Apparently it's been exactly one year since we last posted anything! We just returned from the 2017 Day of Hope family conference, and we wanted to share what we learned. This was the second year having the conference at the Island Hotel. Fortunately the weather was much better than last year, so we were able to spend more time outside!
We kicked off the conference on Thursday night with introductions. Old and new families got up to introduce themselves and to share their wishes. It was a great way to get to know people before having dinner that night.
Friday morning we started off with a welcome talk from Nancy Stack. She shared the many milestones the CRF has accomplished since it started back in 2003. The CRF has raised over $35 million for cystinosis research, funding more than 150 grants with over 67 publications. The CRF funded the original research for Procysbi, the 12 hour form of cysteamine, which was approved back in 2013. They have also funded Dr. Stephanie Cherqui's stem cell research from the beginning.
After Nancy, I briefly spoke about the basics of cystinosis pathophysiology and history. Beyond Fanconi syndrome, corneal disease and muscle wasting, cystinosis also affects the thyroid, pancreas, reproductive organs, liver, heart, lungs and brains. This is why any attempt to cure the disease will have to be multi-systemic and involve correcting the defective cystinosis gene.
Next Dr. Grimm from Stanford talked to us about Fanconi syndrome, which is caused by destruction of the proximal tubules of the kidneys. These tubules are responsible for reabsorbing the electrolytes, nutrients and fluid that are filtered by the kidneys. Damage to the proximal tubules results in excessive thirst and urination because of fluid losses. It also leads to low potassium, low bicarbonate (acidosis), low phosphorus (which leads to rickets), and loss of glucose, amino acids and proteins. Dr. Grimm talked about dosing citrate (or bicarbonate) 3-4 times a day to improve acid levels in the blood. Citrate is converted to bicarbonate by the liver. Dr. Grimm pointed out that it's okay to take citrate with Procysbi, but not bicarbonate (bicarbonate is basic and will dissolve the Procysbi beads prematurely). He also recommended not taking calcium and phosphorus at the same time, since they can precipitate in the gut, preventing absorption of both. Dr. Grimm also shared some retrospective data from Dr. Emma in Italy that suggests indomethacin, which is used routinely in Europe, may be beneficial for growth and protective to the kidneys. This generated a lot of excitement and questions from many families.
Dr. Mak from UCSD talked next about his research on the effects of inflammation on the kidneys and muscles. He has shown that mice with cystinosis have activation of inflammatory pathways mediated by a receptor called NLRP3, which leads to production of a cytokine called interleukin-1 (IL-1), and this may contribute to myopathy and chronic kidney disease. Some of this inflammation may be reversed by repleting vitamin D. He has created a knockout mouse that is missing the cystinosin gene and the gene for NLRP3, which eliminated this inflammatory pathway. These mice still have cystinosis, but they have improved muscle mass and strength, and they don't have Fanconi syndrome. There is a drug called anakinra which blocks IL-1, and he is going to test this drug on mice with cystinosis to see whether it improves kidney function and muscles.
After Dr. Mak we heard an update from Dr. Mary Leonard from Stanford. She has finished the study on bone and muscle disease and is still compiling and analyzing data. She found that bone mineral density was very low in cystinotic bones, with more than half the participants with BMD below the 15th percentile for age. Cystinotic bones were more fragile, with a thinner cortex and more porosity. She thinks this is most likely due to muscle disease. Muscle mass in the limbs was also significantly reduced. More than half the participants had muscle mass less than 10th percentile for age. She is now going to look at a number of lab markers for bone disease, including vitamin D metabolites, PTH, FGF-23 and cytokines to see whether there are clues for pathophysiology and therapeutic targets. She recommended weight bearing exercise, like running or soccer, to help build bones, as well as making sure phosphorus, calcium and vitamin D levels are normal.
Next we heard from Dr. Simpson at UC-Irvine. She spoke about the many ways cystinosis can affect the eyes, beyond just corneal disease. Cystinosis can affect the tear film and conjuctivae to cause dry eye and filamentary keratitis. Cystinosis can also affect the iris, leading to angle-closure glaucoma, which is an emergency. Dr. Simpson pointed out that corneal cystinosis should not cause vision loss, so if you have new vision problems you need to be evaluated for a different cause, such as retinal disease, cataracts, glaucoma or optic nerve problems. Cystinosis can affect the optic nerve through something called pseudotumor cerebri, in which there is too much cerebrospinal fluid production. This can cause headache and blindness, and is detected by a dilated eye exam showing papilledema. Regarding corneal cystinosis, Dr. Simpson recommended monitoring corneal cystine burden with optical coherence tomography, which is more objective then slit-lamp exams. She recommended starting Cystaran drops as soon as a child can tolerate them.
After Dr. Simpson we heard from her husband Dr. Ron Kurtz, who is helping lead the cystine nanowafer project. The nanowafer was developed by Dr. Ghanashyam Acharya with Dr. Simpson. The CRF has the license of the nanowafer and is meeting with the FDA soon to file an IND application to start a clinic trial, hopefully this year.
Next we heard from Dr. Morgan Fedorchak from University of Pittsburgh. She has developed a novel way to treat corneal cystinosis. She created microspheres out of PLGA with cysteamine inside. These microspheres are dissolved by the tears. The microspheres are suspended in a hydrogel. The hydrogel is applied as an eye drop, but when it hits the eye it forms a semi-solid gel that sits under the bottom eyelid. The gel then slowly elutes the drug. She has designed a similar gel for glaucoma that can be applied every 28 days. She anticipates this new hydrogel could be put in once a week or once a day. This type of drug would not require benzalkonium chloride, which is the preservative found in Cystaran eye drops (which can cause irritation and allergic reactions). She is hopeful that a clinical trial can happen in the next couple years!
After Dr. Fedorchak we heard from Dr. Sergio Catz from Scripps. He talked about a protein called LAMP2A that acts as a port of entry to the lysosome. It's an important receptor in chaperone-mediated autophagy. It's built somewhere else in the cell and has to be transported on the cellular highway to the lysosome. When the protein cystinosin is absent, LAMP2A has difficulty getting to the lysosome, and this leads to a build-up of junk outside the lysosome. This can be just as disruptive as stuff building up inside the lysosome (i.e. cystine) and leads to increased cellular stress. He is collaborating with another reseacher, Ana Maria Cuervo, at Albert Einstein College of Medicine. She has already found some molecules that stabilize LAMP2A, improve its trafficking to the lysosome and reduce cellular stress. They are testing these molecules in cystinosis mice.
Next we heard from Dr. Stephanie Cherqui about the upcoming stem cell trial. She has shown that you can remove stem cells from mice with cystinosis and genetically modify them to insert a functional cystinosis gene. These stem cells can be given back to the mice as a transplant, and these stem cells rescue organ function in the mice, effectively curing them. She is hoping to file the IND with the FDA this year, and we may be able to start the trial soon after that. For the trial, patients will come to UCSD for a full evaluation by multiple physicians. They will undergo numerous tests to assess baseline organ function before the trial. Then they will be given G-CSF, which stimulates the bone marrow to produce new cells. Stem cells will be harvested from the patient through cell apharesis. These cells will then be sent to Dr. Kohn at UCLA to be modified. This process takes 3-4 months, so the patients will go home for that period. After the cells have been successfully modified, the patients will return to UCSD for the transplant. They will receive a chemotherapy called busulfan to ablate the bone marrow, then they will receive the stem cell transplant through an IV. They will then remain in the hospital for one month awaiting return of their bone marrow and immune system. During this month they will be at very high risk for infection. After that they will be discharged from the hospital but will need to stay in San Diego for another two months because they will require weekly visits for testing. Six months after the transplant they will return to San Diego and have a full evaluation to determine whether the transplant worked. They will return every 6 months for two years after the transplant. There will be 2 adults in the first phase, then 2 more adults. If the trial goes well they will open it up to adolescents for the last 2 participants. I'm so excited to see who will go first!
After Dr. Cherqui we heard from Tatiana Lobry, a PhD student in Dr. Cherqui's lab. She actually has a sister with cystinosis, which makes her even cooler. She is researching the role of inflammation in the kidney disease of cystinosis. She has identified a protein called galectin-3 that is overexpressed in cystinosis knockout mice. This protein is involved in a pathway that recruits inflammatory cells. She has created a double knockout mouse that is missing the cystinosis gene and the gene for galectin-3. These mice have better kidney function than single cystinosis knockout mice, suggesting that inflammation is contributing to their kidney disease. There are drugs in the pipeline that block galectin-3, and these may have a role in treating cystinosis in the future. She also noted that indomethacin, a non-steroidal anti-inflammatory medicine, inhibits transcription factors that are implicated in galectin-3 expression. This raises the consideration that indomethacin may protect the kidneys by reducing inflammation. Pretty cool!
Next we heard from Dr. Bruce Barshop from UCSD. He talked about the new cystine test and addressed the concerns of many families who reported getting higher levels lately. As he has said before, the new target number is less than 1.9. He said that when you scale the numbers people are getting compared to the previous test, the variability is actually better with the new test. He also reiterated that the blood test should be drawn BEFORE you take your next dose of Procysbi or Cystagon (this is different than the Procysbi trial).
After Dr. Barshop we heard from Dr. Patrice Rioux and Dr. Vincent Stanton, who are working on new pro-drugs for cysteamine. Dr. Rioux helped design Procysbi and used to work for Raptor Pharmaceuticals. He and Dr. Stanton have formed a new company called Thiogenesis Therapeutics. Cysteamine is rapidly metabolized and has be to dosed multiple times a day. The peaks associated with the medication cause significant side effects, like nausea, vomiting and a sulfurous smell. They are working on precursors that could be slowly converted to cysteamine in the intestines. They would maintain a lower basal rate of cysteamine, hopefully avoiding the side effects associated with the peaks. They would also hopefully extend the time between doses. They felt like they could have a trial in the next couple years.
On Friday night we got on fancy buses and headed to "the Dunes," a nice beachfront venue for dinner. There was a gourmet macaroni and cheese bar, with all sorts of yummy barbecued meat. For dessert we had cupcakes and a s'more bar. The kids had fun running around on the beach with little flashlights. Only a few got wet :)
Saturday morning we resumed the conference bright and early with a session by Dr. Grimm. He talked about how siblings of children with chronic illnesses cope. He also talked about the issues of medication compliance in adolescence, and how to let your teenager grow and take responsibility for their own care. The highest risk of losing a kidney transplant is age 19-21 because of medication non-adherence. Knowing how stubborn my children are now, I can only imagine what it will be like to have teenagers.
After Dr. Grimm we heard from Dr. Doris Trauner from UCSD. She talked about the many neurological complications of cystinosis. She also talked about sleep disturbances in cystinosis, and how this may affect memory and mood. She is doing a study on sleep disturbances in cystinosis and needs adult volunteers.
Next we heard from Dr. Ilya Gerstman, who works in Dr. Barshop's lab. He acknowledged that the white blood cell cystine test is error-prone and only captures a moment in time. It would be better to have a different lab test to monitor disease control. He is using a process called metabolomics to analyze thousands of metabolites in the blood that could be used to monitor the therapeutic effects of cysteamine and the effects of cystinosis on the body over time.
After that we had our physician/scientist panel where people could ask questions about the research and about their own children. People had a lot of questions about indomethacin. The data about this drug aren't published yet, so it may be hard to convince your nephrologist that a historically toxic medication may actually protect the kidneys. People also asked a lot about knock knees, flat feet, and bone pain. Dr. Leonard thinks a lot of the bone problems are actually secondary to muscle disease.
After that panel we heard from the adults with cystinosis panel. It was inspiring to hear about how they have overcome many of the challenges and obstacles of cystinosis. They were candid and honest about their fears, and they all expressed cautious optimism for the future, especially regarding the stem cell transplant trial.
Saturday night we all attended the Natalie's Wish Gala. There were over 475 people there. Ashton was asked to speak about Sam and Lars and our cystinosis journey. She did a fantastic job. I'll post her speech separately. That night the CRF raised a record-breaking $3.5 million (last year was $3.3. million!). It was amazing to see so many generous people donate to a cause that doesn't affect them personally. It was an inspiring evening for everyone.
Now only 365 days till the next conference! We're already counting down the days . . .