Engineering hope: UT Southwestern targets rare diseases

They sound like so many of our children: A pair of sisters who love unicorns, ballet and singing to hummingbirds. A 5-year-old boy who pinches his siblings when his parents aren’t watching and has the energy to run for hours. Imagine these youthful moments suddenly beginning to slip away. There are 30 million people in the U.S. suffering from rare diseases. Half of them are kids, and many develop normally until symptoms strike. A pair of pioneering researchers at UT Southwestern have a plan in place to reverse the sobering effects of terminal illnesses through gene therapy. Read story

{Triple screen. Home videos of Jojo, Chrissy, and Amanda fade in and out with soft music underneath. Gina Hann’s voice is heard.}

{Gina Hann}

There are thousands of diseases like ours. There are millions of children who get a diagnosis like ours. Not everyone is fortunate to get a call 24 hours later that there might be a chance they could do something.}

{Title glows in center the screen before fading to black}

Engineering Hope

{Video of Jojo reading/playing at home}

{Gina Hann}

We have four babies. He was always the snuggliest baby.

He’s pure joy. Pure sweet, angelic joy.

{On-Screen Text: Joseph Hann, age 6}

(SUPER: Gina Hann/Mother of 4}

At 3-and-a-half years old, Joseph started to show signs that maybe he had a vision problem.

{SUPER: Matthew Hann/Father}

Then he started bumping into things.

{Show year 2017 over family video}

And then in early January is when he had, when we got the real big hit and he had a massive seizure. Lasted 30 seconds long.

We started researching all of the diseases that we thought it could be and literally Matt walked into the emergency room before he went into his MRI and I said, okay we found 14 diseases. As long as it’s not Batten, we’re going to be good and literally when we were checking out, the doctor handed us this slip. We looked at it and we said, you think he has Batten Disease. It was pretty terrible.

{Animation of what looks like a page from a dictionary:}

[Batten disease is a fatal, inherited disorder of the nervous system.

Symptoms typically present between 5 and 10 years of age.]

His results came back, and we got the first phone call from our neurologist in Tucson and he said that Joseph’s disease, he didn’t just have Batten. He had a really rare form of Batten that there was no clinical trial. There was not even research and that we should make end-of-life plans for him. He was four-and-a-half at this time.

We were introduced through some different contacts to Dr. Minassian by email. The next day we got a call from Dr. Minassian, and he said, ‘look, I’m guessing you know the results of what’s happening…said ‘yep.’ He said ‘well that’s the bad news, and the good news is that right now I am recruiting a molecular biologist named Dr. Steven Gray and he just happens to have been doing work on your son’s form of Batten and that was the craziest, most awesome moment because we literally had for 24 hours walked around thinking that there was no hope at all and then all of a sudden, we had this chance of well, it’s going to be a lot of work. It may not pay off for you personally, but there is work to be done, and we were just super thrilled. It changed everything.

What’s underneath…is good people who are trying to help with something that’s just almost impossible to solve, but they have the means to do it.

{Dip to black.}

I’m Steven Gray, and I’m an associate professor here at UT Southwestern in pediatrics.

I’ve been in the gene therapy space for about 12 years. 

{Video of Dr. Gray in the lab}

A lot of what we do, it’s science, but it’s also a mission of hope where we know every day about the patients that are really counting on us to do all this. Do it right. Do it quickly. Do it responsibly and ultimately move our laboratory research into treatments for patients.

What would you do if it’s your kid? And that still kind of remains our mission and the thing that kind of goes through our minds every day as we work. And so, you don’t put that experiment off till tomorrow. You work a little bit later. You work a little bit harder. 

{SUPER: Berge Minassian, M.D./Professor, Neurology & Neurotherapeutics/Chair, Pediatric Neurology}

Many, many diseases in pediatric neurology, the cause is a single gene that’s absent. We have 30,000 genes. And so the goal here is to replace this one missing gene and science, through the gene therapy work that’s been happening, has brought us to the point where we can use this particular virus called AAVP.

These are viruses that are very, very expensive to produce because they need to be of human grade meaning these are going into human subjects so there’s a system to make them and they have to be ultra, ultra-pure and so you need a very, very special and rather expensive facility and there’s only a few of them across the country.

We are building here one of the best ones through the university’s contribution and others.

{ANIMATION} It’s a benign virus which causes no harm to humans and put inside this virus this missing gene and the virus is like a delivery truck which takes the gene into the brain and delivers it to the brain cells. The missing gene is replaced and when this is done we hope and expect in many different diseases that a child will start functioning normally again. It will not work for everybody, and there are all sorts of hurdles, but the more we research this, the more things improve, the more families we should be able to help.

So for Jojo, we’re hoping to start the clinical trial in 2019. Time is our enemy in this case because his disease is a neurodegenerative disease so you can imagine a perfect boy and his brain is suffering each day from this disease and getting worse and worse.

{Dip to black.}

When we moved here in the 1st or 2nd week of April, Joseph could run around this whole house. He could see. He would ride his tricycle outside. We’ve watched in the course of the last year, his vision decline. He’s mostly blind now. His mobility has declined. That has hit mostly in 2018 actually.

We understand. We understand that it might not work out in our favor, but we also understand that if we don’t do this, it will not work out in anyone’s favor.

{Show screengrabs from Batten Hope webpage}

This last year, we spent all of our time…to raise funds and establish a non-profit in Batten Hope and to do what was necessary to initiate our piece of getting that CLN7 trial started and we did that.

We raised over a million dollars in one year.

Jojo’s family is helping us produce the facility that will produce the virus…so it’s just an incredible effort to help not just their kid, but to think of all the kids as this could be my child and help other kids and future kids.

And for a rare disease, maybe effects a hundred kids in the world, it’s hard to raise the millions of dollars that need to be there to actually move the treatment into kids.

So I think coming here, it was because I had this mission and this vision of just trying to bring this technology to bear on as many diseases and try and open up treatments for as many diseases, as many kids as we can and the environment here was such that people wanted to do that.

Everything that I’m doing started with this ultra-rare disease called Giant axonal neuropathy, and it was really driven by a small family foundation called Hannah’s Hope and this really was a mission of hope.

{Dip to black.}

Text box:

GAN is an inherited genetic disorder.

{fades in}

Most patients do not live past their 20s.

{fades in}

A characteristic sign of the disease is dull, tightly curled hair.

Chrissy, as with most of the GAN kids, had this explosive, bubbly, cheerful personality that nothing could quash.

She loved everything from unicorns to princesses to ballet. 

{SUPER: Steven Grube/Father}

At about a year old, while she could walk a little bit, she was constantly falling.

Text Box:

Two of Steven Grube’s daughters were diagnosed with GAN.

{fades in}

Genetic sequencing confirmed it in 2011.

Those were the first words. I’m sorry. I’ve got the results, and I’m sorry. It was GAN, and I feel to my knees. There was no denying it. There was no more putting it off. No more telling myself it might be something else. Both girls have it, and they’re both going to die.

Just forget it…Don’t stop fighting. Don’t give up…the boundaries of technology change all the time.

Chrissy had the honor of being the first child to receive the clinical therapy, gene trial.

{Cell phone video of Chrissy Grube walking for the first time after gene therapy}

When she started to move, I grabbed my phone and made a video because this is something I had to share. The world needed to see that the gene therapy was working. That she was improving. She was getting better. For the first time ever, she was gaining function!

She was an incredibly courageous girl because she wanted to go forward to do this to be the first.

It was almost anti-climactic. Okay, we put 35-trillion engineered viruses into her spinal fluid and then, okay, shouldn’t more happen? And then it was sort of a long road to monitoring things, seeing how things go.

You have to understand that when Chrissy was about 8, 8-and-a-half years old, she took her last steps.

But within six months of receiving the trial, she was able to move her legs as she hadn’t had the ability to in years.

She was showing obvious, verifiable, objective evidence of improvement that we attributed entirely to the clinical trial.

{Dip to black.}

I came to UT Southwestern really because we took this approach for GAN, moved it into a clinical trial and treated 11 kids and everything that I want to do is do as much of that as possible for as many diseases as possible. If we use this approach to treat a disease like GAN, we can use exactly the same approach, exactly the same virus and just put in a different gene. And so now this opens the door to treating literally thousands of diseases that you can tell the story a hundred times and it’s just as emotional and just as impactful.

I think Chrissy has taught us, has taught me more about humanity than I think anybody else because when she was going in to be the first person in this trial, it wasn’t because she wanted to dance again. It wasn’t because she wanted to run again. It was because she wanted to help her little sister.

It was such a tragic finish to this where she had to go through a surgery for her disease. It was unrelated to our trial, but she had complications of that and passed.

Chrissy died on February 13th, 2016 as a result from complications from scoliosis surgery. One of the main complications from GAN.

We were clear with Amanda from the beginning, after Chrissy’s death, that it wasn’t the fault of the clinical trial that Chrissy passed. We reinforced to Amanda that Chrissy was getting better because of the clinical trial and that there was still hope.

And Amanda received the treatment on October 17th, 2016 just about 15 months after Chrissy died and Amanda went smiling to the operating room to have it done. Amanda believes that this is going to heal her. It’s going to save her life.

She got the highest dose that anybody has gotten so far and right now, it’s the same thing. She’s been treated, and we’re just monitoring long-term to see what this looks like for her.

Just because people say doom and gloom, you still have to hope and prepare for sunny skies.

The big vision is in 5 years-time, this institution can be the place that all of these different children and all these different families around the world look to take on cases like ours, and the fact that we can be a part of that is a huge privilege and we feel that this community has this amazing opportunity to create the best gene therapy institute in the world, and we’re really thrilled to be a part of it.