This year’s Day of Hope Family Conference was an enormous success. We had 61 families from all over the world attend this year. There were families from Australia, Sweden, Norway, Ireland and Canada. We were excited to welcome 16 new families, ranging from newly diagnosed infants to adults.
On Thursday night we all got together for introductions. We all shared a little bit about ourselves, as well as our wishes and hopes. Everyone expressed hope for a cure for cystinosis, but also that no matter what happens, that those affected by cystinosis will not feel limited or defined by their disease, and that everybody would lead happy, healthy lives. After introductions we had delicious Mexican food, something I’ve come to look forward to every year. Our boys chowed down on chicken quesadillas while their friend, Henry Sturgis, ate his weight in chocolate-covered churros. It was the perfect venue for catching up and getting to know the new families.
On Friday morning we got started bright and early. Nancy Stack updated us on the amazing progress of the Cystinosis Research Foundation. Altogether the foundation has raised over $40 million for cystinosis research since its inception in 2003, funding 164 studies in 12 different countries. It’s pretty remarkable that such a vibrant research community has sprung up around such a rare disease. After Nancy spoke it was my privilege to go over the basics of cystinosis at the cellular and organ levels.
Dr. Paul Grimm from Stanford spoke about the genetics of cystinosis. There are over 100 different mutations identified in cystinosis. The most common is the 57kb mutation, which affects 50-75% of people of Northern European descent. What mutations you have determines a lot about how cystinosis manifests. Some people have very severe Fanconi syndrome, while others have very severe corneal disease. Some people don’t sweat or tolerate heat very well. If you have the 57kb mutation, you also have a mutation in the receptor that detects heat from hot chili peppers. This endows you with the ability to eat very spicy foods.
Dr. Grimm also talked about the upcoming Phase 2 trial for a drug called ELX-02 that may allow people with nonsense mutations to make a functional cystinosin protein. It will be administered as an injection, given 2-3 times a week, and may eliminate the need for cysteamine therapy. If you have the nonsense mutation, you should check it out! Dr. Grimm also pointed out that most people in the United States don’t get genetic testing because it’s usually not covered by insurance. If you would like to get your genetics done, there are companies like www.invitae.com that charge about $200 to run your mutation. They will even work with your insurance company to try to get it covered.
Dr. Ranjan Dohil from UC San Diego spoke about the gastrointestinal effects of cystinosis. He showed us his research on how cysteamine itself causes many of the GI symptoms, including a surge of stomach acid production, nausea, and delayed gastric emptying. He also talked about the research that led to delayed-release cysteamine, or Procysbi. He emphasized that fatty foods significantly decrease absorption of Procysbi, which is one of the reasons it’s important to fast before and after. Although the package insert says to fast two hours before and thirty minutes after, he said everyone needs to adjust to their own schedule, lifestyle and needs. Some people may need to wait longer than 30 minutes before eating, if they have delayed gastric emptying. Everyone’s dose will have to be titrated individually.
Dr. Robert Mak from UC San Diego shared his research on muscle disease in cystinosis. He has discovered an inflammation pathway that appears to be implicated in muscle wasting and bone disease in cystinosis. He has found two drugs that block this pathway. In cystinosis knockout mice, these drugs improve bone and muscle mass dramatically. He is hopeful to move forward on a clinical trial in humans.
Dr. Kathleen Rickert was a welcome new face this year. She is an orthopedic surgeon from UC San Diego. Although she has not previously seen patients with cystinosis, she has started a collaborative clinic with Dr. Mak at UCSD to see children and adults with bone deformities. She reviewed the common bone complications in cystinosis, including bowleggedness and knock-knees, and the different medical and surgical ways to manage them. She recommended getting X-rays periodically to monitor progression of the deformities. I look forward to hearing again from her in the future.
Rachel Duong from Massachusetts General Hospital shared results from a study by Dr. Florian Eichler on muscle complications in adults with cystinosis. They used several validated surveys to measure symptoms of muscle weakness and trouble swallowing, and then various tools including grip strength, peak air flow and video swallow evaluations to evaluate the extent of muscle disease. They found that 14 out of 20 patients reported symptoms of weakness, while 17 patient demonstrated weakness on exam. They also found that while 12 out of 20 expressed having trouble swallowing, only 6 actually showed evidence of abnormal swallowing on video fluoroscopy. They will bring these 20 people back in a year to repeat the tests to measure progression, and train them on some potential exercises they can do to improve muscle function.
Dr. Julian Midgley, from Alberta Children’s Hospital in Calgary, Canada, spoke to us about the important and complex process of transitioning from pediatric to adult care. In his unique practice, he is actually allowed to see both children and adults with cystinosis. He recommended starting early and planning ahead; don’t till the child’s 18th birthday. It will be different for each child and each family, and should be tailored to the patient’s needs.
Dr. Morgan Fedorchak from University of Pittsburgh spoke to us on a new controlled-release eye drop she is developing. She uses a thermo-responsive hydrogel that turns from liquid to solid when it touches the eye. The gel is filled with microspheres loaded with cysteamine. She has found that cysteamine is a much harder drug to deal with than other drugs she has used, which has required a lot of additional testing and trouble-shooting. Her initial testing has found that the drug is detectable in rabbit eyes after 24 hours, so hopefully it can be given once a day. Next she plans to test them in cystinosis knockout mice.
Dr. Sergio Catz from Scripps Research Institute spoke to us about his research on chaperone-mediated autophagy. There is a receptor called LAMP2A that recognizes which proteins need to be degraded in the lysosome, and facilitates the internalization of these proteins. In cystinosis cells, this receptor is not located in the lysosomal membrane, which leads to a build up of proteins outside the lysosome. This is not corrected with cysteamine. He is collaborating with another scientist, Ana Maria Cuervo, who has discovered a compound, QX77 (also called CA77), which corrects this defect, and improves cellular trafficking, autophagy and response to external stress. He is testing this compound in cystinosis knockout mice, and looking at the kidneys and eyes. He has also discovered that there are high levels of inflammatory proteins from neutrophils (white blood cells that fight infection) in the serum of cystinosis knockout mice. He has found a compound that blocks secretion of these proteins in cells and he plans to test this compound in cystinosis knockout mice next.
After Dr. Catz, we heard from Dr. Stephanie Cherqui on the upcoming Phase 1-2 clinical trial for autologous hematopoietic stem cell transplant. She is hoping to submit the IND application to the FDA this summer, and recruit the first patients this year. Eligible patients must be over 18 years old and have good organ function. They can have a kidney transplant, but must be at least 12 months out from transplantation. Interested candidates will come to San Diego and go through 2-4 days of screening and information. They do not have to commit at that point. If they decide they want to do it, they will come back for 8-9 days for a full, intensive examination, which will include evaluation of kidneys, eyes, lungs, heart, endocrine glands, muscles, bones and neurologic function and quality of life. If they are deemed healthy enough to participate, they will undergo stem cell harvest. Blood is taken and sent to UCLA. At this point the patient goes back home. At UCLA the stem cells are modified with a lentivirus vector, which takes about 60-90 days. Once this process is complete, the patient returns to San Diego to get the transplant. This consist of single agent chemotherapy (busulfan) to make room in the bone marrow. Then the modified stem cells are infused back into the patient. The following month is the riskiest part, as the chemotherapy wipes out your immune system and makes you susceptible to infections. The patient will have to remain in the hospital for one month until the bone marrow recovers. After that they will remain in San Diego for two additional months, with weekly check ups. Then they can go home, but will return every 6 months for 2 years to be evaluated. If things go well for the first four patients, then the hope would be to do it in adolescents, over 14 years old. I’m very hopeful the trial can start this year. Cross your fingers!
Dr. Bruce Barshop spoke about the new granulocyte cystine test. He showed data demonstrating that overall the newer test has much less variability than the mixed leukocyte test. The goal for the granulocyte cystine test is less than 1.9. The goal for the mixed leukocyte test is less than 1, although that number is apparently a little arbitrary and is based on upper limit of normal for carriers. He unveiled a new shipping kit that will be available soon through Horizon, which will hopefully make the packaging and shipping process much easier. If you’d like a kit, contact your Horizon representative.
Next we heard from Dr. Patrice Rioux and Dr. Vince Stanton from Massachusetts. They have formed a company, Thiogenesis Therapeutics, and are working on developing a better form of cysteamine. They modified cysteamine by adding a molecule to form a new compound. This compound is metabolized in the gut, where some cysteamine is absorbed, but some is left in the GI tract, where it continues to be metabolized and absorbed further downstream. This results in a much lower peak concentration (which will reduce the side effects of odor and nausea) and a more sustained blood level of cysteamine. They found that a large reservoir also ended up in the colon of mice, where it continued to be absorbed. This may result in a medication that could be taken once or twice a day, with better efficacy and fewer side effects than Cystagon or Procysbi. They are hoping to move forward with a study, possibly in Australia, to test toxicity in humans.
After a long day of talks we were ready to get outside and have dinner. The CRF arranged for buses to transport us to the Back Bay park and beach, where we enjoyed a fabulous barbecue feast. My kids were super excited for the return of the light up cotton candy wands. After gorging themselves on macaroni and cheese and brisket, they ran down to the beach to start a lightsaber battle. I had to sample every dessert, which included fresh donuts and made-to-order ice cream cookie sandwiches. I think I gained 10 pounds. It was a beautiful setting and a great night to relax.
On Saturday we heard first from Dr. Mary Leonard, from Stanford. She and Dr. Grimm did a study looking at bone health in children and adults with cystinosis. They did a number of tests, including strength testing, DEXA and high resolution peripheral quantitative computed tomography to analyze the muscles and bones. They found that kids with cystinosis have 32% lower leg strength than healthy controls, and adults have 35% lower strength. Muscle force was 25% lower in kids with cystinosis, and 13% lower in adults. The cortical bone was thinner and had lower surface area, and had a 19% lower failure load. Amount and thickness of spongy bone was lower as well.
Next Dr. Paul Grimm spoke again, this time about juggling the many aspects of cystinosis care, especially in younger children. He talked about the importance of regular dosing of supplements for Fanconi syndrome, especially phosphorus, potassium and bicarbonate/citrate. He also talked about important medication interactions. Calcium should not be given with phosphorus (neither will get absorbed). Procysbi should not be given with bicarbonate (the high pH will dissolve the beads prematurely). Citrate and bicarbonate should not be combined (it causes a fizzy chemical reaction, which is a good recipe for burping). He talked about indomethacin, and using it to reduce fluid and electrolyte losses.
The next talk was from Dr. Doris Trauner from UCSD. I missed her talk, but she reported her results on a study of adults with cystinosis for sleep apnea and its possible connection to memory troubles. The majority of adults tested had sleep apnea, half of which had moderate to severe sleep apnea. This was previously undiagnosed, which suggests that all adults would benefit from being screened. She is still actively recruiting patients to undergo overnight sleep studies.
While Dr. Trauner gave her talk, Dr. Grimm and Dr. Dohil met with the adults with cystinosis, and I met with the kids ages 11-14. For me it was very eye-opening to hear these young kids talk openly about their challenges. It was also cool to see how much they support each other. I hope we can have another session next year.
After the last session we had a question and answer panel with all our researchers and physicians. Following that we had a question and answer panel with our adults with cystinosis. They talked about how they had overcome many of the challenges of cystinosis and living with a chronic illness. They talked about working, staying active, being compliant with medications, and how to live a full life. Every year I hear from them I am inspired by their courage and hope.
Saturday night we reconvened for the Natalie’s Wish gala. We enjoyed the great entertainment and gourmet dinner (including a unicorn cheesecake with edible glitter!), and were blown away by the generosity of the attendees. We had 25 families present checks to the CRF this year, raising $668,000. Altogether the CRF raised an incredible $3.5 million. The best part is that all that money will go directly to research. We left the conference so full of hope, and so grateful for everything the Stack family and the CRF are doing to improve the lives of those with cystinosis. I look forward to seeing everybody again next year. And if you’ve never been to the conference and want to come, please reach out to the CRF. We’d love to see you there next year!