UConn Health trial subject first in world to receive gene therapy infusion  

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The treatment which took place at UConn’s John Dempsey Hospital used gene therapy, a technique in which the patients genetic data is altered to fix an issue inside the genes in their cells. This treatment is the first for glycogen storage disease type Ia, and if effective could largely provide relief for patients. by Photo by Braňo on Unsplash.

On Tuesday, Jan. 18, a clinical trial participant at the University of Connecticut’s John Dempsey Hospital became the first person in the world to receive a Phase 3 gene therapy infusion for glycogen storage disease type Ia (GSD-Ia).  

GSD-Ia is a disease in which glycogen cannot be properly stored in organs such as the liver, according to Dr. Juan Salazar, the chair of Connecticut Children’s Department of Pediatrics.  

“Under normal metabolism, glycogen is a source of sugar,” Salazar said. “We all have enzymes, specifically glucose 6-phosphatase, which helps to break up the glycogen into its smaller parts, so that we can use them for all the energy requirements that we normally have. In this disorder called glycogen storage disease, glycogen cannot be broken down.”  

In individuals with GSD-Ia, the glucose 6-phosphatase enzyme has a defect, which requires a constant source of sugar, according to Salazar.  

In the 1970s, a mixture of cornstarch and water was discovered to work as a temporary treatment for GSD-Ia if taken in certain amounts every few hours.  

“Cornstarch is a source of sugar that is released in small amounts, and it gets metabolized very quickly… If you take too much sugar it’s bad, and if you don’t take enough sugar you can die from it. What the cornstarch does is it meets you halfway in the middle where you have a source that slowly releases a nutrient that is a sugar, that does not lead to accumulation of glycogen.”  

Dr. Juan Salazar, the chair of Connecticut Children’s Department of Pediatrics.

After 20 years of research led by Dr. David Weinstein, former director of the Glycogen Storage Disease Program at UConn Health and Connecticut Children’s, Weinstein and his team initiated trials for the gene therapy with the goal of treating GSD-affected individuals to the point that they would no longer need to take cornstarch every few hours.  

In 2018, UConn Health was also the first in the world to administer the GSD-Ia gene therapy as part of the trial’s Phase 1/2, according to a UConn Today article.  

“The reason we were first overall back in 2018 was because of Dr. David Weinstein,” said Julie Vigil, the administrative director of UConn Health’s Department of Pediatrics. “It was his lab who really created this gene therapy and had partnered with Ultragenyx [the pharmaceutical company sponsoring the gene therapy] as far as developing the whole gene therapy protocol.”  

The technique used for the gene therapy utilizes a virus which does not harm the body. Viruses typically attack the body by damaging cells and the genes inside of them, but an altered virus can be used to implant careful, positive changes in genetic data. Photo by Pixabay from Pexels

The gene therapy for GSD-Ia is an adenoviral vector study targeted to the liver, according to Dr. Rebecca Riba-Wolman, the current director of the Glycogen Storage Disease Program at Connecticut Children’s and UConn Health and principal investigator for the trials.  

“Effectively, they’re using an empty virus to provide the liver with a correct gene for glucose 6-phosphatase,” Riba-Wolman said of the gene therapy. “We don’t truly know the broad efficacy, but we know that we saw an average of 70% decrease [in cornstarch needs]. We know that this therapy won’t affect every cell in the liver, and we know GSD affects other parts of the body as well.”  

The trial’s first phase consisted of testing and safety regulations.  

“Anything that you’re going to put into a human requires a long process,” Salazar said of Phase 1. “You can’t just inject people with something you’ve never injected. In this case, you would treat a cell, and once you treat the cell and find positive results, you go to a small animal, which is usually a mouse. From the mouse model, you move on to a larger animal–in this case Maltese dogs, which have the same genetic defect.”  

In Phase 1/2, trial subjects received the investigational product and participated in a fasting challenge to see how long they could go without needing cornstarch.  

The participants who received the product were able to last at least 15 hours without cornstarch, according to Vigil.  

“The subjects are able to go 15 hours without cornstarch, and that’s as long as the protocol will allow, so we don’t know if they can go over 15,”

Julie Vigil, the administrative director of UConn Health’s Department of Pediatrics.

Phase 3 of the trial, which UConn Health and Connecticut Children’s are currently working on, is “double blinded,” meaning some participants will get the gene therapy infusion and others will get a placebo instead. The purpose of Phase 3 is to prove the effects of the enzyme product and eliminate any source of bias, according to Salazar.  

The subject who received the Phase 3 infusion at UConn Health ― whose identity must be kept anonymous to preserve the integrity of the trial ― was chosen after having met several eligibility requirements, including a liver screening process and antibody test.  

“[The subject] just impressed me with how brave she is,” Salazar said. “[The infusion] may help her, it may not. She could be getting the placebo, but she’s okay with that. She listens to a higher cause, which is really remarkable.”  

UConn Health expects to administer infusions to five or six additional subjects for Phase 3 of the trial. More information about the GSD-Ia trial and its progress can be found on Ultragenyx’s website.  

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