Multiple Sulfatase Deficiency Action Foundation announces research partnership with ‘Cambridge Institute for Medical Research’ April 2018
Lay Overview of the project:
Multiple Sulfatase Deficiency (MSD) is currently an untreatable disease. From studies performed on cells and on samples from patients, we now know some of the processes inside cells that cause or influence the disease. While there is a lot to be gained from studying simple cell culture systems, this does not tell us about how the disease affects different tissues (e.g. nerves compared to muscles) and whether defects in one tissue can have consequences for other parts of the body. For this reason, we need to develop good animal models that share the same features of the disease as we see in patients. We are generating a zebrafish model for MSD that will be used for such purpose. Zebrafish are small tropical fish that are popular as a model for studying the causes of different diseases and for screening compounds to find new drugs to treat these diseases. They are vertebrates and so have very similar tissues and organs as man. Their whole genome has been sequenced and so we know the similarity between the genes and proteins in zebrafish and man. For more information on zebrafish, click here(https://irp.nih.gov/blog/post/2016/08/why-use-zebrafish-to-study-human-diseases). We will study MSD in our zebrafish model and perform a screen to identify compounds which improved the disease in the zebrafish and so therefore may be suitable to treat the disease in man.
Update expect in late 2018
Multiple Sulfatase Deficiency Action Foundation announces research partnership with The Telethon Fondation, Italy, August 2018
Research project: Generation of a mouse model of Multiple Sulfatase Deficiency for investigation of new therapies.
Principle Investigator: Nicola Brunetti-Pierri, MD. Associate Investigator, Telethon Institute of Genetics and Medicine
Lay Abstract of the research project:
Multiple sulfatase deficiency (MSD) is a rare genetic disease caused by deficiencies of multiple enzymes called sulfatases. The activity of sulfatases depends on modification made by another enzyme that is encoded by the SUMF1 gene that is mutated in MSD patients. As a consequence of SUMF1 gene mutations, the activities of all human sulfatases are substantially reduced in MSD patients. MSD is clinically very severe with rapidly progressive abnormalities that affect several organs including the brain and leading to early mortality. There are currently no available therapies for MSD. Several experimental therapies including gene therapy have been proposed. However, investigations of these strategies are limited by the severe phenotype and the short lifespan of the only available MSD mouse model. To overcome these limitations, a novel mouse model of MSD carrying a Sumf1 mutation that is expected to result in a less severe phenotype has been generated in collaboration with Cathleen Lutz, Ph.D. MBA and Maximiliano F. Presa, Ph.D. at The Jackson Laboratory (USA). We propose to fully characterize the clinical, biochemical and pathological features of this novel MSD mouse model. We believe this model will be extremely helpful to investigate novel therapeutic approaches including gene therapy.
MSD Action Foundation announces research partnership with University of Southampton, UK, in collaboration with University of Bielefeld, Germany, and University Medical Center Gottingen, Germany – 14th August 2018
Research project: Identification and Development of FGE Stabilizing Molecules: Towards a Therapy for Multiple Sulfatase Deficiency.
Professor Thomas Dierks (top left), Professor of Biochemistry, University of Bielefeld, Germany.
Dr Karthikeyan Radhakrishnan (top right), Post-doctoral fellow, University of Bielefeld, Germany.
Dr Lars Schlotawa (bottom left), Consultant for Paediatrics, University Medical Center Gottingen, Germany.
Dr Matthias Baud (bottom right), Lecturer in Medicinal Chemistry and Chemical Biology, University of Southampton, United Kingdom.
Research Summary: Multiple Sulfatase Deficiency (MSD) is an extremely rare, fatal, yet untreatable condition with an urgent need for therapy development. The loss of function of an enzyme called Formylglycine generating enzyme (FGE, encoded by the SUMF1 gene), was discovered as the molecular basis for MSD. Based on several studies on FGE, we know that alterations in FGE structure as a result of SUMF1 mutations reduce its stability and result in its loss of function. We are investigating whether stabilization of the structure of FGE in MSD patients could rescue its function and thereby cure or at least mitigate the severity of the disease. As a new therapeutic strategy to treat MSD, we are currently exploring whether small molecule drug candidates can be devised that stabilize and thus reactivate FGE function in cells. These molecules are supposed to bind to the surface of unstable FGE protein and stabilize its conformation, resulting in an increased activity. Our efforts are focused on the development of such “molecular plasters”, using complementary techniques across biochemistry, biology and chemistry in our laboratories in Bielefeld, Göttingen and Southampton. Through this collaborative project, we hope to discover new lead molecules that will form the basis of future generations of much needed drugs to treat MSD.
Multiple Sulfatase Deficiency Action Foundation announces research partnership with ‘Children’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
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.
Multiple Sulfatase Deficiency Action Foundation announces partnership with Perlara PBC, San Francisco, California, April 9, 2018
Research Project: A natural history study of Multiple Sulfatase Deficiency (MSD) in the fruit fly (Drosophila melanogaster) – The objective of discovering and validating phenotypes amenable for high- throughput drug screening, or screenotypes
Principle Investigator: Ethan Perlstein Ph.D.
Co-Applicant: Joshua Mast, Ph.D.
(An extract from Perlara’s website)
Perlara, a drug discovery platform company partnering with highly motivated families and drug developers to cure diseases thought too rare to matter, today announced a PerlQuest partnership with MSD Action Foundation (MSDAF), a research-focused charity based in Ireland. Multiple Sulfatase Deficiency (MSD) is an ultra-rare monogenic lysosomal disorder caused by mutations in the evolutionarily conserved gene SUMF1. MSD Action Foundation is aware of 62 living patients worldwide that are affected but the actual number is thought to be much higher. There are currently no approved treatments for MSD.
SUMF1 encodes a protein called sulfatase-modifying factor 1 – also known as formylglycine-generating enzyme (FGE) – that activates all sulfatase enzymes. The functional equivalent of SUMF1 exists in the model organism Drosophila melanogaster, but the fly homolog is uncharacterized. In Stage One of the PerlQuest, Perlara will complete a natural history study of fly avatars engineered to express patient-derived SUMF1 mutations. The goal is to discover phenotypes amenable for high-throughput drug repurposing and drug discovery screens.
“Multiple Sulfatase Deficiency has been on our radar for a few years since a Wisconsin family contacted me in 2015 asking if there was a way to help move MSD research forward,” says Perlara founder and CEO Ethan Perlstein, PhD. “In January 2016 that family introduced me to Alan Finglas, founder of MSDAF. We’re excited to develop the first MSD fly models with our partner MSDAF, which has embarked on the therapeutic odyssey with remarkable speed and efficiency. What’s more, MSD fly models can be ‘multi-purposed’ to impact the family of single sulfatase deficiencies, or mucopolysaccharidoses (MPS).”
“We are absolutely thrilled and excited about the prospects that the new MSD fly models will bring,” says MSDAF founder Alan Finglas. “It is evident that Perlara have wonderful facilities and expertise and we believe that they will be successful in creating a very good sceenotype fly model that can then be used for drug screening purposes. As the normal life cycle of the fruit fly is just 45 days, drug hits can be validated quickly. We hope to be able to move forward with further studies to repurpose or develop a viable treatment for MSD patients. I am sure a number of MPS conditions can also be impacted by these multi-purpose models as some of their sulfatases/enzymes are also affected in MSD.”
Update expected in late 2018.