Identifying Small Molecules for the Treatment of Multiple Sulfatase Deficiency

Multiple Sulfatase Deficiency Action Foundation announces research partnership withChildren’s Hospital of Philadelphia’ (CHOP), USA, August 8th 2018

Research project: Identifying Small Molecules for the Treatment of Multiple Sulfatase Deficiency

Principle Investigator: Beverly Davidson, PhD

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Professor of Pathology and Laboratory Medicine. Director Raymond J. Perelman Center for Cellular and Molecular Therapeutics, University of Pennsylvania & The Children’s Hospital of Philadelphia. Chief Scientific Strategic Officer.

Co-Applicant: Rebecca Ahrens-Nicklas MD, PhD


Attending Physician, Division of Human Genetics, The Children’s Hospital of Philadelphia

Lay abstract of the research project:

Multiple Sulfatase Deficiency (MSD) is an inherited lysosomal storage disorder (LSD) that predominately involves the brain, bones, and skin. The disease is due to mutations in SUMF1, a gene that provides the instructions for making an important enzyme called formylglycine-generating enzyme (FGE). The FGE enzyme activates all the sulfatases in cells throughout the body.  Sulfatases break down sulfate-containing molecules.  Without functional sulfatases, molecules build up in the lysosomes leading to cellular dysfunction.

No curative therapies exist for MSD. Drug development is hindered by the fact that a meaningful therapy must cross the blood brain barrier. Also, the ultra-rare nature of MSD has led to limited interest from pharmaceutical companies. In the work proposed here, we aim to overcome these challenges by using powerful computational tools to identify FDA-approved drugs that can cross the blood-brain barrier and be re-purposed to treat MSD.

We will collect blood from MSD patients and make induced pluripotent stem cells (iPSCs). These are immature cells that can be used for a wide array of studies. We will look to see what genes are turned on differently in iPSCs from MSD patients as compared to controls.  Next, we will take advantage of the publically available NIH LINCS database that provides data on how genes are turned on or off in response to more than 40,000 drugs, many of which are already FDA-approved and can get into the brain.  We hope to identify drugs that turn on genes that would reverse the effect of the SUMF1 mutation (i.e. would convert gene expression from the diseased-pattern to that of controls).  We will then test if these drugs can turn on sulfatases in MSD patient iPSCs. Promising, approved therapeutics can then be evaluated in animal models with the ultimate goal of moving to clinical trials in patients.  In future studies,  lead compounds could be tested on cells isolated from patients with single sulfatase deficiencies to evaluate their utility in other mucopolysaccharidoses.