A Battle Plan for a War on Rare Diseases

A decade ago, when their son Bertrand was still an infant, Matthew Might and his wife, Cristina realized that there was something terribly wrong.

When he cried, his eyes stayed dry; the shortage of tears damaged his corneas and threatened blindness. Eventually, he suffered seizures, a movement disorder, and a severe developmental delay.

It took four years to get the problem: Bertrand had inherited two mutations of the NGLY1 gene, which plays a key role in recycling cellular waste. That meant the child’s cells were choking on their own trash.

Eventually, Dr. Might found about 60 people with this mutation.

He found a treatment for the condition — an unintended side effect of the over-the-counter antacid Prevacid — and began working with a corporation to supply the stronger version of the drug.

Now director of the Hugh Kaul Precision Medicine Institute at the University of Alabama at Birmingham, he’s begun to make a road map for other families facing rare diseases — the maximum amount as 10 percent of the population, or 30 million Americans.

The Times spoke with Dr. Might about the challenges of finding treatments for these diseases and about the Mights’ experiences with their son. The conversation below has been edited and condensed for space and clarity.

Q. How unusual was what you’ve accomplished for your son — finding other patients and a drug that you’re now working to make more effective?

A. At the instant, it seems to be a rare event. But I don’t think it’s getting to be all that rare going forward.

Because some rare diseases are relatively easy to seek out treatment for, et al. aren’t?

In every case we’ve tried thus far, we’ve found something. We’re just finding existing drugs that already works.

These are drugs that have already been approved for other purposes?

Repurposing may be a key step in addressing rare diseases and avoiding the large costs that come with novel drug development.

What you actually want to try to do is test all the approved drugs that are out there.

Are some diseases particularly suited to the present approach?

Ion channel-driven epilepsies — epilepsies where there’s a transparent electrophysiological origin.

These quite occupy a sweet spot where it involves finding treatments.

They’re kind of accessible with drugs.

Many approved molecules will hit them incidentally, even though that’s not what they’re trying to try to.

Obviously, not every rare disease is as easy to seek out treatment for.

You do have large classes of diseases where it’s not that straightforward.

You can’t directly target the root cause.

Is this personalized medicine the longer term for all of us?

Personalized or precision medicine is completely the longer term — not simply because it’s better to care, but long-term, it'll also reduce cost.

Ultimately, by delivering the proper drug to the right patient at the proper time, it’ll get cheaper, too.

Are we there yet?

I think we are at an inflection point. the prices have come right down to the purpose where it’s reasonable to start out to try to do this for basically everybody.

A pharmacogenetic panel which will tell you your response essentially to each drug on the market costs on the order of $300.

And you’ll have that data for the lifetime of the patient. We’ll sequence everybody at birth at some point.

But is knowing a genetic blip that causes a disease enough to learn the way to treat it?

Right now there’s a niche between diagnostics and therapeutics. Genetics has gotten really good at telling patients what they need, but not what to try to next.

That’s the main target of your current work — to return up with a road map for other families to follow in their look for a treatment?

That’s really the goal of my life right now: to systematize the whole process of finding treatments, so it’s less art and more focused science.

one of the items, I’m building as part of my institute at U.A.B. is that the infrastructure necessary to require a patient from diagnosis to therapy.

This is uncharted territory for physicians.

They’re not won't say, “What you would like to do next to be a science experiment.”

Except for many of those rare diseases, that’s exactly what you have to try to to.

What sorts of experiments?

It might be building a worm or a fly and testing it.

It'd be a chemical screen, where you start testing compounds against a cellular or animal model.

Or it might be a genetic the screen where you’re trying to find other genes that interact with the gene driving your disease.

We craft a search plan for them and say, “This is that the way you would like to travel,” and even connect them with the proper researchers to form that next step.

Is it really feasible for one family or a little number of people to develop their own personalized treatments?

As you network these companies and institutions together, it’s suddenly changing drug development from this insurmountable process into something that’s actually quite achievable for individual patients or patient foundations.

Do companies see enough of financial interest in developing a drug to treat just a couple of hundred patients?

I’ve seen companies become involved in shockingly small diseases.

Patient foundations have a major role to play in “de-risking” the science around therapeutic development. If they “de-risk” it enough, companies will jump in.

Your ultimate goal is to seek out treatment for all 7,000 known rare diseases.

For all 7,000 now, and however more remain to be found.

Is that realistic?

Whether it’s realistic or not, it’s an ethical imperative that we roll in the hay. So, we’ll roll in the hay one at a time.

I’ve learned it’s not so helpful to specialize in what’s possible or realistic anymore.

Just focus on a subsequent step, keep taking subsequent steps, and see how far you'll go.