Rare Disease Report

Hannah's Hero: Steve Gray and the GAN Trial

JUNE 29, 2016
Ricki Lewis, PhD
UPDATE - July 21, 2016 (via Hannah's Hope Fund Facebook Page)

Dear Friends,
We are both overjoyed and overwhelmed that the time has finally come for Hannah to be injected. Dr. Steve Gray just texted this photo to me. Steve will be in the OR with Hannah tomorrow. Many of you have met Steve at our annual Hope and Love Ball. We will keep you updated.

Much love,
Lori and Matt

Send cards to:
c/o The Children's Inn at NIH
7 West Drive, Bethesda, MD 20814

Original Post - June 29, 2016

Steve Gray met Hannah Sames at the inaugural scientific meeting of Hannah’s Hope Fund in Boston, in August, 2008. Steve was 30 years old, Hannah 4.
The opportunity to develop a gene therapy for the hereditary neurological disease that was making Hannah stumble and would get far worse would have been enticement enough for the newly-minted molecular biologist to join the effort that was born that day, but meeting Hannah was love at first sight. Steve has a daughter the same age.
Sometime this summer, Hannah will receive an injection into the cerebrospinal fluid in her spine that contains 120 trillion viruses, each one carrying a working copy of the gene that she lacks, which encodes a protein called gigaxonin. Hannah is one of a few dozen people in the world known to have giant axonal neuropathy, or GAN. She’ll be the fifth child to get the gene therapy – several of the kids are now happily holed up at the NIH Clinical Center, being poked and prodded, posting pix on Facebook, and awaiting their turn at making medical history.
“Finally, the time has come for Hannah's injection,” posted her dad Matt mid-June. Added her mom Lori, "It is amazing to be here with five other GAN families. We are family."
I’ve told the beginning of Hannah’s story, focusing mostly on the herculean efforts of her parents, in my book about gene therapy and at the DNA Science blog at Public Library of Science, the most recent here. As Hannah’s big day approaches, I thought I’d catch up with Steve Gray, whom I first met at lunch with Lori at the American Society of Gene and Cell Therapy meeting in Washington, DC, in 2010. The excitement as they chatted about the possibility of gene therapy saving the lives of kids with GAN was electrifying.


“As a youngster I wanted to be a marine biologist and study sharks. But in freshman year of high school, we wrote to colleges requesting information, and I got brochures from microbiology and molecular biology departments with beautiful fluorescent images of cells. That was what grabbed me. Then I learned about genes. I had an incredible curiosity,” Steve recalls.
A Howard Hughes Medical Institute program enabled Steve to conduct research all four years at Auburn University in Alabama, where he majored in molecular biology. “Once I was in the lab, there was no looking back,” he says. That work in college was engineering herbicide resistance into crops, not very different, at least theoretically, from enabling a child’s motor neurons to make a vital protein. When Steve finished his honors work by sophomore year, he moved on to insect resistance in crops, and senior year to creating DNA vaccines against parvovirus. In graduate school at Vanderbilt University Steve earned his doctorate in molecular biology, studying DNA replication. Although he’d always wanted a career where he’d help people, Steve had never wanted to be a physician.  
The next and crucial step along Steve Gray’s career path was the lab of Jude Samulski, director of the Gene Therapy Center at the University of North Carolina in Chapel Hill. About this time, 2008, Lori Sames visited Dr. Samulski. Hannah had been diagnosed in March with GAN, and the parents were still reeling from the knowledge that their daughter wasn’t just clumsy, but had a disease very much like ALS. They founded Hannah’s Hope Fund (HHF) and in August invited 20 researchers to Boston for a symposium on GAN to identify treatment strategies. Gene therapy emerged as the frontrunner.
Dr. Samulski sent to Boston his new post-doc, Steve Gray, who was investigating how adeno-associated virus (AAV) works. Steve was interested in viral replication, not saving children, but that changed in an instant when he met the charming Hannah at the Boston meeting, her kinky curls an innocuous manifestation of the chaos of deranged intermediate filaments permeating her cells. “I was impressed with the panel Lori assembled. Some were fans of gene therapy and some not, but all agreed, if there was any hope of a solution in a reasonable timeframe, gene therapy was going to be it,” Steve recalls.
As Steve bonded with Hannah, Lori knew that she’d found her scientist – she’d been looking for someone young and enthusiastic. She remembers their first phone conversation after the meeting in Boston. “I was at my parent’s house. We talked for an hour. When he said he had a daughter Hannah’s age, I knew it was meant to be. He had the scientific background AND the passion, the personal connection.”
When HHF offered grant support in October, Steve was stunned. “I was very much a junior investigator. To take on a project of this magnitude … at a typical granting agency I’d never be a lead investigator. Lori caught me when I was wide open to ideas.”


Developing the vector to deliver the gigaxonin gene, AAV9, was trial and error, Steve says. “We didn’t design AAV9. More than 100 variants of AAV were pulled out of nature by Guangping Gao and Jim Wilson. We went through some of them, one at a time, and AAV9 did what we wanted it to do” in zooming in on nervous system cells. The team also uses directed evolution techniques to systematically alter the proteins that make up the viral surface (the capsid) to tailor the virus’s tropism – which cells it targets.
The eight years that passed between the first HHF-sponsored research meeting and treating the first child this past February is a testament to the challenging trajectory of getting a clinical trial off the ground. Carsten Bönnemann, MD, is leading the trial, while Steve Gray led much of the preclinical work, testing effects of adding genes to induced pluripotent stem cells and fibroblasts from patients, and in a mouse model that was less-than-perfect because the rodents don’t get very sick. But in cells, adding the gene reversed or at least stopped the pathology. “How that will translate into a motor neuron with a 3-foot-long axon could be different, but cells themselves can heal pretty quickly,” Steve says.
Gene therapy would bolster the axons of affected motor neurons that are losing function, but aren’t yet dead. And the younger the patient, the more likely success.


Monkeys, not mice, delayed the GAN clinical trial. Steve and his team injected healthy monkeys with AAV9 carrying green fluorescent protein to test what would happen with delivery of any foreign gene. When the monkeys mounted an immune response, alarm bells sounded. “If we have a patient who doesn’t express the gene at all, we were very worried that when the normal protein is made, the patient could develop an immune response that could potentially make them worse,” recalls Steve.
Hannah is one such “null” patient – she inherited a deletion in the gigaxonin gene from each parent. The initial clinical trial description specified that patients must have at least one missense mutation (which changes one amino acid into another) that would lead to at least some protein. In fact, in the 26-item list of “MUST NOT” criteria, #1 is a homozygous deletion like Hannah has, “because they would be immune naïve to the gigaxonin protein.”
Hannah’s parents found themselves in the excruciating position of having led the efforts to raise the millions of dollars needed to get the trial off the ground, but their own child possibly being excluded. And so the researchers designed a side protocol to accommodate null patients, carefully using and monitoring immunosuppressants to help the children’s bodies accept the viruses.
A more philosophical reason for the slow pace to GAN gene therapy is the sheer novelty. “This is the first time anyone’s done anything like this, injecting 35 to 120 trillion engineered viruses into somebody’s CSF. Nobody has ever done that before, for any disease, so we’re held to a level of scrutiny to make sure that everything we are doing is responsible,” Steve says. The implications and applications extend beyond GAN, to perhaps ALS, spinal muscular atrophy, and spinal cord injury. “Even though the scrutiny was frustrating it was also reassuring – we knew a lot of people looked at the protocol and the rationale behind what we are doing,” he added.


Gene therapy has been a long time in coming, with the first FDA approval anticipated for 2017, likely for the visual loss condition Leber congenital amaurosis due to RPE65 deficiency. Next might be hemophilia B. Yet the first clinical experiment for gene transfer – it technically isn’t “therapy” until it works -- was for a form of severe combined immune deficiency, in 1990.
27 years!
In between, others have been treated. Max Randell underwent gene therapy in 1998 at 11 months old and again in 2001, for Canavan disease. He’s about to turn 19; he’d likely have died by half that age without it. Young Eliza O’Neill had gene therapy for Sanfilippo syndrome type A this past May after her parents had isolated her for 722 days to keep her from contracting an AAV infection, which might have excluded her from the clinical trial. And approval of gene therapy in the EU for the disease tested in 1990 is imminent.
I think often about the brave children, the driven and passionate families, and the dedicated investigators who are ushering gene therapy from idea to clinical reality. And I try to imagine what it must be like to be Steve Gray, still in his thirties and one of a handful of people who has been able to take deep understanding of how life works at the molecular level and use it to find a way to fix a profound inborn problem. So I asked Steve, with apologies to Bob Dylan, how does it feel?
“It feels pretty amazing. I was always very curious about genetics, so gene therapy was a natural magnet. But when I connected with HHF, it became real, the possibility that I could make a difference in somebody’s life that I’ve met. It wasn’t just writing a blurb in a grant application about a disease that’s related to whatever you’re working on. There was a real goal of ‘I’m going to invent something to help this person’. It’s a tall order. A lot of people say they’re doing it and a lot say that they want to, and I don’t know how I ended up in the club of people who have actually done it. I’m not smarter than anyone else, but I think a lot of it has to do with the inspiration of the families and the kids with GAN I’ve met. When I was there when the first GAN patient was being dosed, I felt like watching one of my kids being born. It brought tears to my eyes.”
Steve’s kids are now 12, 8, and 2, and have gotten to know the GAN kids waiting at the NIH for the gene therapy that their father made possible. They perhaps sum up best what he does: “dad makes new medicine!”

below is an image of the author (on the right) with Hannah (in the wheelcair).


Stay informed on the latest rare disease news and developments by signing up for our newsletter.
Copyright © RareDR 2013-2018 Rare Disease Communications. All Rights Reserved.