Thank you so much for “coming to see me” today. It is always my pleasure and privilege to see you and talk to you. I feel your support and encouragement, and I am grateful for everything you have done for me, patients, patient organizations, the Snow Foundation, the Ellie White Foundation, Unravel Wolfram Syndrome, Wolfram Syndrome Patient Support Group, Eye Hope Foundation, Wolfram UK, Wolfram Italy, Wolfram Georgia, patient families, and friends. Just reading this blog is helping me because I can feel your support, which makes me feel stronger and committed.
I would like to share my ideas on how to provide a cure for Wolfram with you today as our first clinical trial is ongoing and we are making steady progress in the development of new drugs, regenerative therapy, and gene therapy. I have been thinking and presenting my strategy for therapeutic development of Wolfram syndrome, CURE4WOLFRAM, since 2002. My current version, 4.0, is the following.
1. Stop Progression
ER Calcium Stabilizers
One of the common molecular pathways altered in patients with Wolfram syndrome and diabetes patients 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. Dantrolene sodium is a FDA-approved drug for the treatment of muscle spasticity and high fever induced by anesthesia. We previously reported that dantrolene sodium stabilizes ER calcium levels and prevents cell death in cell and mouse models of Wolfram syndrome. We are currently conducting a clinical trial of dantrolene sodium in adult and pediatric patients with Wolfram syndrome. In collaboration with NIH/NCATS, we are also developing novel ER calcium stabilizers (i.e., second generation dantrolene) for the treatment of Wolfram syndrome.
Another common issue in patients with Wolfram syndrome is ER stress caused by the expression of mutant Wolfram protein produced in patients’ cells. To resolve this issue, we have been developing molecular prosthetics that can optimize the structure of mutant Wolfram protein together with NIH/NCATS and Amylyx, a biotech company in Cambridge, MA.
2. Protect and Regrow Remaining Tissue
Our second step towards a cure for Wolfram syndrome is to protect and regrow remaining tissue using regenerative therapy. We have discovered a naturally produced molecule in our body that can activate the proliferation of damaged beta cells and brain cells. Expression levels of this molecule, MANF, are usually low in our body. We are developing a method to enhance the activity of MANF using a pill that can mimic the functions of MANF and gene therapy (i.e., produce safe virus expressing MANF).
3. Replace Pathogenic Genes
Towards a cure for Wolfram syndrome, a genetic condition, we need to target the root cause of the disease, which is the loss of function of Wolfram syndrome gene, WFS1. Using CRISPR/CAS9 technology, we are attempting to replace a pathogenic Wolfram gene (WFS1 gene) with a healthy Wolfram gene. We are also trying to introduce safe virus expressing normal WFS1 gene into patients’ cells.
Thank you so much for being with me today. Good things happen to people who do good things. I am always hopeful and grateful. Something wonderful is going to happen to us.
With grace and gratitude,