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.

Building a progressive pipeline

Dr. Kelly Shepard

By Dr. Kelly Shepard

One of our favorite things to do at CIRM is deliver exciting news about CIRM projects. This usually entails discussion of recent discoveries that made headlines, or announcing the launch of a new CIRM-funded clinical trial …. tangible signs of progress towards addressing unmet medical needs through advances in stem technology.

But there are equally exciting signs of progress that are not always so obvious to the untrained eye-  those that we are privileged to witness behind the scenes at CIRM. These efforts don’t always lead to a splashy news article or even to a scientific publication, but they nonetheless drive the evolution of new ideas and can help steer the field away from futile lines of investigation. Dozens of such projects are navigating uncharted waters by filling knowledge gaps, breaking down technical barriers, and working closely with regulatory agencies to define novel and safe paths to the clinic.

These efforts can remain “hidden” because they are in the intermediate stages of the long, arduous and expensive journey from “bench to beside”.  For the pioneering projects that CIRM funds, this journey is unique and untrod, and can be fraught with false starts. But CIRM has developed tools to track the momentum of these programs and provide continuous support for those with the most promise. In so doing, we have watched projects evolve as they wend their way to the clinic. We wanted to share a few examples of how we do this with our readers, but first… a little background for our friends who are unfamiliar with the nuts and bolts of inventing new medicines.

A common metaphor for bringing scientific discoveries to market is a pipeline, which begins in a laboratory where a discovery occurs, and ends with government approval to commercialize a new medicine, after it is proven to be safe and effective. In between discovery and approval is a stage called “Translation”, where investigators develop ways to transition their “research level” processes to “clinically compatible” ones, which only utilize substances that are of certified quality for human use. 

Investigators must also work out novel ways to manufacture the product at larger scale and transition the methods used for testing in animal models to those that can be implemented in human subjects.

A key milestone in Translation is the “preIND” (pre Investigational New Drug (IND) meeting, where an investigator presents data and plans to the US Food and Drug Administration (FDA) for feedback before next stage of development begins, the pivotal testing needed to show it is both safe and effective.

These “IND enabling studies” are rigorous but necessary to support an application for an IND and the initiation of clinical trials, beginning with phase 1 to assess safety in a small number of individuals, and phase 2, where an expanded group is evaluated to see if the therapy has any benefits for the patient. Phase 3 trials are studies of very large numbers of individuals to gain definitive evidence of safety and therapeutic effect, generally the last step before applying to the FDA for market approval. An image of the pipeline and the stages described are provided in our diagram below.

The pipeline can be notoriously long and tricky, with plenty of twists, turns, and unexpected obstacles along the way. Many more projects enter than emerge from this gauntlet, but as we see from these examples of ‘works in progress”, there is a lot of momentum building.

Caption for Graphic: This graphic shows the number of CIRM-funded projects and the stages they have progressed through multiple rounds of CIRM funding. For example, the topmost arrow shows that are about 19 projects at the translational stage of the pipeline that received earlier support through one of CIRM’s Discovery stage programs. Many of these efforts came out of our pre-2016 funding initiatives such as Early Translation, Basic Biology and New Faculty Awards. In another example, you can see that about 15 awards that were first funded by CIRM at the IND enabling stage have since progressed into a phase 1 or phase 2 clinical trials. While most of these efforts also originated in some of CIRM’s pre-2016 initiatives such as the Disease Team Awards, others have already progressed from CIRM’s newer programs that were launched as part of the “2.0” overhaul in 2016 (CLIN1).

The number of CIRM projects that have evolved and made their way down the pipeline with CIRM support is impressive, but it is clearly an under-representation, as there are other projects that have progressed outside of CIRM’s purview, which can make things trickier to verify.

We also track projects that have spun off or been licensed to commercial organizations, another very exciting form of “progression”. Perhaps those will contribute to another blog for another day! In the meantime, here are a just a few examples of some of the progressors that are depicted on the graphic.

Project: stem cell therapy to enhance bone healing in the elderly

– Currently funded stage: IND enabling development, CLIN1-11256 (Dr. Zhu, Ankasa Regenerative Therapeutics)

– Preceded by preIND-enabling studies, TRAN1-09270 (Dr. Zhu, Ankasa Regenerative Therapeutics)

– Preceded by discovery stage research grant TR1-01249 (Dr. Longaker and Dr. Helm, Stanford)

Project: embryonic stem cell derived neural cell therapy for Huntington Disease

– Currently funded stage: IND enabling development, CLIN1-10953 (Dr. Thompson, UC Irvine)

– Preceded by preIND-enabling studies, PC1-08117 (Dr. Thompson, UC Irvine)

– Preceded by discovery stage research grant (TR2-01841) (Dr. Thompson, UC Irvine)

Project: gene-modified hematopoietic stem cells for Artemis Deficient severe combined immunodeficiency (SCID)

– Currently funded stage: Phase 1 clinical trial CLIN2-10830 (Dr. Cowan, UC San Francisco)

– Preceded by IND enabling development, CLIN1-08363 (Dr. Puck, UC San Francisco)

– Preceded by discovery stage research grant, TR3-05535  (Dr. Cowan, UC San Francisco)

Project: retinal progenitor cell therapy for retinitis pigmentosa

– Currently funded stage: Phase 2 and 2b clinical trials, CLIN2-11472, CLIN2-09698 (Dr. Klassen, JCyte, Inc.)

– Preceded by IND enabling development, DR2A-05739 (Dr. Klassen, UC Irvine)

– Preceded by discovery stage research grant, TR2-01794 (Dr. Klassen, UC Irvine)

Living proof science can find a cure

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.

https://www.instagram.com/p/B_BSQaonFXb/

It’s a lovely moment. It’s also a moment that just a few years ago seemed almost impossible. That’s because Ronnie was born with severe combined immunodeficiency (SCID). SCID kids have no functioning immune system so even a simple infection, such as a cold, can be life-threatening.

Many of those hardest hit by COVID-19 have compromised immune systems. But try fighting the virus if you have no immune system at all. The odds would not be good.

Happily, we don’t have to imagine it because Ronnie is one of around 60 children who have undergone CIRM-supported stem cell/gene therapies that have helped repair their immune system.

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.

CIRM-funded therapy helps “bubble babies” lead a normal life

Ja’Ceon Golden; ‘cured” of SCID

At CIRM we are very cautious about using the “c” word. Saying someone has been “cured” is a powerful statement but one that loses its meaning when over used or used inappropriately. However, in the case of a new study from U.C. San Francisco and St. Jude Children’s Research Hospital in Memphis, saying “cure” is not just accurate, it’s a celebration of something that would have seemed impossible just a few years ago.

The research focuses on children with a specific form of Severe Combined Immunodeficiency (SCID) called X-Linked SCID. It’s also known as “bubble baby” disease because children born with this condition lack a functioning immune system, so even a simple infection could be fatal and in the past they were kept inside sterile plastic bubbles to protect them.

In this study, published in the New England Journal of Medicine, researchers took blood stem cells from the child and, in the lab, genetically re-engineered them to correct the defective gene, and then infused them back into the child. Over time they multiplied and created a new blood supply, one free of the defect, which helped repair the immune system.

In a news release Dr. Ewelina Mamcarz, the lead author of the study, announced that ten children have been treated with this method.

“These patients are toddlers now, who are responding to vaccinations and have immune systems to make all immune cells they need for protection from infections as they explore the world and live normal lives. This is a first for patients with SCID-X1.”

The ten children were treated at both St. Jude and at UCSF and CIRM funded the UCSF arm of the clinical trial.

The story, not surprisingly, got a lot of attention in the media including this fine piece by CNN.

Oh, and by the way we are also funding three other clinical trials targeting different forms of SCID. One with UCLA’s Don Kohn,  one with Stanford’s Judy Shizuru, and one with UCSF’s Mort Cowan