Robert J Desnick
Icahn School of Medicine at Mount Sinai, NY·Medicine & Clinical Research
Congenital erythropoietic porphyria (CEP) is an ultra-rare inherited disease. It occurs when both copies of the gene for uroporphyrinogen III synthase (UROS) carry mutations.
- Fields
Medicine & Clinical Research
Genetics
Pharmacology
- Topics
congenital erythropoietic porphyria
rare disease
heme biosynthesis
- Grants
- 1 known grant, through Aug 2029
What they work on
- Determine the safety of oral ciclopirox olamine, a repurposed antifungal acting as a pharmacologic chaperone, in adults with CEP, using an N-of-1 phase 1/2 trial with a six-month run-in and escalating doses of 2 then 4 mg/kg.
- Test whether ciclopirox raises residual activity of the UROS enzyme enough to lower accumulated light-sensitive porphyrins and fluorocyte percentages in patients' blood.
- Assess whether treatment improves hemoglobin levels, anemia symptoms and reticulocyte measures, reducing the red-cell destruction that drives transfusion dependence.
- Evaluate changes in sunlight tolerance and quality of life as proof-of-concept clinical endpoints of the chaperone therapy.
More about the research
UROS is an enzyme in the pathway that makes heme, the iron-containing part of hemoglobin. Most of these mutations are missense changes, single amino-acid swaps that make the enzyme unstable and much less active, though not completely inactive. As a result, porphyrins pile up in red blood cells. Porphyrins are light-sensitive molecules, here the uroporphyrin and coproporphyrin I isomers. Their buildup bursts red blood cells and leads to transfusion-dependent anemia and an enlarged spleen. It also causes painful blistering on sun-exposed skin that can become infected and disfiguring. A bone marrow transplant can cure transfusion-dependent children, but donor matching, transplant complications and limited expertise restrict its use. Transfusions and iron removal do not address the underlying cause.
Why it matters
People with congenital erythropoietic porphyria currently have no drug that treats the cause of their disease. Their options are limited to transfusions or a risky transplant. If oral ciclopirox proves safe and effective, it could offer patients a pill that partly restores their faulty enzyme. That could ease anemia, sun sensitivity and skin damage, much as chaperone drugs have done for cystic fibrosis and Fabry disease.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Yvette Yien
University of Pittsburgh, PA·Biochemistry
Determine how the mitochondrial unfoldase CLPX regulates PPOX and FECH, the final two enzymes of heme synthesis, in differentiating red blood cells.
Krystalyn Hudson
University of Virginia, VA·Microbiology & Immunology
Test whether red blood cell units rich in reticulocytes, young red cells that still contain mitochondria, raise alloantibody rates after transfusion, using mouse models that mimic repeat blood donation.
Elizabeth Leibold
University of Utah, UT·Biochemistry
Determine whether loss of Irp2 serine 157 phosphorylation disrupts red blood cell production from within blood-forming cells, using bone marrow transplantation and flow cytometry of cell cycle, proliferation and iron.
The school
Icahn School of Medicine at Mount Sinai: 45 labs on PI Pages, $1.0B a year on research, 62 research doctorates a year.
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