Three UC’s Join Forces to Launch CRISPR Clinical Trial Targeting Sickle Cell Disease

Sickle shaped red blood cells

The University of California, San Francisco (UCSF), in collaboration with UC Berkeley (UCB) and UC Los Angeles (UCLA), have been given permission by the US Food and Drug Administration (FDA) to launch a first-in-human clinical trial using CRISPR technology as a gene-editing technique to cure Sickle Cell Disease.

This research has been funded by CIRM from the early stages and, in a co-funding partnership with theNational Heart, Lung, and Blood Institute under the Cure Sickle Cell initiatve, CIRM supported the work that allowed this program to gain FDA permission to proceed into clinical trials.    

Sickle Cell Disease is a blood disorder that affects around 100,000 people, mostly Black and Latinx people in the US. It is caused by a single genetic mutation that results in the production of “sickle” shaped red blood cells. Normal red blood cells are round and smooth and flow easily through blood vessels. But the sickle-shaped ones are rigid and brittle and clump together, clogging vessels and causing painful crisis episodes, recurrent hospitalization, multi-organ damage and mini-strokes.    

The three UC’s have combined their respective expertise to bring this program forward.

The CRISPR-Cas9 technology was developed by UC Berkeley’s Nobel laureate Jennifer Doudna, PhD. UCLA is a collaborating site, with expertise in genetic analysis and cell manufacturing and UCSF Benioff Children’s Hospital Oakland is the lead clinical center, leveraging its renowned expertise in cord blood and marrow transplantation and in gene therapy for sickle cell disease.

The approach involves retrieving blood stem cells from the patient and, using a technique involving electrical pulses, these cells are treated to correct the mutation using CRISPR technology. The corrected cells will then be transplanted back into the patient.

Dr. Mark Walters

In a news release, UCSF’s Dr. Mark Walters, the principal investigator of the project, says using this new gene-editing approach could be a game-changer. “This therapy has the potential to transform sickle cell disease care by producing an accessible, curative treatment that is safer than the current therapy of stem cell transplant from a healthy bone marrow donor. If this is successfully applied in young patients, it has the potential to prevent irreversible complications of the disease. Based on our experience with bone marrow transplants, we predict that correcting 20% of the genes should be sufficient to out-compete the native sickle cells and have a strong clinical benefit.”

Dr. Maria T. Millan, President & CEO of CIRM, said this collaborative approach can be a model for tackling other diseases. “When we entered into our partnership with the NHLBI we hoped that combining our resources and expertise could accelerate the development of cell and gene therapies for SCD. And now to see these three UC institutions collaborating on bringing this therapy to patients is truly exciting and highlights how working together we can achieve far more than just operating individually.”

The 4-year study will include six adults and three adolescents with severe sickle cell disease. It is planned to begin this summer in Oakland and Los Angeles.

The three UCs combined to produce a video to accompany news about the trial. Here it is:

Hitting our Goals: Scoring a half century

Way, way back in 2015 – seems like a lifetime ago doesn’t it – the team at CIRM sat down and planned out our Big 6 goals for the next five years. The end result was a Strategic Plan that was bold, ambitious and set us on course to do great things or kill ourselves trying. Well, looking back we can take some pride in saying we did a really fine job, hitting almost every goal and exceeding them in some cases. So, as we plan our next five-year Strategic Plan we thought it worthwhile to look back at where we started and what we achieved. Goal #2 was Expand.

Scientist preparing a sample vial for automated analysis in the lab.

When CIRM first started there was an internal report that said if we managed to help get one project into a clinical trial before we ran out of money we would be doing well. At the time that seemed quite reasonable. The field was still very much in its infancy and most of the projects we were funding, particularly in the early days, were Discovery or basic research projects.

But as the field advanced we got a little bolder. By 2010 we were funding not just our first clinical trial, but the first clinical trial in the world using embryonic stem cells. This was the Geron trial targeting spinal cord injury. Sadly the excitement didn’t last very long. After treating just five patients Geron pulled the plug on the trial, deciding that targeting cancer was a better bet.

Happily, Geron returned all the money we had loaned them, plus interest, so we were able to use that to fund more research. Soon enough we had a number of other promising candidates heading towards a meeting with the US Food and Drug Administration (FDA) to try and get permission to start a clinical trial.

By 2014, ten years after we began, we actually had ten projects either running or getting ready to start a clinical trial. We thought that was really good. But at CIRM, really good is never good enough.

For our Strategic Plan in 2015 we decided to shoot for the moon and aim to get another 50 clinical trials over the next five years. At the time it seemed, to be honest, a bit bonkers. How on earth were we going to do that. But then our Therapeutics team went a hunting!

In the past we had the luxury of mostly just waiting for people with promising projects to approach us for funding. With an ambitious goal of getting 50 more clinical trials, we couldn’t afford to wait. The Therapeutics team scouted around for promising projects, inside and outside California, inside and outside the US, and pitched them on the benefits of applying for funding. Slowly the numbers started to rise.

By the end of 2016 we had 12 new trials. In 2017 we were really cruising along, adding 16 more trials. 2018 there was another 14 and that was also the year we passed the 50 clinical trials total since CIRM was created. We celebrated at a Board meeting with a balloon and a cake (we’re a state agency, our budget doesn’t extend to confetti). Initially the inscription on the cake read ‘Congratulations: 50 Clinical Trails’. Happily, we were able to fix it before anyone noticed. But even with the spelling error, it would still have tasted just fine.

Patient advocate Rich Lajara with the Big Balloon celebration for funding 50 clinical trials

By the time we got to mid-2020 we were stuck on 47 and with time, and money, running out it looked like we might miss the goal. But then our team put in one last effort and with weeks to spare we funded four more clinical trials for a total of 51 (68 since we started in 2004).

So, the moral is dream big but work hard. Now let’s see what we can dream up for our next Strategic Plan.

Month of CIRM – Our Therapeutics Team Goes Hunting

All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the voters approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future. Today we have a guest blog by CIRM Senior Science Officer Lisa Kadyk, outlining how she and her colleagues actively search for the best science to fund.

Lisa Kadyk, Ph.D.

Hi everyone,

This is Lisa Kadyk, a Science Officer from the CIRM Therapeutics team, here to tell you about some of the work our team does to support the CIRM mission of accelerating stem cell treatments to patients with unmet medical needs.  Our job involves seeking out and recruiting great scientists to apply to CIRM and supporting those we fund.

Therapeutics team members manage both the awards that fund the final preclinical studies required before testing a therapeutic in a clinical trial (CLIN1), and the awards that fund the clinical trials themselves (CLIN2). 

I mentioned above that we actively recruit new applicants for our CLIN1 and CLIN2 awards – which is not an activity that is typical of most funding agencies – so why and how do we do this?  

It all comes down to our mission of accelerating the development of therapies to help patients with unmet medical needs.  It turns out that there are many potential applicants developing cutting edge therapies who don’t know much or anything about CIRM, and the ways we can help them with getting those therapies to the clinic and through clinical trials.    So, to bridge this gap, we Science Officers attend scientific conferences, read the scientific literature and meet regularly with each other to stay abreast of new therapeutic approaches being developed in both academia and industry, with the goal of identifying and reaching out to potential applicants about what CIRM has to offer. 

What are some of the things we tell potential applicants about how partnering with CIRM can help accelerate their programs?   First of all, due to the efforts of a very efficient Review team, CIRM is probably the fastest in the business for the time between application and potential funding.  It can be as short as three months for a CLIN1 or CLIN2 application to be reviewed by the external Grants Working Group and approved by the CIRM Board, whereas the NIH (for example) estimates it takes seven to ten months to fund an application.   Second, we have frequent application deadlines (monthly for CLIN1 and CLIN2), so we are always available when the applicant is ready to apply.  Third, we have other accelerating mechanisms in place to help grantees once they’ve received funding, such as the CIRM Alpha Stem Cell Clinics network of six clinical sites throughout California (more efficient clinical trial processes and patient recruitment) and Clinical Advisory Panels (CAPs) – that provide technical, clinical or regulatory expertise as well as patient advocate guidance to the grantee.  Finally, we Science Officers do our best to help every step of the way, from application through grant closeout.

We now feel confident that our recruitment efforts, combined with CIRM’s more efficient funding pipeline and review processes, are accelerating development of new therapies.  Back in 2016, a new CIRM Strategic Plan included the goal of recruiting 50 successful (i.e., funded) clinical trial applicants within five years.  This goal seemed like quite a stretch, since CIRM had funded fewer than 20 clinical trials in the previous ten years.  Fast-forward to the end of 2020, and CIRM had funded 51 new trials in those five years, for a grand total of 68 trials.    

Now, with the passage of Proposition 14 this past November, we are looking forward to bringing more cell and gene therapeutic candidates into clinical trials.   If you are developing one yourself, feel free to let us know… or don’t be surprised if you hear from us!  

Much to be Thankful for

It’s traditional this time of year to send messages of gratitude to friends and family and colleagues. And we certainly have much to be thankful for.

Thanks to the voters of California, who passed Proposition 14, we have a bright, and busy, future. We have $5.5 billion to continue our mission of accelerating stem cell treatments to patients with unmet medical needs.

That means the pipeline of promising projects that we have supported from an early stage can now apply to us to help take that work out of the lab and into people.

It means research areas, particularly early-stage work, where we had to reduce our funding as we ran out of money can now look forward to increased support.

It means we can do more to bring this research, and it’s potential benefits, to communities that in the past were overlooked.

We have so many people to thank for all this. The scientists who do the work and championed our cause at the ballot box. The voters of California who once again showed their support for and faith in science. And the patients and patient advocates, the reason we were created and the reason we come to work every day.

As Dr. Maria Millan, our President & CEO, said in a letter to our team; “We are continually faced by great opportunities brilliantly disguised as insoluble problems.”  Here’s to the opportunities made possible by CIRM and for its continuation made possible by Prop 14!”

And none of this would be possible without the support of all of you. And for that we are truly Thankful.

From everyone at CIRM, we wish you a happy, peaceful and safe Thanksgiving.

CIRM-funded therapy to ease the impact of chemotherapy

Treatments for cancer have advanced a lot in recent years, but many still rely on the use of chemotherapy to either shrink tumors before surgery or help remove cancerous cells the surgery missed. The chemo can be very effective, but it’s also very toxic. Angiocrine Bioscience Inc. is developing a way to reduce those toxic side effects, and they just got a nice vote of confidence for that approach.

The US Food and Drug Administration (FDA) has granted Angiocrine Regenerative Medicine Advanced Therapy (RMAT) designation for their product AB-205.

RMAT is a big deal. It means the therapy, in this case AB-205, has already shown it is safe and potentially beneficial to patients, so the designation means that if it continues to be safe and effective it may be eligible for a faster, more streamlined approval process. And that means it can get to the patients who need it, outside of a clinical trial, faster.

What is AB-205? Well it’s made from genetically engineered cells, derived from cord blood, designed to help alleviate or accelerate recovery from the toxic side effects of chemotherapy for people undergoing treatment for lymphoma and other aggressive cancers of the blood or lymph system.

CIRM awarded Angiocrine Bioscience $6.2 million in 2018 to help carry out the Phase 2 clinical trial testing the therapy. In a news release ,CIRM President & CEO, Dr. Maria Millan, said there is a real need for this kind of therapy.

“This is a project that CIRM has supported from an earlier stage of research, highlighting our commitment to moving the most promising research out of the lab and into people. Lymphoma is the most common blood cancer and the 6th most commonly diagnosed cancer in California. Despite advances in therapy many patients still suffer severe complications from the chemotherapy, so any treatment that can reduce those complications can not only improve quality of life but also, we hope, improve long term health outcomes for patients.”

In a news release Dr. Paul Finnegan, Angiocrine’s CEO, welcomed the news.

“The RMAT designation speaks to the clinical meaningfulness and the promising efficacy data and safety profile of AB-205 based on our Phase 1b/2 study. This is an important step in accelerating the development of AB-205 towards its first market approval. We appreciate the thorough assessment provided by the FDA reviewers and the support from our partner, the California Institute for Regenerative Medicine.” 

The investment in Angiocrine marked a milestone for CIRM. It was the 50th clinical trial we had funded. It was a cause for celebration then. We’re hoping it will be a cause for an even bigger celebration in the not too distant future.

The company hopes to start a Phase 3 clinical trial in the US and Europe next year.

Exploring tough questions, looking for answers

COVID-19 and social and racial injustice are two of the biggest challenges facing the US right now. This Thursday, October 8th, we are holding a conversation that explores finding answers to both.

The CIRM Alpha Stem Cell Clinic Network Symposium is going to feature presentations about advances in stem cell and regenerative research, highlighting treatments that are already in the clinic and being offered to patients.

But we’re also going to dive a little deeper into the work we support, and use it to discuss two of the most pressing issues of the day.

One of the topics being featured is research into COVID-19. To date CIRM has funded 17 different projects, including three clinical trials. We’ll talk about how these are trying to find ways to help people infected with the virus, seeing if stem cells can help restore function to organs and tissues damaged by the virus, and if we can use stem cells to help develop safe and effective vaccines.

Immediately after that we are going to use COVID-19 as a way of exploring how the people most at risk of being infected and suffering serious consequences, are also the ones most likely to be left out of the research and have most trouble accessing treatments and vaccines.

Study after study highlights how racial and ethnic minorities are underrepresented in clinical trials and disproportionately affected by debilitating diseases. We have a responsibility to change that, to ensure that the underserved are given the same opportunity to take part in clinical trials as other communities.

How do we do that, how do we change a system that has resisted change for so long, how do we overcome the mistrust that has built up in underserved communities following decades of abuse? We’ll be talking about with experts who are on the front lines of this movement.

It promises to be a lively meeting. We’d love to see you there. It’s virtual – of course – it’s open to everyone, and it’s free.

Here’s where you can register and find out more about the Symposium

Encouraging news for treatment targeting retinitis pigmentosa

While most people probably wouldn’t put 2020 in their list of favorite years, it’s certainly turning out to be a good one for jCyte. Earlier this year jCyte entered into a partnership with global ophthalmology company Santen Pharmaceuticals worth up to $252 million. Then earlier this week they announced some encouraging results from their Phase 2b clinical trial.

Let’s back up a bit and explain what jCyte does and why it’s so important. They have developed a therapy for retinitis pigmentosa (RP), a rare vision destroying disease that attacks the light sensitive cells at the back of the eye. People are often diagnosed when they are in their teens and most are legally blind by middle age. CIRM has supported this therapy from its early stages into clinical trials.

This latest clinical trial is one of the largest of its kind anywhere in the world. They enrolled 84 patients (although only 74 were included in the final analysis). The patients had vision measuring between 20/80 and 20/800. They were split into three groups: one group was given a sham or placebo treatment; one was given three million human retinal progenitor cells (hRPCs), the kind attacked by the disease; and one was given six million hRPCs.

jCyte CEO Paul Bresge

In an article in Endpoints News, jCyte’s CEO Paul Bresge said there was a very specific reason for this approach. “We did enroll a very wide patient population into our Phase IIb, including patients that had vision anywhere from 20/80 to 20/800, just to learn which patients would potentially be the best responders.”

The results showed that the treatment group experienced improved functional vision and greater clarity of vision compared to the sham or placebo group. Everyone had their vision measured at the start and again 12 months later. For the placebo group the mean change in their ability to read an eye chart (with glasses on) was an improvement of 2.81 letters; for the group that got three million hRPCs it was 2.96 letters, and for the group that got six million hRPCs it was 7.43 letters.

When they looked at a very specific subgroup of patients the improvement was even more dramatic, with the six million cell group experiencing an improvement of 16.27 letters.

Dr. Henry Klassen

Dr. Henry Klassen, one of the founders of jCyte, says the therapy works by preserving the remaining photoreceptors in the eye, and helping them bounce back.

“Typically, people think about the disease as a narrowing of this peripheral vision in a very nice granular way, but that’s actually not what happens. What happens in the disease is that patients lose like islands of vision. So, what we’re doing in our tests is actually measuring […] islands that the patients have at baseline, and then what we’re seeing after treatment is that the islands are expanding. It’s similar to the way that one would track, let’s say a tumor, in oncology of course we’re looking for the opposite effect. We’re looking for the islands of vision to expand.”

One patient did experience some serious side effects in the trial but they responded well to treatment.

The team now plan on carrying out a Phase 3 clinical trial starting next year. They hope that will provide enough evidence showing the treatment is both safe and effective to enable them to get approval from the US Food and Drug Administration to make it available to all who need it.

From bench to bedside – CIRM plays a vital role in accelerating science

Dr. Maria T. Millan, President & CEO of CIRM

The field of stem cell research and regenerative medicine has exploded in the last few years with new approaches to treat a wide array of diseases. Although these therapies are quite promising, they face many challenges in trying to bring them from the laboratory and into patients. But why is this? What can we do to ensure that these approaches are able to cross the finish line?

A new article published in Cell Stem Cell titled Translating Science into the Clinic: The Role of Funding Agencies takes a deeper dive into these questions and how agencies like CIRM play an active role in helping advance the science. The article was written by Dr. Maria T. Millan, President & CEO of CIRM, and Dr. Gil Sambrano, Vice President of Portfolio Development and Review at CIRM.

Although funding plays an essential role in accelerating science, it is not by itself sufficient. The article describes how CIRM has established internal processes and procedures that aim to help accelerate projects in the race to the finish line. We are going to highlight a few of these in this post, but you can read about them in full by clicking on the article link here.

One example of accelerating the most promising projects was making sure that they make important steps along the way. For potential translational awards, which “translate” basic research into clinical trials, this means having existing data to support a therapeutic approach. For pre-clinical and clinical awards, it means meeting with the Food and Drug Administration (FDA) and having an active investigational new drug (IND) approved or pre-IND, important steps that need to be taken before these treatments can be tested in humans. Both of these measures are meant to ensure that the award is successful and progress quickly.

Another important example is not just giving these projects the funding in its entirety upfront, rather, tying it to milestones that guide a project to successful completion. Through this process, projects funded by CIRM become focused on achieving clear measurable objectives, and activities that detract from those goals are not supported.

Aside from requirements and milestones tied to funding, there are other ways that CIRM helps bolster its projects.

One of these is an outreach project CIRM has implemented that identifies investigators and projects with the potential to enhance already existing projects. This increases the number of people applying to CIRM projects as well as the quality of the applications.

Another example is CIRM’s Industry Alliance Program, which facilitates partnerships between promising CIRM-funded projects and companies capable of bringing an approved therapy to market. The ultimate goal is to have therapies become available to patients, which is generally made possible through commercialization of a therapeutic product by a pharmaceutical or biotechnology company.

CIRM has also established advisory panels for its clinical and translational projects, referred to as CAPs and TAPs. They are composed of external scientific advisors with expertise that complements the project team, patient advocate advisors, and CIRM Science Officers. The advisory panel provides guidance and brings together all available resources to maximize the likelihood of achieving the project objective on an accelerated timeline.

Lastly, and most importantly, CIRM has included patient advocates and patient voices in the process to help keep the focus on patient needs. In order to accelerate therapies to the clinic, funders and scientists need input on what ultimately matters to patients. Investing effort and money on potential therapies that will have little value to patients is a delay on work that really matters. Even if there is not a cure for some of these diseases, making a significant improvement in quality of life could make a big difference to patients. There is no substitute to hearing directly from patients to understand their needs and to assess the balance of risk versus benefit. As much as science drives the process of bringing these therapies to light, patients ultimately determine its relevance.

‘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.

Time and money and advancing stem cell research

The human genome

Way back in the 1990’s scientists were hard at work decoding the human genome, trying to map and understand all the genes that make up people. At the time there was a sense of hope, a feeling that once we had decoded the genome, we’d have cures for all sorts of things by next Thursday. It didn’t quite turn out that way.

The same was true for stem cell research. In the early days there was a strong feeling that this was going to quite quickly produce new treatments and cures for diseases ranging from Parkinson’s and Alzheimer’s to heart disease and stroke. Although we have made tremendous strides we are still not where we hoped we’d be.

It’s a tough lesson to learn, but an important one: good scientific research moves at its own pace and pays little heed to our hopes or desires. It takes time, often a long time, and money, usually a lot of money, to develop new treatments for deadly diseases and disorders.

Many people, particularly those battling deadly diseases who are running out of time, are frustrated at the slow pace of stem cell research, at the years and years of work that it takes to get even the most promising therapy into a clinical trial where it can be tested in people. That’s understandable. If your life is on the line, it’s difficult to be told that you have to be patient. Time is a luxury many patients don’t have.

But that caution is necessary. The last thing we want to do is rush to test something in people that isn’t ready. And stem cells are a whole new way of treating disease, using cells that may stay in the body for years, so we really need to be sure we have done everything we can to ensure they are safe before delivering them to people.

The field of gene therapy was set back years after one young patient, Jesse Gelsinger, died as a result of an early experimental treatment. We don’t want the same to happen to stem cell research.

And yet progress is being made, albeit not as quickly as any of us would like. At the end of the first ten years of CIRM’s existence we had ten projects that we supported that were either in, or applying to be in, a clinical trial sanctioned by the US Food and Drug Administration (FDA). Five years later that number is 56.

Most of those are in Phase 1 or 2 clinical trials which means they are still trying to show they are both safe and effective enough to be made available to a wider group of people. However, some of our projects are in Phase 3, the last step before, hopefully, being given FDA approval to be made more widely available and – just as important – to be covered by insurance.

Other CIRM-funded projects have been given Regenerative Medicine Advanced Therapy (RMAT) designation by the FDA, a new program that allows projects that show they are safe and benefit patients in early stage clinical trials, to apply for priority review, meaning they could get approved faster than normal. Out of 40 RMAT designations awarded so far, six are for CIRM projects.

We are working hard to live up to our mission statement of accelerating stem cell treatments to patients with unmet medical needs. We have been fortunate in having $3 billion to spend on advancing this research in California; an amount no other US state, indeed few other countries, have been able to match. Yet even that amount is tiny compared to the impact that many of these diseases have. For example, the economic cost of treating diabetes in the US is a staggering $327 billion a year.

The simple truth is that unless we, as a nation, invest much more in scientific research, we are not going to be able to develop cures and new, more effective, treatments for a wide range of diseases.

Time and money are always going to be challenging when it comes to advancing stem cell research and bringing treatments to patients. With greater knowledge and understanding of stem cells and how best to use them we can speed up the timeline. But without money none of that can happen.

Our blog is just one of many covering the topic of “What are the hurdles impacting patient access to cell and gene therapies as part of Signal’s fourth annual blog carnival.