Dra. Gema Esteban Bueno

Especialista en Medicina Familiar y Comunitaria Coordinadora del Equipo multidisciplinar del Síndrome de Wolfram Español

 

Below are the most important activities led by  Dr. Gema Esteban Bueno as head of the Spanish Clinical Wolfram Syndrome Team and scientific head of the Spanish Association for Research and Assistance to Wolfram Syndrome (AEIASW).. It also lists the scientific-bibliographic resources that seek to disseminate, support and improve the quality of life of those affected by  Wolfram Syndrome and their families, while seeking better medical assistance from healthcare professionals. Most bibliographic resources are in Spanish.

Projects underway

ü  The Spanish Clinical Team of the Wolfram Syndrome is in the final phase of its project Study of the Clinical Phenotype and Evolutionary Course of Spanish Patients with Wolfram Syndrome. PI-0410-2016 CS 2016 – PROJECTS I+I. We look forward to publishing our results soon

ü  Soon in Spain the clinical trial coordinated at the International level by Dr. Timothy Barrett will begin and that in Spain will coordinate Dra. Gema Esteban Bueno  with the Spanish multidisciplinary group of the Syndrome of wolfram that will value patients in Almería

ü  The Spanish multidisciplinary Wolfram Syndrome team has begun to evaluate patients who do not have the criteria of inclusion to participate in the valproic acid trial to study and recommend if appropriate, GLP-1 therapy thanks to the collaboration with Dr. Mariana Igoillo-Esteve and her team.

Following this project, Dr. Gema Esteban Bueno has created a SAMFYC genetics clinical-rare diseases Group of SAMFYC in December 2019 in which is part of the Research Team of this project and whose objective is to continue the work initiated.

https://www.lavozdealmeria.com/noticia/12/almeria/167673/almeria-lidera-el-principal-equipo-andaluz-contra-las-enfermedades-rara

Protocol of action before the health act of the genetic counseling: It is currently under review for completion. Document that discloses the main genetic characteristics of Wolfram Syndrome and proposes a model of action to the healthcare professional that should offer genetic advice. This document in turn will be a means of information for patients and families about their condition, ways to prevent or mitigate it, warn about the consequences of the disease, the likelihood of transmission and how this can be avoided or improved by also providing information that would allow at-risk couples to make reproductive decisions.

Scientific Article:

Title: Natural history and clinical characteristics of 50 patients with Wolfram Syndrome.

Authors: Gema Esteban Bueno, Dyanne Ruiz-Castañeda, Javier Ruiz Martínez, Manuel Romero Muñoz, Pedro Carrillo Alascio.

 Document:  Wolfram Best Practices (WBP). Wolfram Syndrome Action Guide for Cynic Practice.

Authors:  Coordinator Gema Esteban Bueno. Authors; Spanish Clinical Group of Wolfram Syndrome. Other experts participate as external reviewers and throughout the process involves a representative of patients belonging to the Spanish Association for research and assistance to Wolfram Syndrome in order to adjust to the concerns/needs of families.

This guide has taken almost 3 years to develop given the complexity of its design when collecting degrees of evidence, expert recommendations and patient needs. Pretains to be an instrument that allows on the one hand, guide professionals involved in assisting SW patients by assisting them in making management decisions, as well as reducing variability in clinical practice by relying on a rigorous evidence-based methodology, which has the consensus of experts on the subject; and, on the other hand, be a support for patients where they can find useful information on the management of their disease, as well as the availability of resources that they can access in order to increase their quality of life.

It is a document endorsed by the Ministry of Health of Andalusia (Spain) and the Spanish Society of Family and Community Medicine SAMFYC. It will be available online free access by October 2020

Book: biopsychosocial perspective of rare diseases: Wolfram Syndrome as an rare disease model.  “perspectiva biopsicosocial de las enfermedades raras: el Síndrome de wolfram como modelo” (Authors: Gema Esteban Bueno Y Dyanne Ruiz Castañeda)

This document that will be published soon in book format, aim to guide professionals and patients about the current state of rare diseases in Spain. From a biopsychosocial perspective, issues such as the health impact of them are touched, the importance of an intervention that addresses biological, psychological and social aspects of patients and their families; and finally, Wolfram Syndrome is taken as an ER model to explain the work that the Spanish Clinical Group of SW has done in recent years, with the aim of improving the quality of life of this group. In this way, there are finally guidelines that may be applicable to the attention of various ERs.

Available in free access at: https://www.ceasga.es/app/download/7882419264/Libro%20Enf%20Raras%202%20complete.pdf?t=1584607465

Book Chapter: Socio-hermeneutic analysis of social aspects related to Wolfram Syndrome. Authors: Juan Romay Coca,  Gema Esteban Bueno, Alberto Soto Sánchez

Location: Rare Diseases: Contributions to Social and Biomedical Research / Coord. by Juan Romay Coca,2019, ISBN 978-84-949321-3-7, pp. 99-113

Language: Spanish. Parallel titles: Socio-hermeneutics analyze of social aspects related with Wolfram Syndrome

Available for free on; https://www.researchgate.net/publication/331487439_Analisis_socio-hermeneutico_de_los_aspectos_sociales_relacionados_con_el_Sindrome_de_Wolfram

Best regards,

Gema

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Professor Timothy G Barrett

University of Birmingham, United Kingdom

UPDATE ON TREATWOLFRAM CLINICAL TRIAL

Dear friends and colleagues, to recap, this is a trial of sodium valproate given by mouth, for 3 years, to try and slow down the progress of vision loss in Wolfram. It involves 4 countries in Europe and is comparing the effects of sodium valproate to placebo. The trial recruited its first patient in January 2019. We currently have 12 recruits at our children’s hospital site in Birmingham, looked after by my colleague Dr Renuka Dias. We had a pause due to Coronavirus, but I am very pleased to say that Dr Ben Wright has just recruited our first adult patient at the adult site in Birmingham. With lots of help from our international colleagues, we now have all the regulatory approvals in place in each country. We spoke with Dr Gema Esteban in Spain this week, and she will recruit her first patient in October. We hope to complete recruitment in June 2021.

We now have really accurate and reproducible assessments in each site so that we can pool the results. Our independent data monitoring committee sees all the unmasked results and if there is a strong signal of effect, or signal of no effect, they will let us know without waiting for the end of the trial.

I am very grateful to everyone who is taking part or about to take part in this trial; and we are learning a lot about how to deliver clinical trials in Wolfram, for the future. Wolfram syndrome UK have been brilliant in supporting families to attend study visits; and we are very grateful to The Snow Foundation, Eye Hope Foundation, and Association Syndrome de Wolfram for support to collect research samples, which will be available to the whole Wolfram syndrome community.

Sincerely

Dr Timothy Barrett

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Dr. Urano’s September 2020 Update

Dear Friends,

First of all, I want to express my gratitude for everything you’ve helped me achieve. Your kind words and encouragement keep me motivated and inspired.  I pray you and your family are healthy and in good spirits. I have no doubt better days are ahead, and we can rise about this crisis.

My three guiding principles are: Improve clinical care, Raise awareness, and Provide a cutting-edge treatment for Wolfram syndrome.

Here is our progress:
therapeutic-development-pipelines-and-timeline

A Drug-Repurposing Clinical Trial

Our drug-repurposing clinical trial of dantrolene sodium in patients with Wolfram syndrome has been almost concluded. Nineteen patients could successfully complete the required six-month phase, and many of them decided to stay on dantrolene sodium another 18 months. The results of this open-label clinical trial (all the participants took dantrolene sodium) show that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Although the study was small, a select few patients seemed to have improvements in diabetes-related outcomes, which might correlate with a positive trend in other outcome measures, including visual acuity and brain functions. This study justifies further investigation into using dantrolene sodium and other new drugs targeting the same molecular pathway for the treatment of Wolfram syndrome.

Novel Drugs

We are aware that a drug-repurposing is not the best approach to halt the progression of Wolfram syndrome. We need cutting-edge treatments designed explicitly for Wolfram syndrome. Based on the clinical trial data of dantrolene sodium in patients with Wolfram syndrome, we have been actively developing novel drugs in collaboration with the drug development team at the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences in the United States and a few biotech companies. We are currently focusing our efforts on developing AMX0035 together with Amylyx in Cambridge, MA, and ibudilast together with Professor Ehrlich at Yale University.

Regenerative Gene Therapy

My current focus is to develop gene therapy for Wolfram syndrome. Our ultimate goal is to provide a cure using regenerative gene therapy. We have been trying to improve diabetes, visual acuity, and brain functions using viral vectors of a healthy Wolfram gene and a regenerative factor called MANF in mouse models. We are getting encouraging preliminary results and have published two articles recently. We are currently testing two ways to deliver genes through intravitreal (for optic nerve) and intraventricular (for brain) injections.

Base Editing Gene Therapy

In collaboration with Dr. David Liu’s team at Harvard University/Broad Institute and Dr. Catherine Verfaillie’s team at the Katholieke Universiteit Leuven, we have been developing a novel gene therapy called Base Editing for Wolfram syndrome. This technology uses some components from CRISPR systems together with other enzymes to directly replace abnormal WFS1 gene with normal WFS1 gene. Although we are still at the early preclinical stage using cell models of Wolfram, we hope that we can bring this technology to our patients in the next 3-10 years. Please stay tuned.

New Genetics Clinic

To further improve the clinical care for patients with Wolfram syndrome and Wolfram-related disorders, I have created a new genetics clinic at Center for Advanced Medicine, Washington University Medical Center. We offer genetic evaluations, education, and counseling for patients and family members of all ages with or suspected to have Wolfram syndrome or WFS1-related disorders. We also provide personalized management plans based on the type of your gene variants together with other specialists at our medical center, such as Dr. Marshall, Dr. White, Dr. Hoekel, and beyond. To make an appointment with me, please call 314-747-7300 or 314-747-3294 (if you are participating in our research clinic/registry or interested in participating in the research). You can also send an email to WolframSyndrome@wustl.edu. We could cover the costs for genetic testing if your insurance does not cover the entire amount of the costs.

Finally, I want to express my gratitude to Dr. Hershey, Dr. Marshall, Mrs. Samantha Blankenship, Dr. White, and other physicians and scientists for running the Wolfram research clinic study, Mrs. Cris Brown and Mrs. Stacy Hurst for managing the Wolfram registry and clinical study, scientists in my lab, collaborators all over the world, including Dr. Barrett, Dr. Plaas, Dr. Terasmaa, Dr. Millman, Dr. Ehrlich, and supporters for my research.

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 have no doubt better days are ahead. We will go through this challenging period with unusual optimism and courage. Thank you, Stephanie Gebel and Snow Foundation. Welcome to the foundation. Pat Gibilisco. We will continue working as one team and change history together.
Fumihiko “Fumi” Urano, MD
Sincerely,

Fumi Urano, MD, PhD

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,

Update on TreatWolfram Clinical Trial

September 2020

Dear friends and colleagues, to recap, this is a trial of sodium valproate given by mouth, for 3 years, to try and slow down the progress of vision loss in Wolfram. It involves 4 countries in Europe, and is comparing the effects of sodium valproate to placebo. The trial recruited its first patient in January 2019. We currently have 12 recruits at our children’s hospital site in Birmingham, looked after by my colleague Dr Renuka Dias. We had a pause due to Coronavirus, but I am very pleased to say that Dr Ben Wright has just recruited our first adult patient at the adult site in Birmingham. With lots of help from our international colleagues, we now have all the regulatory approvals in place in each country. We spoke with Dr Gema Esteban in Spain this week, and she will recruit her first patient in October. We hope to complete recruitment in June 2021.

We now have really accurate and reproducible assessments in each site so that we can pool the results. Our independent data monitoring committee sees all the unmasked results and if there is a strong signal of effect, or signal of no effect, they will let us know without waiting for the end of the trial.

I am very grateful to everyone who is taking part or about to take part in this trial; and we are learning a lot about how to deliver clinical trials in Wolfram, for the future. Wolfram syndrome UK have been brilliant in supporting families to attend study visits; and we are very grateful to The Snow Foundation, Eye Hope Foundation, and Association Syndrome de Wolfram for support to collect research samples, which will be available to the whole Wolfram syndrome community.

Sincerely

Dr Timothy Barrett

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