Seventh CRF International Research Symposium
By Stephen Jenkins, MD, CRF Board Member
The seventh biennial CRF International Research Symposium in Irvine, California was a huge success. Scientists from all over the world came together to share their CRF-funded research on cystinosis. Many researchers attended for their first time, and they were warmly welcomed into our community.
As a parent of two children with cystinosis, I was most excited to hear about new potential therapies. This was my third time attending the symposium, so it was exciting to see the progress that scientists have made. Earlier projects that focused on mechanisms and cellular biology have yielded potential therapeutic targets, and now the scientists are testing these therapies in animals.
The keynote speaker of the conference was Dr. Morton J. Cowan, from UC San Francisco, who is a distinguished researcher and physician who has pioneered gene therapy for different types of severe combined immunodeficiency (SCID).
Dr. Cowan’s presentation was followed by Dr. Stéphanie Cherqui, who gave an update on the first gene-corrected autologous stem cell transplant in a human with cystinosis. So far, the trial participant, who we now all know is Jordan Janz, has done well. He has a good level of corrected cells (vector copy number of 2 as measured in the blood cells) and his white blood cell cystine levels have dropped from 7.8 nmol at the time of transplant to 1.5 nmol three months after transplant. This is an important proof of concept that the blood cells have been repaired, but what about the tissue? Preliminary results based on confocal microscopy of the skin show reduced cystine crystals. His urine output has decreased as well, and he has been able to reduce his phosphorus supplementation, suggesting a possible improvement in Fanconi syndrome. He will return to California in April for his six-month check-up, where they will do biopsies to look at cystine in the tissue. It was a very exciting talk!
Dr. Morgan Fedorchak gave us an update about controlled-release cysteamine eye drops, which she has been testing in rabbits (without cystinosis) and will now be testing in cystinosis knockout mice.
Dr. Laura Rega shared research she has done with Dr. Francesco Emma on compounds that stimulate TFEB and improve regulation of lysosome turnover and autophagy. When given to cystinosis knockout mice, there was a significant reduction in kidney cystine, even without cysteamine therapy. There also appeared to be improvement in Fanconi syndrome. Next, they plan to test these compounds in cystinosis knockout rats, and hopefully humans in the future.
Dr. Pierre Courtoy has previously found that knocking out a certain protein called “megalin” in the kidney prevents cystine accumulation and protects the proximal tubules. He hypothesized that inhibiting megalin with large doses of amino acids would have a similar effect. Early results were promising, however, the long-term studies are less conclusive.
Dr. Paul Goodyer gave an update on a new medication that may treat patients with CTNS nonsense mutations. They’ve tested it on three patients for three weeks, and there was no evidence of toxicity. The study identified a dosing threshold where WBC cystine levels begin to fall. Additional studies from the lab show that the drug can repair the defect in cellular autophagy as well. From lessons learned in the first phase, the protocol will be adjusted and then expanded at additional sites in the USA.
Dr. Robert Mak is collaborating with Dr. Hal Hoffman, a prior symposium keynote speaker, on studying the effects of inflammation in cystinosis. They believe that by blocking the inflammasome pathway they can improve Fanconi syndrome.
They have been testing two compounds in this pathway in knockout mice, and they have had improvement in urine output and markers of Fanconi syndrome. New oral medication that blocks this pathway is currently being tested in a phase III trial, so they plan to obtain this compound for additional studies.
Dr. Francesco Bellomo shared research he has done with Dr. Emma on whether the ketogenic diet may be beneficial in cystinosis. They have tested it in knockout mice and found that it reduced polyuria, glycosuria and tubular proteinuria, a sign that it may help Fanconi syndrome. It also reduced inflammation and fibrosis in the kidneys. It is unclear why a ketogenic diet had this effect, so they are going to continue research on this question. The ketogenic diet may lead to ketoacidosis, and people with cystinosis already have metabolic acidosis, so any dietary treatment should require close monitoring and testing in humans.
Dr. Sergio Catz has been studying the effects of cystinosis on chaperone-mediated autophagy for several years, and he tested a molecule in this pathway that may rescue this important function in cells. He created jellybeans containing the compound and fed them to knockout mice, and they had decreased polyuria, phosphaturia and proteinuria, which may mean improvement in Fanconi syndrome. There was no change in cystine levels, so it would likely need to be taken along with cysteamine.
In addition to these exciting updates on possible therapies for cystinosis, we heard talks about bone, muscle, and neurologic disease, which are very important issues as people with cystinosis live longer. We heard many talks about the molecular mechanisms of cystinosis, which may yield therapeutic targets in the future. Multiple scientists also shared new models for studying the disease, including genetically engineered rats, zebrafish and stem-cell derived organoids. Dr. Benjamin Freedman was invited to give the keynote address on his work creating polycystic kidney organoids two years ago, and now he is currently working on creating cystinosis organoids which could be used to study the disease and test new drugs.
It was exciting to see the scientists ask each other tough questions and help each other troubleshoot their experiments in a collaborative way.
Every symposium breeds new connections, and I’m excited to see what comes out of these partnerships. I am grateful for all their hard work and I’m amazed at how much the CRF and these scientists have been able to accomplish. It gives me and my family so much hope for the future.