MANF Therapeutics is developing mesencephalic astrocyte-derived neurotrophic factor (MANF) as a therapeutic protein for the treatment of certain protein-misfolding and neurological disorders. MANF is currently in pre-clinical development as a disease modifying treatment for Parkinson’s disease and Wolfram’s Syndrome. In Wolfram’s, many of the key disease etiologies, including vision loss, hearing loss, diabetes and neurodegeneration have protein misfolding as a key molecular signature that MANF could potentially address. The lead application for MANF in Wolfram’s is for the treatment of vision loss. MANF has demonstrated safety and efficacy in animals for the treatment of retinal degeneration, including the increased protection and function of rods, cones and retinal ganglion cells in the retina. Leading scientists in the Wolfram’s community believe MANF could be the first disease-modifying treatment developed for the disease. MANF Therapeutics is in the process of raising capital to support preparations for clinical trials, and thereafter the initiation of human clinical trials in Wolfram’s Syndrome and Parkinson’s. Once the capital is raised, it will take approximately 12-18 months to start clinical development.
Dear Friends,
The spring has come and the winter has gone. I experienced so many challenging events and incidents during the past winter season, and I feel that we hit the bottom and things have started to move up in the right direction. Your kind words and encouragement are the engine for my quest to a cure for Wolfram syndrome. It is my pleasure to tell you about our ongoing clinical trial and therapeutic strategies.
A Drug-Repurposing Clinical Trial
Our drug-repurposing clinical trial of dantrolene sodium in patients with Wolfram syndrome is still ongoing. 19 patients could successfully complete the required 6-month phase, and many of them have decided to stay on dantrolene sodium another 18 months. We have determined the appropriate doses for adult and pediatric patients and started seeing encouraging results in their remaining beta cell functions. As this is an open-label study, we cannot conclude that these encouraging results are due to dantrolene sodium. We plan to continue this study until the end of 2019 and move on to the next step.
Because dantrolene sodium was not specifically designed to treat Wolfram syndrome, it may not be optimally suited to address all aspects of Wolfram syndrome pathophysiology. We have been developing novel drugs (endoplasmic reticulum calcium stabilizers) for the treatment of Wolfram syndrome together with a drug development team at the National Institutes of Health. Our new drug candidate seems be safer, more potent and goes to the brain and eyes more efficiently than dantrolene sodium. We are testing this candidate drug in brain cells differentiated from induced pluripotent stem cells (iPSCs) derived from our patients and plan to conduct further studies in humanized Wolfram mice and rats.
Molecular Prosthetics
Another common molecular issue in patients with Wolfram syndrome is cellular stress caused by the expression of mutant Wolfram (WFS1) proteins derived from mutant Wolfram gene (WFS1) variants. To resolve this issue, we have been developing a molecular prosthesis that can optimize the structure of mutant Wolfram protein together with a biotech company in the US. Molecular prosthetics are drugs that can get into the cells and correct the abnormal structure of mutant Wolfram protein in patients’ cells.
Regenerative Gene Therapy
Our ultimate goal is to provide a cure using regenerative gene therapy. We have been trying to improve visual acuity and brain functions using safe virus expressing healthy Wolfram gene (WFS1) and a regenerative factor called MANF in a rodent model of Wolfram syndrome. In parallel, we are attempting to replace a pathogenic Wolfram gene with a healthy Wolfram gene using a gene editing technology (CRISPR/CAS9). This work is currently being done using induced pluripotential stem cells (iPSCs) generated for study of treatments for Wolfram syndrome.
Humanized Wolfram Rats and Mice
To test these cutting-edge therapies, especially gene therapy, we need animal models carrying human Wolfram gene mutations. We have successfully created rats and mice carrying human Wolfram gene mutations. We have started characterizing these animals to assess the efficacy of new treatments.
As always, please feel free to contact me with any questions or concerns (urano@wustl.edu). I would like to know what you think and how you feel. Thank you again for your support. We will decrease human suffering together.
With passion and gratitude,
Fumihiko “Fumi” URANO, MD, PhD
Professor of Medicine and Pathology, Samuel E Schechter Endowed Chair
Barnes-Jewish Hospital/Saint Louis Children’s Hospital
Washington University School of Medicine
Washington University School of Medicine
Dear Wolfram Community,
As we prepare for the research clinic and the community conference with the Snow Foundation, a few other things have been going on that we want you to know about!
First, we have published a paper that describes how the size of brain regions change over time in Wolfram syndrome. This paper is based on the brain imaging that we have done over the last 8 years in the Wolfram research clinic. You can find the paper online here: Evidence for altered neurodevelopment and neurodegeneration in Wolfram syndrome using longitudinal morphometry. The findings have important implications for current and future clinical trials for treating Wolfram syndrome neurodegeneration.
Second, we have continued to interact with other groups that are working on current and future clinical trials, both here in the US, the UK and Belgium.
Finally, we have been working with investigators in Estonia on their mouse model for Wolfram syndrome to determine whether they display similar changes in the brain to people with Wolfram syndrome. If this mouse model is similar in its brain features, we then would be able to do more specific brain studies that might suggest brain-specific treatments.
If you have any questions about any of these research projects, please let me know! I am always happy to talk to you.
Sincerely,
Tamara Hershey, PhD
Professor Scientific Director and Principal Investigator WU Wolfram Research Clinic tammy@wustl.edu
Did you know? All of your wine purchases can now directly support The Snow Foundation.
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