MANF (mesencephalic-astrocyte-derived neurotrophic factor) is believed to have broad potential because it is a naturally-occurring protein produced by the body for the purpose of reducing and preventing apoptosis (cell death) in response to injury or disease, via the unfolded protein response. By manufacturing MANF and administering it to the body, Amarantus is seeking to use a regenerative medicine approach to assist the body with higher quantities of MANF when needed. Amarantus is the front-runner and primary holder of intellectual property (IP) around MANF, and is initially focusing on the development of MANF-based protein therapeutics.
Publication: ScienceDirect.com | Publication Date: July 2020
Authors: Dawid P.Grzela, Beata Marciniak, Lukasz Pulaski
Abstract
Wolfram Syndrome is a rare, autosomal recessive genetic disorder with clinical symptoms appearing in early childhood. Here, we report a generation of iPSCs from fibroblasts of a patient affected by this disease. Read more
Dear Families:
We (Drs. White, Marshall, Urano, and Hershey) are excited to announce that we are now funded to perform a clinical trial of liraglutide (Victoza®; NovoNordisk) in Wolfram Syndrome. Led by Drs. White and Marshall, this study will focus on the tolerability and safety of liraglutide and possible beneficial effects. We are inviting all participants over 10 years old in the Wolfram Research Clinic to participate in this study.
Liraglutide is a compound that is a glucagon-like peptide-1 (GLP-1) receptor agonist; that is, it acts like the natural hormone GLP-1. GLP-1 increases the release of insulin from the pancreas after a meal and slows down the digestion of the meal; this lowers blood sugars in people with type 2 diabetes. Liraglutide is approved by the Food and Drug Administration (FDA) for use in adults and children older than 10 years old with type 2 diabetes. In animal models of Wolfram syndrome, liraglutide has also been shown to slow the progression of diabetes, and possibly neurodegeneration. It is not known if this is also true in people with Wolfram Syndrome.
Participation in this study would require injecting liraglutide once a day for 12 months. Being on liraglutide will likely lower blood sugars and insulin doses, but it is unlikely to eliminate the need for insulin completely. In addition, evaluations of insulin secretion, vision, and an MRI would be conducted at the annual research clinic, and data would be shared between those two studies. Participation in this study is voluntary, and you will be free not to participate or to stop participating at any time, and you will still be able to keep participating in the research clinic.
If you are interested in learning more about this study we will discuss it with you during your visit to the Wolfram Syndrome Research Clinic, or you can contact Dr. Neil White at (314) 286-1157 or Dr. Bess Marshall at (314) 454-6051, and we can discuss it with you further.
Neil H. White, MD (314) 286-1157
Bess A. Marshall, MD (314) 454-6051
Fumihiko Urano, MD, Ph.D.
Tamara Hershey, PhD
Publication: Nature.com | Publication Date: May 4, 2020
Authors: Jana Mahadevan, Shuntaro Morikawa, Takuya Yagi, Damien Abreu, Simin Lu, Kohsuke Kanekura, Cris M. Brown & Fumihiko Urano
Abstract
Endoplasmic reticulum (ER) stress-mediated cell death is an emerging target for human chronic disorders, including neurodegeneration and diabetes. However, there is currently no treatment for preventing ER stress-mediated cell death. Here, we show that mesencephalic astrocyte-derived neurotrophic factor (MANF), a neurotrophic factor secreted from ER stressed cells, prevents ER stress-mediated β cell death and enhances β cell proliferation in cell and mouse models of Wolfram syndrome, a prototype of ER disorders. Read more
Dear Friends,
I hope you and your family are safe and well during this COVID-19 pandemic. Three things are always on my mind: Improve clinical care, Raise awareness, and Provide a cutting-edge treatment for Wolfram syndrome. As I mentioned on January 1st, I am determined to make 2020 the game-changing year for us despite this challenging time. Today, I would like to share the good news with you.
We have been testing if gene editing by CRISPR-Cas9, in combination with patient-derived induced pluripotent stem cells (iPSCs), can be utilized for the treatment of Wolfram Syndrome.I am glad to inform you that gene editing worked in Wolfram patient iPSC-derived beta cells. We were able to use these cells to cure one of the problems, making normal beta cells by correcting WFS1 gene mutation. We could cure diabetes in cells and mice. This is a proof of concept demonstrating that correcting gene defects that cause or contribute to medical problems— in this case, in the Wolfram syndrome gene — we can cure the problems. This is a major discovery in the gene therapy field, and it has been just published in a high-profile medical research journal, Science Translational Medicine.https://medicine.wustl.edu/news/diabetes-reversed-in-mice-with-genetically-edited-patient-derived-stem-cells/
Based on this discovery, it is now possible that by correcting the genetic defects in these cells, we may correct other problems Wolfram Syndrome patients experience, such as visual impairment and neurodegeneration. So, we are currently working on eye and brain cells derived from iPSCs of patients with Wolfram Syndrome to replicate this success for other problems. Many, many thanks to my patients, colleagues at Washington University and supporters in the world. Thank you, Stephanie Snow Gebel and the Snow Foundation.
As always, please feel free to contact me with any questions (urano@wustl.edu). I would like to know what you think and how you feel. Thank you again for your continued support and encouragement, especially in this very trying time, not only for our country, but the world. We will work as one team and change history together.
“That’s one small step for us today, leading to one giant leap toward a cure for Wolfram Syndrome.”
Sincerely,
Fumi Urano, MD, PhD
April 23, 2020
Publication: Nature.com | Publication Date: March 16, 2020
Authors: Chiara La Morgia, Alessandra Maresca, Giulia Amore, Laura Ludovica Gramegna, Michele Carbonelli, Emanuela Scimonelli, Alberto Danese, Simone Patergnani, Leonardo Caporali, Francesca Tagliavini, Valentina Del Dotto, Mariantonietta Capristo, Federico Sadun, Piero Barboni, Giacomo Savini, Stefania Evangelisti, Claudio Bianchini, Maria Lucia Valentino, Rocco Liguori, Caterina Tonon, Carlotta Giorgi, Paolo Pinton, Raffaele Lodi & Valerio Carelli
Abstract
Wolfram syndrome (WS) is a recessive multisystem disorder defined by the association of diabetes mellitus and optic atrophy, reminiscent of mitochondrial diseases. The role played by mitochondria remains elusive, with contradictory results on the occurrence of mitochondrial dysfunction. Read more
Publication: Orphanet Journal of Rare Diseases | Publication Date: February 22, 2020
Authors: Raul Alfaro, Tasha Doty, Anagha Narayanan, Heather Lugar, Tamara Hershey & M. Yanina Pepino
Abstract
Background: Wolfram syndrome is a rare genetic disease characterized by insulin-dependent diabetes, optic nerve atrophy, sensorineural hearing loss and neurodegeneration. Read more
January 29, 2020
Dear Friends,
I hope 2020 has been going well for you. Thank you for your email, letters, and messages at the end of last year. I really appreciated your encouragement. I am determined to make 2020 the game-changing year for us. Three things are always on my mind: Improve clinical care, Raise awareness, and Provide a cutting-edge treatment for Wolfram syndrome. I have four goals for 2020.
1. Set up a new clinical trial for Wolfram syndrome using a new drug (more specifically, get an orphan drug designation, create a trial protocol, and secure funds)
2. Complete preclinical studies for gene therapy for optic nerve atrophy in Wolfram (more specifically, complete studies in rodent and iPSC models) and start setting up a clinical study.
3. Start preclinical studies for gene therapy for brain dysfunction in Wolfram syndrome.
4. Set up genetic testing for genetic forms of diabetes and ER stress-related disorders and create a clinical service for those patients.
As always, please feel free to contact me with any questions (urano@wustl.edu). I would like to know what you think and how you feel. Thank you again for your continued support and encouragement. I am determined to make a difference in the future of our patients. We will work as one team and change history together.
Sincerely,
Fumi Urano
Publication: American Diabetes Association | Publication Date: January 2020
Authors: Meihang Li, Sihua Wang, Kuanfeng Xu, Yang Chen, Qi Fu, Yong Gu, Yun Shi, Mei Zhang, Min Sun, Heng Chen, Xiuqun Han, Yangxi Li, Zhoukai Tang, Lejing Cai, Zhiqiang Li, Yongyong Shi, Tao Yang and Constantin Polychronakos
Abstract
It is estimated that ∼1% of European ancestry patients clinically diagnosed with type 1 diabetes (T1D) actually have monogenic forms of the disease. Because of the much lower incidence of true T1D in East Asians, we hypothesized that the percentage would be much higher. Read more
Publication: BMC Medical Genetics | Publication Date: January 14, 2020
Authors: Maryam Sobhani, Mohammad Amin Tabatabaiefar, Soudeh Ghafouri-Fard, Asadollah Rajab, Asal Hojjat, Abdol-Mohammad Kajbafzadeh & Mohammad Reza Noori-Daloii
Abstract
Conclusions: The mutational and phenotypic spectrum of WS is broadened by our report of novel WFS1 mutation. Our results reveal the value of molecular analysis of WFS1 in the improvement of clinical diagnostics for WS. Read more
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