I have received many emails and phone calls regarding our therapeutic development for Wolfram syndrome in the past several weeks. Thank you so much for your kind words and encouragement. I would like to update you about our ongoing efforts on therapeutic development. I hope this blog will answerer some of your questions.
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.
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 the 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.
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 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 viral vectors of the 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 the study of treatments for Wolfram syndrome.
Humanized Wolfram Rats and Mice
To test cutting-edge therapies, especially gene therapies, 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 (firstname.lastname@example.org). I would like to know what you think and how you feel. Thank you again for your support. I’d like to decrease human suffering and fulfill unmet medical needs with you.