Monday, October 19, 2015

Hunter's hope

Ryan Austin’s family and friends call him a lion because of the gritty way he’s endured procedures, sickness and seven-hour drug infusions to fight his horrible disease.

But as his mother recently administered medication through a port, or hole, along his rib cage for his weekly marathon treatment, he was every bit a scared, wounded, perhaps angry 4-year-old...

Ryan has a genetic disease called Hunter syndrome, and his prospects aren’t good. His parents have sworn to hang tough with their boy until a cure is found for the victims, who nationwide can be counted in hundreds rather than thousands.

Although Hunter syndrome is generally viewed as a killer, there are glimmers and whispers of hope from physicians and scientists nationwide over treatment improvements and clinical trials that could lengthen patients’ lives. If everything went beautifully, an Ohio-based scientist‘s gene therapy, not yet tried in people, could be curative...

Doctors say Hunter syndrome generally kills patients by the time they are 20 or 25 years of age, and many times by the age of 12.

“We are going to fight and we are going to prove them wrong,” Ryan’s mother said last week in the Austins’ Papillion home...

The medication infused by Ryan’s mother, called Elaprase, has helped the boy. He has had a growth spurt. He is moving better, his fingers aren’t curled as much and he dances a bit. But the drug doesn’t reach the brain because of what is known as the “blood-brain barrier,” and so his mental decline continues.

His father said Ryan is at about a 2-year-old’s mental level, and while he talked some at one time, he hardly speaks anymore. It’s hard to know what Ryan needs and how much pain he’s in.

“He doesn’t cry until it gets to a point where it’s unbearable for him, which is a lot,” his mother said...

The Austins met with Burton (Dr. Barbara Burton) of Lurie Children’s Hospital of Chicago. They heard her use the term “fighting the inevitable.”

“They deserve to hear the truth,” Burton said last week.

But Burton also said the situation is gradually changing. Elaprase, the drug that provides an enzyme-replacement therapy for the body, was approved by the Food and Drug Administration nine years ago. Burton is involved in a clinical trial to distribute a reformulated kind of that drug into the brain through the spinal fluid. The Austins hope Ryan will soon receive that therapy.

Neither of those treatments is a cure.

But Douglas McCarty, a scientist with the Research Institute at Nationwide Children’s Hospital in Columbus, Ohio, has had success with a Hunter syndrome gene replacement therapy in mice. “It works very well,” McCarty said last week.

McCarty hopes eventually to inject into patients’ bloodstreams 100 billion copies of the correct gene to the right cells, through a virus that would circulate through the body and brain. The gene would then produce the necessary enzyme in what would ideally be a one-time, permanent treatment and cure.

The scientist said that only through clinical trials will he be able to determine how much damage already caused by the disease can be corrected by gene therapy...

McCarty said he would like to move to human trials late next year, but he needs $3.7 million to produce the virus, do toxicology studies and conduct the trial on nine patients. He hopes to obtain some of that money from the National Institutes of Health and some from advocacy groups and organizations.

“Honestly,” Burton said, “I think there is hope.”


1 comment:

  1. Duncan FJ, Naughton BJ, Zaraspe K, Murrey DA, Meadows AS, Clark KR, Newsom DE, White P, Fu H, McCarty DM. Broad functional correction of molecular impairments by systemic delivery of scAAVrh74-hSGSH gene delivery in MPS IIIA mice. Mol Ther. 2015 Apr;23(4):638-47.


    Mucopolysaccharidosis (MPS) IIIA is a neuropathic lysosomal storage disease caused by deficiency in N-sulfoglucosamine sulfohydrolase (SGSH). Genome-wide gene expression microarrays in MPS IIIA mice detected broad molecular abnormalities (greater than or equal to twofold, false discovery rate ≤10) in numerous transcripts (314) in the brain and blood (397). Importantly, 22 dysregulated blood transcripts are known to be enriched in the brain and linked to broad neuronal functions. To target the root cause, we used a self-complementary AAVrh74 vector to deliver the human SGSH gene into 4-6 weeks old MPS IIIA mice by an intravenous injection. The treatment resulted in global central nervous system (CNS) and widespread somatic restoration of SGSH activity, clearance of CNS and somatic glycosaminoglycan storage, improved behavior performance, and significantly extended survival. The scAAVrh74-hSGSH treatment also led to the correction of the majority of the transcriptional abnormalities in the brain (95.9%) and blood (97.7%), of which 182 and 290 transcripts were normalized in the brain and blood, respectively. These results demonstrate that a single systemic scAAVrh74-hSGSH delivery mediated efficient restoration of SGSH activity and resulted in a near complete correction of MPS IIIA molecular pathology. This study also demonstrates that blood transcriptional profiles reflect the biopathological status of MPS IIIA, and also respond well to effective treatments.