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!
