clinical trial

Here you will find news updates, papers and links from the Clinical Trial Team in Birmingham.
26 November 2018(Publish Date)
TREATWOLFRAM CLINICAL TRIAL UPDATE
Tim Barrett

Dear Tracy, Jody, I wanted to update you and your correspondents about the status of the clinical trial since the Wolfram family conference in October.

The medicine and placebo. So Guy's and St Thomas's Pharmacy Manufacturing Unit (GSTT) have sourced a company that will make the medicine; and have been putting a supply contract in place. Meanwhile the clinical trial sponsor, University of Birmingham, have been negotiating their contract with GSTT to pay for the work. This is due to be signed off this week; after which GSTT will make the placebo tablets. This takes 2 weeks. The plan is for GSTT to do the final quality checks, and get the medicine and placebo to the clinical trials pharmacy department at Birmingham Women's and Children's Hospital (BWCH) the week beginning Monday 18 Dec.

Clinical trial site: BWCH. The children;s hospital site will be the first to open. The costs for running the study are being finalised; there has been a lot of negotiation. I am really pleased to say that BWCH had its site initiation visit today, with training in the study being provided to the local study team. All being well, the site will be open to recruit participants from w/b Monday 18 Dec. We will start by posting out participant and parent information sheets to all children and young adults under care of BWCH. I had hoped that we could post out patient information sheets soon after the family conference. Unfortunately, the rules around clinical trial governance mean that I am not allowed to post out these sheets until a site has been officially opened. I am sorry about this. Potential participants will have consent taken, study procedures undertaken, and medicine or placebo dispensed, from the first Wolfram MDT clinic in January. We hope to recruit 25 children and young adults to the BWCH site during 2019.

Clinical trial site: University Hospitals Birmingham. This site will be the second to open; most likely during January or February 2019. The costs for running the study are being negotiated. We are also discussing how to offer MRI scans and eye tests to adult participants.

International clinical sites: we expect Poland to be the first site to open, hopefully in February, followed by France, then Spain.

I know the development of this clinical trial has been lengthy, and frustrating for many of you. For that I can only apologise. In mitigation, I am learning that clinical trials are governed by strict rules designed to keep participants' safety the top priority. We are getting really close now, please bear with us, and thankyou to those of you who have sent in comments and suggestions.

We will do our best to offer participation to all patients in the first half of 2019.

Sincerely

Tim Barrett
On Behalf of the clinical trials team
26 September 2018(Publish Date)
Update from Fumi Urano
Dear Friends,

Thank you for your continued trust, support, and encouragement. People like you keep me going. Although I cannot attend the Wolfram UK conference this year, I often think about patients and their families and friends in the UK. Therefore, I would like to update you about our ongoing clinical trial and therapeutic development.

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 for another 18 months. We have determined the appropriate doses for adult and paediatric 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. It is too early to determine the effect of Dantrolene sodium on visual acuity. We plan to continue this study until the end of 2019/early 2020.

We are aware that a drug-repurposing is not the best approach to halt the progression of Wolfram syndrome. We need cutting-edge treatments specifically designed for Wolfram syndrome. We have been actively developing novel treatments together with the drug development team of National Institutes of Health/National Center for Advancing Translational Sciences in the US and a few biotech companies in the US and Japan.

ER Calcium Stabilizers
One of the common molecular pathways altered in patients with Wolfram syndrome is imbalanced cellular calcium homeostasis. More specifically, endoplasmic reticulum (ER) calcium levels are lower in patients with Wolfram syndrome, leading to cell dysfunction and death. To overcome this challenge, we are currently testing if an ER calcium stabilizer, Dantrolene sodium, can delay the progression of Wolfram syndrome. We are aware that Dantrolene sodium may not be the best ER calcium stabilizer for Wolfram syndrome patients. We are developing novel ER calcium stabilizers (i.e., second-generation Dantrolene) for the treatment of Wolfram syndrome together with a biotech company in Japan and National Institutes of Health in the US. These second-generation ER calcium stabilizers should be more potent and safer, and should go to the brain and eyes more efficiently than Dantrolene sodium.

Molecular Prosthetics
Another common issue in patients with Wolfram syndrome is ER stress caused by the expression of mutant Wolfram protein due to Wolfram gene mutations produced in patients cells. To resolve this issue, we have been developing 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 viral vectors of healthy Wolfram gene and a regenerative factor called MANF in mouse models. Using a gene-editing CRISPR/CAS9 technology, we are attempting to replace a pathogenic Wolfram gene with a healthy Wolfram gene. This work is currently being done using induced pluripotential stem cells (iPSCs) generated for study of treatments for Wolfram syndrome.

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,
Fumi Urano, MD, PhD
Professor of Medicine and Pathology and Immunology, Samuel E Schechter Endowed Chair
Physician, Medicine and Medical Genetics and Genomics, Washington University Medical Center, USA

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