PGM3 Clinical Trial
Official title:
Immunologic Effects of Supplemental Monosaccharide and Nucleoside Derivatives in Patients With Inherited Disorders of Glycosylation
Background:
- A congenital disorder of glycosylation (CDG) affects the cells that make up the organs and
tissues. In these cells, sugar molecules do not properly attach to other molecules, which are
the basic building blocks of cells. Changes in sugars seen in people with CDGs may lead to
allergies and can change people s ability to fight infections. Researchers want to see if a
sugar supplement called N-acetylglucosamine can help people with CDGs who have detectable
changes in their immune systems.
Objective:
- To see if N-acetylglucosamine can help cells to function in a healthy way in people with
CDGs.
Eligibility:
- People at least 2 years of age who have a CDG and immune system changes.
Design:
- Participants will be screened with a physical exam, medical history, and blood tests.
- One month later, participants will repeat the blood tests from the screening visit.
Blood will be drawn on 2 different days in the same week.
- Participants will get N-acetylglucosamine supplements and instructions for how to take
them. N-acetylglucosamine is a powder that can be added to food or drink.
- Participants will have a physical exam and blood tests every month during the study.
- After taking N-acetylglucosamine for about 4 months, participants will have more blood
tests. They will get more N-acetylglucosamine supplements and a nucleoside supplement.
The second supplement may be a powder or tablets that may be crushed and added to food.
Participants will take both supplements for 5 months.
- After about 10 months in the study, participants will have 2 more visits in the same
week for the same blood tests.
Autosomal recessive hypomorphic loss-of-function mutations in phosphoglucomutase 3 (PGM3)
have been shown to result in a novel congenital disorder of glycosylation (CDG) presenting
with a hyper-IgE clinical phenotype. PGM3 is required for the biosynthesis of uridine
diphosphate N-acetylglucosamine (UDP-GlcNAc), a critical building block for N- and O-linked
glycans, which are essential for many immune pathways in humans. PGM3 deficient patients
exhibit reduced UDP-GlcNAc levels, as well as both cell specific and global defects in N- and
O-linked glycosylation, respectively. Understanding how glycosylation defects result in
atopic diatheses and immune dysregulation will provide novel insight into their
immunopathogenesis. Developing successful therapies in these patients may further provide
novel targets or approaches to the treatment of allergic diseases in the general population.
Patients with other CDGs have shown dramatic clinical improvement when given oral
supplementation with mannose and fucose. Among our patients with PGM3 deficiency, in vitro
supplementation with the non-diabetogenic amino-sugar N-acetylglucosamine (GlcNAc) normalized
intracellular UDP-GlcNAc and surface CTLA-4 expression. We therefore propose an exploratory
study to provide up to 50 patients with exogenous GlcNAc and triacetyluridine with the
objectives of assessing the effects on immune function and changes in cellular glycosylation
patterns. We will begin with PGM3 patients who will self-administer sequential, escalating
doses of oral GlcNAc and uridine ( UMP or TAU). Given our preliminary in vitro data, we
hypothesize that supplementation will provide sufficient substrate to promote increased
UDP-GlcNAc, restore N- and O-linked glycans, and improve immune function in PGM3 deficient
patients.
Patients will self-administer oral GlcNAc 3 times per day beginning with 12.5 mg/kg/day and
increasing the dose every 2 weeks. Once a maximum tolerated dose is found (less than or equal
to 100 mg/kg/day), GlcNAc supplementation will continue for 6 weeks, at which point we will
add oral uridine. We will titrate uridine to find its maximum tolerated dose
(less than or equal to 200 mg/kg/day) and continue dual dosing for an additional 12 weeks. If
at the end this time period there has been no change in absolute lymphocyte count,
supplementation will be stopped. The dietary supplements to be used in this study have very
low toxicity and have been well-tolerated in studies of patients with colitis, galactosemia,
Alzheimer s, multiple sclerosis, and in treatment of 5-fluorouracil overdose.
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