National Organization for Rare Disorders (NORD), a disease is consider rare if it affects fewer than 200,000 people. If you combine the over 7,000 known rare diseases, about 30 million people in the U.S. are affected by one of these conditions. A majority of these conditions have no cure or have very few treatment options, but a CIRM funded trial (approximately $12 million) for a rare pediatric disease has showed promising results in one patient using a gene therapy approach. The hope for the field as a whole is that this proof of concept might pave the way to use gene therapy to treat other diseases.

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 that results in abnormal accumulation of cystine (hence the name cystinosis) 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 problems.  There is currently a drug treatment for cystinosis, but it only delays the progression of the disease, has severe side effects, and is expensive.

Dr. Stephane Cherqui at UC San Diego (UCSD), in partnership with AVROBIO, is conducting a clinical trial that uses a gene therapy approach to modify a patient’s own blood stem cells with a functional version of the defective gene. The corrected stem cells are then reintroduced into the patient with the hope that they will give rise to blood cells that will reduce cystine buildup in the body.  

22 year old Jordan Janz was born with cystinosis and was taking anywhere from 40 to 60 pills a day as part of his treatment. Unfortunately the medication affected his body odor, leaving him smelling like rotten eggs or stinky cheese. In 2019, Jordan was the first of three patients to participate in Dr. Cherqui’s trial and the results have been remarkable. Tests have shown that the cystine in his eyes, skin and muscle have greatly decreased. Instead of the 40-60 pills a day, he just takes vitamins and specific nutrients his body needs. What’s more is that he no longer has a problem with body odor caused by the pills he once had to take. Although it will take much more time know if Jordan was cured of the disease, he says that he feels “essentially cured”.

In an article from the Associated Press, Jordan is optimistic about his future.

“I have more of a life now. I’m going to school. I’m hoping to open up my own business one day.”

You can learn more about Jordan by watching the video below:

Although gene therapy approaches still need to be closely studied, they have enormous potential for treating patients. CIRM has funded other clinical trials that use gene therapy approaches for different genetic diseases including X-SCID, ADA-SCID, ART-SCID, X-CGD, and sickle cell disease.

CIRM-Funded Clinical Trial for Sickle Cell Gives Hope to People Battling the Disease

Marissa Cors (right) with her mother Adrienne Shapiro

Marissa Cors has lived with Sickle Cell Disease (SCD) for more than 40 years. The co-founder of The Sickle Cell Experience Live, an online platform designed to bring more awareness to Sickle Cell Disease around the world, says it’s hard, knowing that at any moment you may have to put your life on hold to cope with another attack of excruciating pain.

“It is incredibly frustrating to have a disease that is constantly disrupting and interfering with your life. The daily pain and fatigue make it difficult to have a normal life. You may be experiencing manageable pain one minute and then a crisis will hit – knocking you to the ground with horrible pain and requiring pain management and hospitalization. It makes going to school or having a job or even a normal adult relationship near impossible.”

SCD is an inherited disease caused by a single gene mutation resulting in abnormal hemoglobin, which causes red blood cells to ‘sickle’ in shape.  Sickling of red blood cells clogs blood vessels and leads to progressive organ damage, pain crises, reduced quality of life, and early death. 

The disease affects around 100,000 Americans, mostly Black Americans but also members of the Latinx community. Marissa says coping with it is more than just a medical struggle. “Born into the cycle of fatigue, pain and fear. Depending on a healthcare system filled with institutionalized bias and racism. It is a life that is difficult on all facets.” 

CIRM is committed to trying find new treatments, and even a cure for SCD. That’s why the CIRM Board recently awarded $8,333,581 to Dr. David Williams at Boston Children’s Hospital to conduct a gene therapy clinical trial for sickle cell disease.  This is the second project that is part of an agreement between CIRM and the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, to co-fund cell and gene therapy programs under the NHLBI’s  “Cure Sickle Cell” Initiative.  The goal of this agreement is to markedly accelerate clinical development of cell and gene therapies to cure SCD.

In recent years we have made impressive strides in developing new approaches to treating sickle cell disease,” says Dr. Maria T. Millan, President & CEO of CIRM. “But we still have work to do. That’s why this partnership, this research is so important. It reflects our commitment to pushing ahead as fast as we can to find a treatment, a cure, that will help all the people battling the disease here in the U.S. and the estimated 20 million worldwide.”

The team will take a patient’s own blood stem cells and insert a novel engineered gene to silence abnormal hemoglobin and induce normal fetal hemoglobin expression.  The modified blood stem cells will then be reintroduced back into the patient.  The goal of this therapy is to aid in the production of normal shaped red blood cells, thereby reducing the severity of the disease. 

For Marissa, anything that helps make life easier will be welcome not just for people with SCD but their families and the whole community. “A stem cell cure will end generations of guilt, suffering, pain and early death. It will give SCD families relief from the financial, emotional and spiritual burden of caring someone living with SCD. It will give all of us an opportunity to have a normal life. Go to school, go to work, live with confidence.” 

Scientists Engineer Stem Cells to Fight HIV

Image of the virus that causes AIDS – courtesy NIH

If that headline seems familiar it should. It came from an article in MIT Technology Review back in 2009. There have been many other headlines since then, all on the same subject, and yet here we are, in 2020, and still no cure for HIV/AIDS. So what’s the problem, what’s holding us back?

First, the virus is incredibly tough and wily. It is constantly mutating so trying to target it is like playing a game of ‘whack a mole’. Secondly not only can the virus evade our immune system, it actually hijacks it and uses it to help spread itself throughout the body. Even new generations of anti-HIV medications, which are effective at controlling the virus, can’t eradicate it. But now researchers are using new tools to try and overcome those obstacles and tame the virus once and for all.

Dr. Scott Kitchen: Photo David Geffen School of Medicine, UCLA

UCLA researchers Scott Kitchen and Irvin Chen have been awarded $13.65 million by the National Institutes of Health (NIH) to see if they can use the patient’s own immune system to fight back against HIV.

Dr. Irvin Chen: Photo UCLA

Dr. Kitchen and Dr. Chen take the patient’s own blood-forming stem cells and then, in the lab, they genetically engineer them to carry proteins called chimeric antigen receptors or CARs. Once these blood cells are transplanted back into the body, they combine with the patient’s own immune system T cells (CAR T). These T cells now have a newly enhanced ability to target and destroy HIV.

That’s the theory anyway. Lots of research in the lab shows it can work. For example, the UCLA team recently showed that these engineered CAR T cells not only destroyed HIV-infected cells but also lived for more than two years. Now the team at UCLA want to take the lessons learned in the lab and apply them to people.

In a news release Dr. Kitchen says the NIH grant will give them a terrific opportunity to do that: “The overarching goal of our proposed studies is to identify a new gene therapy strategy to safely and effectively modify a patient’s own stem cells to resist HIV infection and simultaneously enhance their ability to recognize and destroy infected cells in the body in hopes of curing HIV infection. It is a huge boost to our efforts at UCLA and elsewhere to find a creative strategy to defeat HIV.”

By the way, CIRM helped get this work off the ground with an early-stage grant. That enabled Dr. Kitchen and his team to get the data they needed to be able to apply to the NIH for this funding. It’s a great example of how we can kick-start projects that no one else is funding. You can read a blog about that early stage research here.

CIRM has already funded three clinical trials targeting HIV/AIDS. Two of these are still active; Dr. Mehrdad Abedi at UC Davis and Dr. John Zaia at City of Hope.

‘A Tornado at the Front Door, a Tsunami at the Back Door’

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.

Jordan Janz and Dr. Stephanie Cherqui in her lab at the UC San Diego School of Medicine: Photo courtesy UC San Diego

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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.”

The treatment

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.”

The 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.

The future

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.”

Video of Dr. Cherqui and Jordan Janz talking about the therapy

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 alphastemcellclinic@ucsd.edu.

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.

NIH collaboration aims to develop affordable gene therapies for sickle cell disease and HIV

Sickle cell disease (SCD) and HIV have a major burden on the health of impoverished communities all over the world.

Of the 38 million people living with HIV all over the world, approximately 95% reside within developing countries, with 67% in sub-Saharan Africa, half of whom are living without any treatment.

Fifteen million babies will be born with SCD globally over the next 30 years. Of those births, 75% will occur in sub-Saharan Africa. In this region, SCD is the underlying cause of 1 in 12 newborn deaths and an estimated 50-90% of infants born with SCD in developing countries will die before their 5th birthday.

It is because of this epidemic around the world that the National Institutes of Health (NIH) and The Bill & Melinda Gates Foundation have formed a collaboration, with the bold goal of advancing safe, effective and durable gene-based therapies to clinical trials in the United States and relevant countries in sub-Saharan Africa within the next seven to 10 years. The ultimate goal is to scale and implement these treatments globally in areas hardest hit by these diseases.

Through this collaboration, the NIH plans to invest at least $100 million over the next four years towards gene therapies related to SCD and HIV and in return The Bill and Melinda Gates Foundation will match this investment with an additional $100 million towards the same goal.

Currently, due to their intrinsic complexity and cost of treatment requirements, gene based therapies are generally limited to hospitals in wealthy countries. The collaborative effort between the NIH and the Gates Foundation seeks to change that by investing in the development of curative therapies that can be delivered safely, effectively and affordably in low-resource settings.

In a news release, NIH Director Dr. Francis Collins discusses the potential this agreement holds:

“This unprecedented collaboration focuses from the get-go on access, scalability and affordability of advanced gene-based strategies for sickle cell disease and HIV to make sure everybody, everywhere has the opportunity to be cured, not just those in high-income countries.”

In the same news release, Dr. Trevor Mundel, President of the Global Health Program at The Bill & Melinda Gates Foundation echoes the same sentiment:

“In recent years, gene-based treatments have been groundbreaking for rare genetic disorders and infectious diseases. While these treatments are exciting, people in low- and middle-income countries do not have access to these breakthroughs. By working with the NIH and scientists across Africa, we aim to ensure these approaches will improve the lives of those most in need and bring the incredible promise of gene therapy to the world of public health.”

Similarly, CIRM and the National Heart, Lung, and Blood Institute (NHLBI), an institute within the NIH, have entered a landmark agreement on curing SCD. CIRM has already funded one program under this agreement and has another $27 million available to fund other potential therapies.

CIRM Board Approves New Clinical Trial for Rare Childhood Disease

Today the governing Board of the California Institute for Regenerative Medicine (CIRM) approved a grant of almost $12 million to Dr. Stephanie Cherqui at the University of California, San Diego (UCSD) to conduct a clinical trial for treatment of cystinosis.

This award brings the total number of CIRM funded clinical trials to 55. 

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.  There is currently a drug treatment for cystinosis, but it only delays the progression of the disease, has severe side effects and is expensive.

Dr. Cherqui’s clinical trial will use a gene therapy approach to modify a patient’s own blood stem cells with a functional version of the defective CTNS gene. Based on pre-clinical data, the approach is to reintroduce the corrected stem cells into the patient to give rise to blood cells that will reduce cystine buildup in affected tissues.  

Because this is the first time this approach has been tested in patients, the primary goal of the clinical trial is to see if the treatment is safe.  In addition, patients will be monitored for improvements in the symptoms of their disease.  This award is in collaboration with the University of California, Los Angeles which will handle the manufacturing of the therapy.

CIRM has also funded the preclinical work for this study, which involved completing the testing needed to apply to the Food and Drug Administration (FDA) for permission to start a clinical trial in people.

“CIRM has funded 24 clinical stage programs utilizing cell and gene medicine approaches to date,” says Maria T. Millan, M.D., the President and CEO of CIRM.  “This project continues to broaden the scope of unmet medical need we can impact with these types of approaches.”