Dr. Urano's Blog

Strategy for developing drugs for the treatment of Wolfram syndrome – my current efforts

I have two goals for treating patients with Wolfram syndrome.

1. Halt the progression by drugs.
2. Restore damaged tissues using iPSCs cells modified by the genome editing.

As I mentioned before, we created iPSCs (induced pluripotent stem cells) using skin cells from patients with Wolfram syndrome. These cells can be differentiated into any types of cells.

I’d like to briefly summarize my efforts on goal #1 today. To discover drugs, I am currently leading three projects.

1. Looking for FDA-approved drugs that can potentially halt progression of Wolfram syndrome.

We looked for drugs that can protect cell death mediated by the leakage of calcium from the endoplasmic reticulum (ER) to the cytosol. We found four FDA approved drugs and one supplement so far. We are testing these drugs in Wolfram iPSC-derived neural progenitor cells and mouse models of Wolfram syndrome.

2. Looking for a new class of drugs that can protect cell death mediated by endoplasmic reticulum dysfunction.

We have developed a drug screening method to identify drugs that can protect cell death mediated by ER dysfunction. In collaboration with a non-profit organization, we are actively looking for a new class of drugs that can potentially halt the progression of Wolfram.

3. Testing if MANF (mesencephalic astrocyte-derived neurotrophic factor) can suppress the ER calcium leakage-mediated neuronal cell dysfunction in Wolfram iPSC-derived neural progenitor cells.

I will talk about more on MANF some other time. I thought that this was a good biomarker for Wolfram syndrome because expression of this molecule is increased by ER dysfunction. However, the increase of MANF might be an adaptive mechanisms of our cells to cope with abnormal ER function.