Rare disease gets go-ahead to run clinical trial

crf

A young girl with cystinosis: Photo courtesy CRF

Cystinosis is one of those diseases most people have never heard of and should be very grateful they haven’t. It’s rare – affecting only around 500 children and young adults in the US and just 2,000 people worldwide – but it’s nasty. Up to now the treatments for it have been very limited. But a new clinical trial, just given the go-ahead by the Food and Drug Administration (FDA), could help change that.

Cystinosis usually strikes children before they are two years old and can lead to end stage kidney failure before their tenth birthday. It is caused by a genetic mutation that allows an amino acid, cysteine, to build up in and damage the kidneys, eyes, liver, muscles, pancreas and brain.

There is one approved therapy, cysteamine, but this only delays progression of the disease, has severe side effects and people taking it still require kidney transplants, and develop diabetes, neuromuscular disorders and hypothyroidism.

All those are reasons why, in September 2016, the CIRM Board approved $5.2 million for U.C. San Diego researcher Stephanie Cherqui, Ph.D. and her team to try a different approach. Their goal is to take blood stem cells from people with cystinosis, genetically-modify them to remove the mutation that causes the disease, then return them to the patient. The hope is that the modified blood stem cells will create a new, healthy, blood system free of the disease.

Results from pre-clinical work testing this approach in mice have been so encouraging that the FDA has given the go-ahead for that work to now be tested in people.

In a news release Nancy Stack, the Founder and President of the Cystinosis Research Foundation (CRF), the largest provider of grants for cystinosis research in the world, says this is exciting news for a community that has been waiting for a breakthrough:

“We are thrilled that CRF’s dedication to funding Dr. Cherqui’s work has resulted in FDA approval for the first-ever stem cell and gene therapy treatment for individuals living with cystinosis. This approval from the FDA brings us one step closer to what we believe will be a cure for cystinosis and will be the answer to my daughter Natalie’s wish made fifteen years ago, ‘to have my disease go away forever.’ We are so thankful to our donors and our cystinosis families who had faith and believed this day would come.”

Dr. Cherqui says if this is successful it could help more than just people with cystinosis:

“We were thrilled that the stem cells and gene therapy worked so well to prevent tissue degeneration in the mouse model of cystinosis,. This discovery opened new perspectives in regenerative medicine and in the application to other genetic disorders. Our findings may deliver a completely new paradigm for the treatment of a wide assortment of diseases including kidney and other genetic disorders. If so, CRF, through their years of support will have helped an untold number of patients with untreatable, debilitating diseases.”

Those with questions on the trials can call toll free: 844-317-7836 (STEM) and/or visit www.cystinosisresarch.org

A life-threatening childhood disease and the CIRM-funded team seeking a stem cell cure featured in new video

“My hope for Brooke is she can one day look back and we have to remind her of the disease she once had.”

That’s Clay Emerson’s biggest hope for his young daughter Brooke, who has cystinosis, a life-threatening genetic disease that appears by the age of two and over time causes damage to many organs, especially the kidneys and eyes but also the liver, muscle, brain, pancreas and other tissues. The Emersons and other families affected by the disease are featured in a recent video produced by the Cystinosis Research Foundation.

I doubt many can watch the seven-minute piece without getting a lump in their throat or watery eyes. One of many heart wrenching scene shows Brooke’s mother, Jill Emerson, preparing a day’s worth of medicine that she administers through a tube connected to Brook’s stomach.

“Brooke takes about 20 doses of medication a day and that’s throughout the 24hr period in a day. The poor kid hasn’t had a full night’s sleep ever in her entire life because I have to wake her up to take her life-saving medicine.”

Jill Emerson prepares a day’s worth of medicine for her daughter Brooke. Unfortunately, the treatments only slow the progression of cystinosis but don’t cure it. (Video Still: Cystinosis Research Foundation)

But these treatments only slow down the progression of this incurable disease. Even perfect compliance with taking the medicine doesn’t stop severe complications of the disease including kidney failure, diabetes, muscle weakness, and difficulty swallowing just to name a few. Cystinosis also shorten life spans. Natalie, the video’s narrator, a young woman with cystinosis wonders how much time she has left:

“There are people in their 20s who have recently died from cystinosis. I am 25 years old and I often think about how long I have to live. I’m praying for a cure for all of us.”

Her prayers may be answered in the form of a stem cell gene therapy treatment. UCSD researcher Dr. Stephanie Cherqui, who is also featured in the video, received $5 million in CIRM funding to bring her team’s therapy to clinical trials in people.

At a cellular level, cystinosis is caused by mutations in a gene called CTNS which lead to an accumulation of the amino acid cysteine. The excess cysteine eventually forms crystals causing devastating damage to cells throughout the body. Cherqui’s treatment strategy is to take blood stem cells from affected individuals, insert a good copy of the CTNS gene using genome editing into the cells’ DNA, and then transplant the cells back into the patient.

Cystinosis_Cherqui

Dr. Stephanie Cherqui and her team are working hard to bring a stem cell gene therapy treatment for cystinosis to clinical trials. (Video Still: Cystinosis Research Foundation)

Her team has preliminary evidence that the strategy works in mice. Now, they will use the CIRM grant to complete these pre-clinical studies and prepare the genetically engineered blood stem cells for use in patients. These steps are necessary to get the green light from the Food and Drug Administration (FDA) to begin clinical trials, hopefully some time this year.

Cherqui says that if all goes well, the treatment approach may have benefits beyond cystinosis:

“If we can bring this to the finish line, we can then show the way to maybe hundreds, maybe thousands of other genetic diseases. So this could be a real benefit to mankind.”

The power of the patient’s voice: how advocates shape clinical trials and give hope to those battling deadly diseases

stack-family-2017-3046-12

The Stack family: L to R Alex, Natalie, Nancy & Jeff

Tennis great Martina Navratilova was once being interviewed about what made her such a great competitor and she said it was all down to commitment. When pressed she said “the difference between involvement and commitment is like ham and eggs; the chicken is involved but the pig is committed.”

That’s how I feel about the important role that patients and patient advocates play in the work that we do at CIRM. Those of us who work here are involved. The patients and patient advocates are committed. This isn’t just their life’s work;  it’s their life.

I was reminded of that last week when I had the privilege of talking with Nancy Stack, the Patient Representative on a Clinical Advisory Panel (CAP) we have created for a program to treat cystinosis. She has an amazing story to tell. But before we get to that I have to do a little explaining.

Cystinosis is a rare disease, affecting maybe only 2,000 people worldwide, that usually strikes children before they are two years old and can lead to end stage kidney failure before their tenth birthday. Current treatments are limited, which is why the average life expectancy for someone with this is only around 27 years.

When we fund a project that is already in, or hoping to be in, a clinical trial we create a CAP to help assist the team behind the research. The CAP consists of a CIRM Science Officer, an independent scientific expert in this case for cystinosis, and a Patient Representative.

The patient’s voice

The Patient Representative’s role is vital because they can help the researchers understand the needs of the patient and take those needs into account when designing the trial. In the past, many researchers had little contact with patients and so designed the trial around their own needs. The patients had to fit into that model. We think it should be the other way around; that the model should fit the patients. The Patient Representatives help us make that happen.

Nancy Stack did just that. At the first meeting of the CAP she showed up with a list of 38 questions that she and other families with cystinosis had come up with for the researchers. They went from the blunt – “Will I die from the treatment” – to the practical –  “How will children/teens keep up with school during the process?” – and included a series of questions from a 12-year old girl with the disease – “Will I lose my hair because I’ve been growing it out for a long time? Will I feel sick? Will it hurt?”

Nancy says the questions are not meant to challenge the researcher, in this case U.C. San Diego’s Stephanie Cherqui, but to ensure that if the trial is given the go-ahead by the US Food and Drug Administration (FDA) that every patient who signs up for it knows exactly what they are getting into. That’s particularly important because many of those could be children or teenagers.

Fully informed

“As parents we know the science is great and is advancing, but we have real people who are going to go through this treatment so we have a responsibility to know what will it mean to them. Patients know they could die of the disease and so this research has real world implications for them.”

“I think without this, without allowing the patients voice to be heard, you would have a hard time recruiting patients for this kind of clinical trial.”

Nancy says not only was Dr. Cherqui not surprised by the questions, she welcomed them. Dr. Cherqui has been supported and funded by the Cystinosis Research Foundation for years and Nancy says she regards the patients and patient advocates as partners in this journey:

“She knows we are not challenging her, we’re supporting her and helping her cover every aspect of the research to help make it work.”

Nancy became committed to finding a cure for cystinosis when her daughter, Natalie, was diagnosed with the condition when she was just 7 months old. The family were handed a pamphlet titled “What to do when your child has a terminal disease” and told there was no cure.

Birthday wish

In 2003, on the eve of her 12th birthday, Nancy asked Natalie what her wish was for her birthday. She wrote on a napkin “to have my disease go away forever.” The average life expectancy for people with cystinosis at that point was 18. Nancy told her husband “We have to do something.”

They launched the Cystinosis Research Foundation and a few weeks later they held their first fundraiser. That first year they raised $427,000, an impressive amount for such a rare disease. Last year they raised $4.94 million. Every penny of that $4.94 million goes towards research, making them the largest funders of cystinosis research in the world.

“We learned that for there to be hope there has to be research, and to do research we needed to raise funds. Without that we knew our children would not survive this disease.”

Natalie is now 26, a graduate of Georgetown and USC, and about to embark on a career in social work. Nancy knows many others are not so fortunate:

“Every year we lose some of our adults, even some of our teens, and that is unbelievably hard. Those other children, wherever they may live, they are my children too. We are all connected to each other and that’s what motivates me every day. Having a child with this disease means that time is running out and there must be a commitment to work hard every day to find a cure, and never giving up until you do.”

That passion for the cause, that compassion for others and determination to help others makes the Patient Representative on the CAP so important. They are a reminder that we all need to work as hard as we can, as fast as we can, and do everything we can to help these trials succeed.

And we are committed to doing that.


Related Links:

Funding stem cell research targeting a rare and life-threatening disease in children

cystinosis

Photo courtesy Cystinosis Research Network

If you have never heard of cystinosis you should consider yourself fortunate. It’s a rare condition caused by an inherited genetic mutation. It hits early and it hits hard. Children with cystinosis are usually diagnosed before age 2 and are in end-stage kidney failure by the time they are 9. If that’s not bad enough they also experience damage to their eyes, liver, muscles, pancreas and brain.

The genetic mutation behind the condition results in an amino acid, cystine, accumulating at toxic levels in the body. There’s no cure. There is one approved treatment but it only delays progression of the disease, has some serious side effects of its own, and doesn’t prevent the need for a  kidney transplant.

Researchers at UC San Diego, led by Stephanie Cherqui, think they might have a better approach, one that could offer a single, life-long treatment for the problem. Yesterday the CIRM Board agreed and approved more than $5.2 million for Cherqui and her team to do the pre-clinical testing and work needed to get this potential treatment ready for a clinical trial.

Their goal is to take blood stem cells from people with cystinosis, genetically-modify them and return them to the patient, effectively delivering a healthy, functional gene to the body. The hope is that these genetically-modified blood stem cells will integrate with various body organs and not only replace diseased cells but also rescue them from the disease, making them healthy once again.

In a news release Randy Mills, CIRM’s President and CEO, said orphan diseases like cystinosis may not affect large numbers of people but are no less deserving of research in finding an effective therapy:

“Current treatments are expensive and limited. We want to push beyond and help find a life-long treatment, one that could prevent kidney failure and the need for kidney transplant. In this case, both the need and the science were compelling.”

The beauty of work like this is that, if successful, a one-time treatment could last a lifetime, eliminating or reducing kidney disease and the need for kidney transplantation. But it doesn’t stop there. The lessons learned through research like this might also apply to other inherited multi-organ degenerative disorders.