How to Cure Cystinosis

I still remember in 2011 when Ashton came home from the Cystinosis Research Foundation Day of Hope conference and told me there was a scientist who had cured cystinosis in a mouse model with hematopoietic stem cell transplant.  Hematopoietic stem cells, or HSCs, are the stem cells in the bone marrow that develop into blood cells, including the red cells that carry oxygen, and the white cells that make up our immune system.  I had just finished my hematology block in medical school, and what Ashton was telling me sounded preposterous.  Bone marrow transplants are definitely effective for certain blood diseases like multiple myeloma and immunodeficiencies, but it didn’t make any sense that stem cells destined to become blood cells could repair damaged kidney, liver, muscle and thyroid tissue.  Boy, was I wrong!

Dr. Stephanie Cherqui.  Photo from Cystinosis Research Foundation.

In 2009 Dr. Stephanie Cherqui showed that if you give a cystinosis mouse a bone marrow transplant, it leads to reduction of cystine in all organs, including the cornea, and preservation of kidney function.  She showed the same thing in cystinosis mice who received a HSC transplant.  The effect was still present 15 months after the transplant.  This paved the way for FDA approval for a bone marrow transplant trial for cystinosis, which is still waiting to enroll its first patient.

The idea of curing a genetic disease like cystinosis with an allogeneic bone marrow or HSC transplant is pretty exciting.  But bone marrow transplants are not risk-free.   The biggest complication is graft-vs-host disease, where the transplanted bone marrow cells actually attack the recipient, leading to severe skin, liver and gastrointestinal disease.  You also have to kill the patient's bone marrow before transplant with chemotherapy, putting the patient at high risk for infection.  Thankfully Dr. Cherqui has found a way around this.

Rather than give the person with cystinosis someone else's hematopoietic stem cells, why not take some blood from the cystinosis patient and genetically modify the stem cells to express the correct Cystinosin genes, and then give them back as an autologous transplant?  This way you already have a perfect match.  You basically eliminate the risk of graft-vs-host disease, and you don't have to use the same intensity of chemo to suppress the bone marrow prior to transplant.  Sounds pretty great, huh?

In 2013, Dr. Cherqui published research showing she had found a way to deliver the correct Cystinosin gene to stem cells with a virus, specifically a lentivirus.  The virus goes into the cell and copies its DNA, including the correct Cystinosin gene, into the stem cell's DNA.  The stem cells were then transplanted back into the mice from which they were taken, and these cystinosis mice had the same reduction in cystine and organ preservation as the mice that got allogeneic HSC transplantation.  

With these amazing results, Dr. Cherqui has now moved toward clinical trials in humans, and is currently working on safety studies for the FDA.  Hopefully in the next few years there will be a trial for autologous HSC transplant in actual patients.  All of this is possible because of the Cystinosis Research Foundation, who has funded Dr. Cherqui's research.  We are so grateful for Dr. Cherqui's tireless dedication. I won't be surprised when she wins the Nobel prize. The cure is coming!