GSD Program

First Patient Receives Gene Therapy for GSD


This past April, the U.S. Food and Drug Administration approved the Glycogen Storage Disease program at UConn Health for the first gene therapy clinical trial for type 1a. On July 24, Dr. Weinstein and his team successfully administered the novel gene therapy through a 30-minute infusion.

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Moving On Up!

The mission of the Glycogen Storage Disease (GSD) Program is to pursue research while providing the best evidence-based care for children and adults with the disease.

Program Move
In January 2017, the Glycogen Storage Disease program relocated from the University of Florida (Gainesville) to the University of Connecticut Health in Farmington, CT where it began clinical care and scientific research in affiliation with the Connecticut Children’s Medical Center. The GSD program is the largest of its kind in the world, providing clinical care to patients worldwide with this rare metabolic liver disease. Led by pediatric endocrinologist and scientist Dr. David Weinstein, the majority of the Florida team also made the move to Connecticut with the program. The move was spearheaded by local philanthropists and the Global Center for Glycogen Storage Disease, who were joined by numerous families and donors in generous support of the program.

Clinical Care
Due to the rareness of the glycogen storage diseases and the expertise of the team, patients travel from around the world for clinical care. Patients followed by the program travel to Connecticut from 49 states and 48 countries. The program presently follows over 600 patients with GSD, and over 200 patients already have traveled to Connecticut for therapy.

Current Research

The GSD team is active in both clinical and laboratory research. Murine research is currently being conducted by GSD team members in the laboratory facilities at the University of Connecticut Cell and Genome Sciences building. This research includes the following studies:

  • Gene and cell therapies for GSD Ia and Ib
  • Immune cell studies including neutropenia and neutrophil functions (GSD Ib)
  • Generation and characterization of new mouse models for GSD Type VI and GSD IX
  • Synergistic heterozygosity
  • Relationships between miRNA and liver pathology (adenomas and cancer)

In addition to lab research, a sponsored clinical trial comparing extended release cornstarch (Glycosade) with the current standard of care (Argo cornstarch) is underway. This is an international, multi-site trial, with the bulk of participants being recruited by Connecticut Children’s. Other sites are located in England, the Netherlands, and France.

The GSD Program is the only U.S. representative in the International Study for Glycogen Storage Disease (ISGSD). The vast majority of patients participate in the GSD Natural History Study conducted by the ISGSD to assess how treatment impacts outcomes in these disorders. The program also has a biorepository collecting blood samples from patients with GSD, and these are used to develop new therapies ex-vivo.

The Following Research will be initiated in 2018: Hepatic gene therapy for GSD 1a and pharmaceutical trials for the new lipid-lowering medications for all GSD types are both critical endeavors that have been years in the making and will have significant impact on the GSD community. The National Institutes of Health Recombinant Advisory Committee approved GSD 1a gene therapy trial in June 2017. Prior to commencing the trial, the FDA must approve the protocol and that is set to be finalized this spring of 2018. Other initiatives include whole genome sequencing for patients with no known genetic etiology for GSD and a trial of medications to prevent scarring in the liver.

Meet the Team

The GSD Team
David Weinstein, MD, MMSc, Program Director
Youngmok Lee, PhD, Basic Science Coordinator; Laboratory Research
Monika Dambska, MD, Clinical Research Coordinator
Ana Estrella, MD, Laboratory Coordinator
Kathy Ross, RD, LDN, Metabolic Dietitian
Iris Ferrecchia, RN, CHC, Outpatient Nurse
Emma Labrador, RN, BSN, CCRP, Inpatient Nurse
Amber Barry, RN, BSN, Inpatient Nurse
Gail Butler, RN, BSN, CPN, Inpatient Nurse
Kathy Dahlberg, MA, Research Advocate
Traci Resler, MS, Program Coordinator
Nitaben Desai, Medical Laboratory Technician
Mihaela Artemie, Medical Laboratory Technician
Elizabeth Swietek, Medical Technologist
Ilan Small, Laboratory Intern
Noah Drazen, Laboratory Intern

The Foundation Team
Jennifer Grey, Associate Vice President for Development, UConn Health
Natalee Martin, Associate Director for Development, UConn Health
Tammy Griffin, Assistant to the Associate VP for Development, UConn Health

Back Row: Mihaela Artemie, Traci Resler, Kathy Ross, Dr. David Weinstein, Monika Dambska, Kathy Dahlberg, Youngmok Lee Front Row: Ana Estrella, Emma Labrador, Amber Barry, Iris Ferrecchia, Gail Butler and Roberta Resaz (visitor) Team members not pictured: Nitaben Desai, Medical Laboratory Technician; Elizabeth Swietek, Medical Technologist, Ilan Small, Laboratory Intern; Noah Drazen, Laboratory Intern

Research Update

by Dr. David Weinstein

1. Recreation of GSD-Ib mouse model at UConn:
UConn Health, “Center for Mouse Genome Modification” received the GSD-Ib mouse model from the NIH on April 26, 2017. Because of the barrier level/biosafety level difference (UConn has higher biosafety requirements), in order to use the GSD-Ib mouse model from outside origin, we were forced to recreate the GSD Ib mouse model. The re-derivation process included embryo transfer and disease screening. This has been completed, and the new GSD Ib mouse model was released for us to use on July 20, 2017.

2. GSD-Ib gene therapy:
Working with Dr. Janice Chou at NIH, we have developed two different gene therapy vectors which have been tested in the mouse model of GSD-Ib. One of the vectors demonstrated superior efficacy to restore gene expression and enzymatic activity of glucose-6-phosphate-transporter, G6PT. After gene therapy, the GSD-Ib mice were able to survive full lives (70-80 weeks: corresponding human 70-80 years old). In addition to the improved survival, they demonstrated normalized blood metabolites and successfully fasted for 24 hours. Current gene therapy, however, was not able to cure neutropenia in GSD-Ib mice. As a result, mice are being treated with liver gene therapy as an initial approach followed by stem cell transplants. An article on successful gene therapy in GSD-Ib mice was recently submitted for publication.

3. GSD-Ib mouse hematopoietic stem cell transplantation:
Because current gene therapy cannot cure the immune cell dysfunction in GSD-Ib, hematopoietic stem cell transplantation is needed to cure immune function such as neutropenia. As a first step of this approach, we need to optimize and develop hematologic stem cell transplantation for the GSD-Ib mouse. This work has commenced, but initiation of the studies was delayed due to the requirement for a new mouse model (as outlined above in section 1).

4. Creation of a GSD Ib neutrophil generating cell line:
Neutropenia research was previously limited by the need to obtain fresh neutrophils from patients. Patients were forced to travel to the lab where 300mL of blood was obtained. Neutrophils had to be used in real time, and the lack of cells impacted on the ability for research to be performed. To overcome this challenge, a cell line was created at the University of Connecticut which produces human GSD Ib neutrophils. Created from leukemia cells, the HL60 cell line allows unrestricted generation of GSD Ib neutrophils. The creation of the new cell line was completed within the past month, and studies now are being performed exploring new therapies to improve neutrophil function and numbers in GSD-Ib. (Please see the HL-60 cell line generation study and result at the end of this document).

5. GSD-Ib mesenchymal stem cell research:
Mesenchymal stem cells (MSCs) are multipotent stromal cells that can differentiate into a variety of cell types. In GSD-Ib, we assume that MSCs are involved in tissue regeneration and inflammatory responses such as inflammatory bowel disease (IBD). Study on MSCs in GSD-Ib will give us better understanding and help us find treatment for the related secondary diseases and complications in GSD-Ib.

6. GSD-Ib macrophage study:
Macrophages are a type of white blood cell that engulfs and digests cellular debris, foreign substances, microbes and cancer cells. Macrophages are a critical part of the host immune system and protects our body from invading pathogens such as bacteria and virus. Since macrophages have the same origin and similar function with neutrophils, we have suspected the macrophages have functional defects related to cellular metabolism of GSD-Ib. In this study, we are investigating cellular functions and phenotypes related to the disease.

The following equipment was purchased for the GSD Ib research. The purchasing price is listed on each item is specially discounted prices for GSD Laboratory after negotiation. Regular retail prices would be very much higher.

1. SpectraMax i3x Multi-Mode Detection Platform, Molecular Devices Inc.: $42,970.51
We are using this multi-functional machine for DNA analysis (concentration and purity for genotyping and gene therapy vector preparation), blood metabolites analysis (measure blood triglyceride, lactate, glucose, uric acid, cytokines etc.), protein analysis (measure specific protein expression) and cellular function analysis (neutrophil function).

2. CFX96 Touch; Real-Time PCR Detection System, Bio-Rad Life science product: $21,000
This system is used for gene expression detection, DNA copy number calculation, and cDNA synthesis. With this machine, we can analyze various target gene expression in the GSD-Ib knock out cells and mouse/human tissues. Finding significant changes in gene expression could be applied to develop new treatment for the disease.

3. Refrigerated- Micro 21 Microcentrifuge Thermo Scientific: $3,646.80
In molecular biology, centrifuges are very common laboratory equipment to purify and separate samples such as DNA and RNA. This refrigerated centrifuge is essential equipment for handling temperature sensitive fragile RNA and protein (related to gene expression analysis). It is also used for other temperature sensitive reagents.

4. Cytospin™ 4 Cytocentrifuge, Thermo Fisher Scientific: $8,680
This special centrifuge has designed for making the cells visible. To see the cell structure and shape, cells have to be attached to slide glass and stained with special dyes. Immune cells such as neutrophils have same characteristics as other cells. Therefore, we need to make the cell attached to the slide glass first to see under microscope. This equipment is being used for GSD-Ib HL60 cell line (neutrophil cell line) generation study and will be used in hematopoietic stem cell researches in the future.

5. ZOE Fluorescent Cell Imager, Bio-Rad Life science product: $9,000
This new generation microscope allows our team to see gene expression (protein expression) on the cells using fluorescent dyes (green, red, yellow or blue). Images can be seen and pictures taken to permanently store the images. This equipment is being used in the GSD-Ib HL60 cell line (neutrophil cell line) generation study.

6. -86°C Low Temperature Freezer, Fisher Science: $10,050 each for a total of $20,100
Research samples such as tissue, serum/plasma, DNA, RNA, protein and expensive reagents cannot be stored in regular freezer. This extremely low temperature maintaining freezer enables to store those samples or reagents without degradation.

7. Enduro GDS (Gel Documentation System), Denville Scientific: $9024.07
DNA is invisible until stained by special dyes such as Ethidium Bromide or SYBR green. This equipment uses UV light to visualize the stained DNA and analyze the size of the DNA. This is essential machine for molecular biology. We utilize it in genotyping and DNA sequencing researches.

The following laboratory equipment and supplies will be required over the upcoming year to support the GSD Ib research

  • Flow cytometer to study GSD-Ib immune cell population and functions: $45,000
  • Analysis reagents for RNA, Protein works and Flow cytometer assay kits: $70,000
  • Cell culture ($12,000)
  • DNA&RNA kits ($8,000)
  • Protein analysis including antibodies ($20,000)
  • Assay kits ($15,000)
  • Lab supplies (tips, tubes, buffers, pipets and etc., $15,000)

Gene therapy in GSD Ib likely will depend on the results of the GSD Ia study. The National Institutes of Health Recombinant Advisory Committee approved the GSD Ia gene therapy trial in June 2017. The FDA approved the protocol in April 2018.

Clinical studies on kidney disease in GSD Ib were published in GSD Ib, and trials are presently on-going assessing Glycosade as a daytime treatment for all of the GSDs. The team will also be commencing trials in the near future on a new drug which has lowered triglycerides by 70% in preliminary trials.

Collaborators:

  • Dimension Therapeutics
  • Viking Therapeutics
  • Dover Life Sciences
  • Vitaflo / Nestle

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