Thank you for your support. Our progress in 2019.

Dear Friends,

As the year 2019 is coming to an end, I would like to summarize our progress this year. Tomorrow, I would like to tell you my plan for 2020.

We have been focusing our efforts on the development of regenerative and gene therapy. We successfully created the adeno-associated virus (AAV) that can deliver therapeutic molecules to target organs, especially eye cells this year. This is important because AAV is a safe virus specifically utilized for gene therapy. My team is trying to deliver a normal Wolfram gene (WFS1) and a regeneration factor (MANF) into damaged retinal eye cells (specifically the retinal ganglion cells) to maintain and improve visual acuity in patients with Wolfram syndrome. WFS1 protein is highly expressed in normal retinal ganglion cells (RGCs), a type of neuron (brain cells), in the retina of the eye. Due to WFS1 gene mutations, normal WFS1 protein is not expressed in Wolfram patients’ RGCs as you know. Thus, it is important to deliver the normal WFS1 gene into patients’ RGCs to maintain and improve eyesight. We have been attempting to regenerate damaged RGCs by delivering MANF into patients’ RGCs.

To experiment on the RGCs in vitro (in the tissue culture dish), my team made them from iPSCs derived from patients with Wolfram syndrome. Remember what iPSCs are? Induced pluripotent stem cells (iPSCs) that can be made into any type of tissue. In this instance, we made retinal ganglion cells.

To experiment on the RGCs in vivo (in the living organism), we created humanized Wolfram mice and rats—rodent models of Wolfram syndrome—with encouraging results. The AAV (a safe virus used in gene therapy) was able to introduce MANF into RGCs efficiently in a mouse model of Wolfram syndrome. This is great news. However, we need to speed up the pace of this research. Repairing the eye cells will have a huge impact on the quality of life for patients with Wolfram.

The above types of experiments were done in a tissue culture dish and the gene-corrected insulin-producing pancreatic beta cells were transplanted into a mouse model, which cured diabetes in mice. The next step is to correct the gene mutations in retinal cells in a tissue culture dish, and then directly in Wolfram mice instead of using the tissue culture dish.

Here’s a quick update on another area of Wolfram research. Our clinical trial of dantrolene sodium for adult and pediatric patients with Wolfram syndrome was a mild success. The results will be published next year. It marginally helped some patients, and they continue to take dantrolene sodium. It did not help those with severe Wolfram symptoms. My team could not exclude the placebo effect. However, based on the results, I feel confident that counteracting ER stress (the type of cell stress causing Wolfram syndrome) can benefit Wolfram patients.

A better drug is needed to efficiently counteract ER stress, and my team is working on two new drugs targeting ER stress. Preclinical data, using cell and animal models, and the safety profile on both drugs look good. A multi-center trial using one of these drugs is in the planning stages, and the goal is to make this happen within the next 12-18 months.

As always, please feel free to contact me with any questions or concerns ( 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.

Fumi Urano
December 31, 2019