Monday, May 11, 2015

newport beach 2015

Here is a movie of some of the highlights from our recent vacation to California.  Even though we had to come home early, it was pretty fun!  We listened to a lot of alt-J on the trip, hence the song choice.

Here are some photos too:

Lars in flight
On the way to the beach at Crystal Cove State Park

Sam doesn't like posing for family pictures

Checking out the tidepools

Obligatory Disneyland photo

On the Jungle Cruise

Building our own lightsabers (best souvenir ever)

Watching the Jedi training

Our Disneyland tour guides Paige and Taylor

Loving the Tea Cups

Lars loves cuddling with Uncle Taylor


At the Balboa Pier

Grandma and Lars pondering the mysteries of the cosmos

At Laguna Beach with Sam's best buddy Henry Sturgis

On Captain Dave's whale watching boat
Sea sick

Hundreds of dolphins!  We also saw a mother and calf grey whale

All the CRF photos are courtesy of Lars Wanberg
Sam and Lars with their friends Henry and Tina

Sharing our wishes at the Day of Hope conference

My mom and dad at their first CRF conference

Giving a talk about the cystinosis basics

Lars the photo bomber
The kids got a visit from a mad scientist

Digging at the Balboa Bay Resort beach
Lars building a sand castle with Dr. Grimm's son

My heroes: Jeff and Nancy Stack and Stephanie Cherqui

Lars and the cystinosis crew

Friday, May 1, 2015

Is Rituximab Working?

We had a nephrology appointment for Samuel and Lars today.

Lars's portion was very quick.  His kidneys still show no sign of Fanconi syndrome, and his growth trajectory has stayed in the 90th percentile.  He's gaining on Sam in weight pretty quickly.  He was excited to show the doctor the g-tube button I drew on his tummy last night.  Early diagnosis is huge! 

Sam's portion was lengthy, to say the least.  A lot has happened.  Sam got two doses of rituximab, a week apart, the beginning of April.  Then we went to Newport Beach, CA for family vacation and the Cystinosis Research Foundation family conference the third week of April.  Sam had a cough and runny nose when we drove to California, and seemed to be more tired.  We went to Disneyland on that Tuesday, and that totally wore him out by about 3 PM.  He refused to walk anymore and slept in his stroller from about 4 PM to 8 PM while Lars continued going on rides.  That night he vomited multiple times and had trouble keeping his potassium and citrate down.   On Wednesday we slept in and Sam didn't feel well.  He rallied for an afternoon at Laguna Beach with his best buddy Henry Sturgis, but afterwards he was too sick to eat dinner with us.  We thought that he was just exhausted from a busy vacation with lots of days in the hot sun.

That night we met up at the Balboa Bay Resort for the CRF welcome dinner.  He was surrounded by so many old friends, including Henry and Jackson, that he forgot he was sick and went wild.  Friday was the first day of meetings, so we dropped Sam and Lars off at the babysitters, which is Sam's absolute favorite thing (more than Disneyland!).  He said he didn't feel well, and instead of joining in on the fun and games, he sat by the television.  When we went to pick him up he told us his right wrist was hurting, and he refused to move his right arm.  He had pain with walking too, especially on the right side, and had to be carried.  He spent Friday night wrapped up in a blanket, sitting in the stroller, instead of playing on the beach. Henry came and checked on him lots of times to see how he was doing.  He is such a good friend.  When we brought Sam back to the hotel he was in agonizing pain in his right wrist and wouldn't walk because his legs hurt.     

We called our nephrologist back home who thought it sounded like a viral infection.  He recommended supportive care.  We let him sleep in on Saturday morning, hoping some more rest would help.  His wrist was still very painful that morning, and he was acting really sluggish.  Ashton called our nephrologist again, and he became more concerned that this was a possible drug reaction.  He recommended that we take him to a hospital in California to be seen by a doctor.  We knew this carried the risk of him being admitted to the hospital there.  Luckily we were at a conference with many doctors, including Dr. Grimm, who used to see Sam in the RP103 trial.  Dr. Grimm was very kind to evaluate Samuel.  He was concerned that Sam had a reactive arthritis, that could be viral, or it may have something to do with Sam's prednisone taper.  He recommended going back up to 30 mg of prednisone and then driving back to Utah to be seen at Primary Children's.  We agreed that this was probably the best plan so with very heavy hearts we left the conference early to head home.

Sam threw up a lot on the way home, but eventually it stopped.  His wrist stopped hurting too, and suddenly he wanted to eat again.  I think lots of prayers were answered that day.  We made it back in 10 hours.  We went to Primary Children's, and fortunately Sam's nephrologist was there rounding.   Sam's potassium was low, but our nephrologist didn't think he needed to be admitted, especially since his wrist was looking better.  We had been holding Sam's lisinopril because of dehydration, so the protein in his urine had shot up pretty high again.  We went home and hydrated Sam with lots of pedialyte.

We were lucky Sam didn't have to be hospitalized.  We continued him on prednisone 30 mg for a total of 5 days, and then tapered down by 5 mg every couple days.  We had to re-live all the tantrums and mood lability again, but his other symptoms improved and he was able to go back to school.  We've tapered him down to 5 mg daily right now, and this doesn't make him too cranky.

At today's visit, Sam's growth has plateaued.  We might have to supplement with tube feeds again, but for now we'll keep monitoring.  His potassium is still pretty low, so we had to go up on that today.  He was on 20 mEq four times a day (a lot!) and now he'll be on 27 mEq four times a day.  Dang that Fanconi's syndrome.  His bicarbonate and phosphate are normal and his glomerular filtration is good.  His albumin has normalized too, which is a good sign.

So is the rituximab working for his membranous nephropathy?  We measured his B-cells before and after starting therapy.  We can confidently say that the rituximab has obliterated his B-cells.  In studies of adults with membranous nephropathy, once the B-cells are gone, you don't have to continue rituximab infusions, so our doctor has decided we can wait on further treatments.

Whether rituximab will lead to disease remission remains unclear.  If Sam continues to have the same level of inflammation in his kidneys and protein in his urine, his kidneys will start to decline, and he would need a kidney transplant in 1-2 years.  That's a scary thought, but even more scary is the notion that kidney transplant isn't necessary curative for this condition.  If the antibodies are still around, they will attack the donor kidney too.  So we really need to get rid of those antibodies.

Dr. Cherqui's strategy to cure cystinosis is to take hematopoietic stem cells from the patient, modify them with gene therapy, and then transplant them back.  In this process, the patient's bone marrow has to be eradicated with chemotherapy before the autologous transplant.  I've been musing about whether this could cure Sam's membranous nephropathy too.  Get rid of the immune cells, including the plasma cells that are making the culprit antibodies, and then transplant back healthy, undifferentiated stem cells, that would grow up to be responsible, kind immune cells, with nothing against Sam's kidneys.  I actually found a small series where autologous stem cell transplant was tried in 12 patients with treatment-refractory membranous nephropathy.  Patients did have an initial significant reduction in the level of protein in their urine, but it didn't last.  The big difference, however, is they did not have bone marrow eradication prior to transplantation, so the bad guy immune cells were still hanging around.  It makes me think that Dr. Cherqui's human trials can't come soon enough.

There was one glimmer of hope today.  When Sam was first diagnosed with membranous nephropathy, his albumin/creatinine ratio was over 14,000 (that's crazy high).  The lowest we could get it with prednisone and lisinopril was 4800.  Today it was actually down to 3600 g.  Not a complete response, but maybe the rituximab is working . . .    

Wednesday, April 22, 2015

Day of Hope CRF Family Conference 2015

We just got back from Newport Beach, California, where we attended the Cystinosis Research Foundation's family conference.  We look forward to it all year.  This year we were really excited to have my parents join us.

The conference kicked off on Thursday with the welcome dinner.  It's one of the best nights because we get to see so many friends from around the country (and world!).  It's like a big family reunion.  Thanks to the internet we can follow along with our many cystinosis family friends, but nothing beats getting together and catching up.

Sam and Lars didn't waste any time getting together with their buddies.  Unfortunately they both insisted on bringing their lightsabers (Disneyland souvenirs) with them.  Sam found Henry Sturgis and they immediately started having lightsaber duels right in the middle of the crowd.  I appointed myself designated babysitter and escorted them, along with Jackson Blum, to the lawn outside where they could be as rowdy as they wanted.  It was fun to see all the little kids running around in herds.  When we left that night Sam was so sad to be separated from Henry.  He cried, "I don't want to be apart from Henry!" all the way to the hotel.  We assured him they could have breakfast together the next morning, which they did.

Friday morning started off early with family introductions.  There was a record number of families this year!  Everyone got up and shared their wishes for themselves and their children.  We wrote our wishes on colorful paper birds and put them on a large picture of a tree.   I wish for the same thing every year, and that is that Sam and Lars will have long, happy and healthy lives.  Ashton wished that some day Sam and Lars would be able to be dads.

Nancy started off the first session by talking about the many milestones accomplished by the Cystinosis Research Foundation so far.  I followed her with a talk about the basics and history of cystinosis -- a little primer to provide context for the research talks.

Dr. Paul Grimm talked about the nuances of cysteamine therapy.  He talked about both Cystagon and Procysbi, and the proper way to take them.  One of the important points he made was the effects of food on the absorption of cysteamine.  Many people find if they take it with food, they have fewer side effects.  That's because food interferes with absorption of cysteamine, so it's not working as well.  Protein and fatty foods are the worst things to take with Cystagon.  Procysbi works best if you take it with something acidic, like orange juice.  The beads dissolve early if you take it with something with a basic pH, like milk, so you get reduced efficacy.  Procysbi should be taken at least 2 hours after eating, and you should wait at least a half hour after taking it before eating again.  Dr. Grimm also made the point that the goal is not to get WBC cystine levels all the way to zero.  Carriers of the cystinosis gene (like me) don't have cystine levels of zero.  If you use too much cysteamine you run the risk of developing copper deficiency, which leads to collagen abnormalities, skin lesions and poor wound healing.  

Dr. Mary Leonard, a nephrologist from Stanford, talked about the new study she is doing with Dr. Grimm on bone and muscle health in cystinosis.  This is a really important topic that has not received a lot of research attention in the past, especially bone health.  People with cystinosis have lots of risk factors for abnormal bone density and structure.  They are planning to do a comprehensive evaluation of 30 children and adults with cystinosis using high-resolution quantitative CT scans, DXA scans, and exercise equipment to assess muscle strength.  This study will provide background data needed to do future studies on possible interventions like mineral supplementation and hormones.  The most important things we can do now for good bone health include adequate nutrition, phosphorus and vitamin D supplementation, and weight-bearing activity.

Dr. Bruce Barshop from UCSD talked about a new white blood cell cystine test he has developed.  The old WBC cystine test has a lot of variability because there are two main types of white blood cells: granulocytes and lymphocytes.  The granulocytes contain the cystine.  The ratio of granulocytes and lymphocytes varies from person to person and day to day.  During a viral illness, lymphocytes spike to a higher number, so much less cystine is recovered in the lab test, which can give a falsely low cystine level (a little troubling!).  Dr. Barshop has developed a new test using immunomagnetic beads to separate the granulocytes from the lymphocytes, giving a more pure preparation with more reliable cystine levels.  With the new test, individual hospital labs won't have to process the blood anymore.   This means any lab can send blood in a yellow top tube express overnight to Barshop's lab to be analyzed.  This will be a huge blessing to people in smaller towns or rural areas where hospital labs are not trained to process blood for WBC cystine testing.  There will also be a new reference range for target cystine levels.  Basically 1.7 will become the new 1.0.  

After Dr. Barshop's talk, we had a Q&A panel with representatives from Raptor Pharmaceuticals and Sigma Tau.  People were able to voice their concerns about drug access (especially outside the U.S.), cost and insurance coverage, and side effects.  

Dr. Sergio Catz from the Scripps Research Institute talked about his lysosome research.  Typically we think of cystinosis as a disease of cystine accumulation INSIDE the lysosome.  He has found, however, that because another receptor (LAMP-2A) in the lysosome membrane is impaired, there is also accumulation of proteins OUTSIDE the lysosome, and this also leads to cellular dysfunction.  He has also found a drug that improves cystine emptying from the lysosome by stabilizing a protein called Rab27, which is expressed at lower levels in cystinosis.  This work has been done in cell cultures, so the next step is to test the drug in knockout mice.

Dr. Francesco Emma, all the way from Bambino Gesu Children's Hospital in Rome, Italy, talked about screening existing drug libraries for new molecules for treating cystinosis.  His lab looked at 1280 different drugs in cystinosis cells to find molecules that reduce cystine levels and protect the cells from apoptosis (a type of cell death).  They found one drug that does both of these things, and it could be a potential new therapy for cystinosis.  The good news is it's already approved by the FDA for something else.  His lab is testing it now in knockout mice.  Hopefully in the next year he will be able to reveal the identity of this exciting mystery drug!

Next we heard from Dr. Stephanie Cherqui, who gave us an update on her stem cell research.  She explained the mechanism of how hematopoietic stem cell transplantation rescues organ function in mice with cystinosis, which I broke down in previous blog posts (here and here).  She gave us progress updates on the safety studies that the FDA requires prior to human trials, and so far, everything has gone smoothly.  She predicts that she will be done with the safety studies in 8 months, and then she can go back to the FDA to start the phase I trial.  The plan is to recruit two people per year, with a total of 6 people.  She has organized the Cystinosis Stem Cell and Gene Therapy Consortium, which is large group of physicians and scientists who will design the trial and evaluate the participants throughout the study.  2016 is going to be a big year!!

After Dr. Cherqui, we heard from Dr. Celine Rocca, who works with Dr. Cherqui at UCSD.  She presented her research on the effects of HSC transplantation on corneal cystinosis.  She showed that after allogeneic HSC transplant, cystinosis knockout mice had significant reduction in cystine crystals, restoration of normal corneal thickness and lower intraocular pressure 12 months later.  This is the first time someone has shown that HSC transplantation can treat an inherited corneal disease.

Dr. Jennifer Simpson from UC Irvine spoke about the many ways cystinosis affects the eyes.  We usually only think about the corneal crystals, but every compartment of the eye is affected, including the retina, conjunctiva, iris and ciliary bodies.  One of the biggest take home message was that we shouldn't blame all eye symptoms on the cystaran eye drops.  Dry eyes, red eyes or painful eyes can be signs of other eye diseases, like keratitis and glaucoma.  She is working on cystinosis guidelines for ophthalmologists, many of whom have little experience treating ocular cystinosis.

Next Dr. Ghanashyam Acharya, from Baylor College of Medicine, updated everyone on the nanowafer his lab has developed to treat corneal cystinosis.  He recently published a paper on the nanowafer technology, which the popular media received with a great deal of excitement (see the NPR article here).  The nanowafer is so effective, it may replace eye drops for many diseases. Fortunately Ghanashyam worked with Baylor to give the Cystinosis Research Foundation the license for the nanowafer to treat cystinosis, so the CRF is working on filing with the FDA to start a human trial.  The hope is to enroll people in December! 

Next we had the physician/scientist panel.  We asked many of the questions that people posted on Facebook.  Many people had questions about muscle wasting and what can be done to stop it.  Dr. Trauner, a neurologist, noted we don't have an effective treatment for muscle wasting, so further research needs to be done. Levocarnitine, vitamin D, vitamin B complex and CoEnzyme Q10 are all thought to help muscle function, but there isn't any hard evidence. 

Some people asked when was the best time to start eye drops, and whether waiting till the child is symptomatic was too late.  Dr. Simpson said children should be started as soon as they are diagnosed.  

Several people also had questions regarding male infertility, since boys with cystinosis develop hypogonadism.  No one on the panel had much experience in this field, but Dr. Leonard said she would talk with her colleagues in hematology/oncology, since they have a lot of experience with preserving fertility in young children prior to chemotherapy.  We need to recruit a reproductive endocrinologist to the CRF family! 

Someone asked the question about what supplements we need to be careful with, and Dr. Grimm noted that giving someone too much phosphorus at one time can drop the calcium in the blood and cause tetany.

After the panel, Betty Cabrera, who is working with Stephanie Cherqui on the stem cell trial, spoke to us about the Cure Cystinosis International Registry.  It's really important for everyone with cystinosis to register and fill out the survey on CCIR so that scientists will have the baseline information they need to do more research.  She noted that it's one of the most important things we can do as a community to help find a cure.  Even if you've registered before, it's important to update your information annually.  The CRF has recently revamped the survey to include more pertinent questions for the nanowafer and stem cell trials.  To register, click here.        
While we were listening to grown-up talks, the kids were back with the babysitters getting royal treatment.  They watched movies, played games, did crafts, and ate all the potato chips they could cram in.  They received a visit from the "Rad Hatter," a mad scientist, Captain America and a princess named Elsa from some movie I'd never heard of.  The kids loved it. 

Friday night we had dinner on the beach and lawn.  Lars headed straight for the water and spent the night digging holes on the beach.  Sam usually does the same, but that night he was feeling sick, so he spent the night wrapped up in a blanket in our stroller. 

Nancy and Natalie Stack surprised Dr. Grimm with a short film highlighting his life and dedication to pediatric nephrology and patients with cystinosis.  They presented him with a special book of photos and letters from his cystinosis patients.  There was ice cream, frozen bananas and those wonderful light-up cotton candy wands.  Soon the beach was covered with flashing green, red and blue lights as the kids ran around with their wands.  

Unfortunately that was the extent of our participation this year.  Sam became too sick that night, and Saturday morning we had to get in the car and rush back to Salt Lake City so he could be seen at Primary Children's.  

We missed the Saturday morning sessions, including the teen and adult panel, which is always one of my favorite parts.  We also missed the big Natalie's Wish gala, which really bummed us out.  They showed the new 2015 CRF movie, which featured our family. They raised an incredible $2.3 million dollars that night.  My parents were still there and presented the check from our 2014 fundraiser, where we raised over $18,000 for cystinosis research.  I was really jealous when I learned my parents got to sit with Ghanashyam at dinner.  That dude is my hero.  

Only 350 days until next year's conference!