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Rome – GIOSTAR CEO with Prince Nicolo and Princess Rita of Rome Sep. 2014

 

 

Mannose Supplements Induce Embryonic Lethality And Blindness in Phosphomannose Isomerase Hypomorphic Mice

 

Associated Data

Supplementary Materials

Abstract

Patients with congenital disorder of glycosylation (CDG), type Ib (MPI-CDG or CDG-Ib) have mutations in phosphomannose isomerase (MPI) that impair glycosylation and lead to stunted growth, liver dysfunction, coagulopathy, hypoglycemia, and intestinal abnormalities. Mannose supplements correct hypoglycosylation and most symptoms by providing mannose-6-P (Man-6-P) via hexokinase. We generated viable Mpi hypomorphic mice with residual enzymatic activity comparable to that of patients, but surprisingly, these mice appeared completely normal except for modest (∼15%) embryonic lethality. To overcome this lethality, pregnant dams were provided 1–2% mannose in their drinking water. However, mannose further reduced litter size and survival to weaning by 40 and 66%, respectively. Moreover, ∼50% of survivors developed eye defects beginning around midgestation. Mannose started at birth also led to eye defects but had no effect when started after eye development was complete. Man-6-P and related metabolites accumulated in the affected adult eye and in developing embryos and placentas. Our results demonstrate that disturbing mannose metabolic flux in mice, especially during embryonic development, induces a highly specific, unanticipated pathological state. It is unknown whether mannose is harmful to human fetuses during gestation; however, mothers who are at risk for having MPI-CDG children and who consume mannose during pregnancy hoping to benefit an affected fetus in utero should be cautious.—Sharma, V., Nayak, J., DeRossi, C., Charbono, A., Ichikawa, M., Ng, B. G., Grajales-Esquivel, E., Srivastava, A., Wang, L., He, P., Scott, D. A., Russell, J., Contreras, E., Guess, C. M., Krajewski, S., Del Rio-Tsonis, K., Freeze, H. H. Mannose supplements induce embryonic lethality and blindness in phosphomannose isomerase hypomorphic mice.

Keywords: congenital disorder of glycosylation, MPI-CDG, lens, eye defects

A potentially lethal form of rare congenital disorder of glycosylation (CDG), type Ib [CDG-Ib; or phosphomannose isomerase (MPI)-CDG] can be treated with mannose as a dietary supplement (1). Supplementation overcomes impaired glycosylation caused by hypomorphic mutations in MPI because mannose bypasses the impaired conversion of fructose-6-phosphate (Fru-6-P) to mannose-6-phosphate (Man-6-P), which is the major source of Man-6-P derived from glucose. Mannose alleviates patients’ stunted growth, hypoglycemia, liver dysfunction, coagulopathy, and protein-losing enteropathy (2). Exogenous mannose is converted to Man-6-P by hexokinase (HK), replenishing this deficient precursor needed for multiple glycosylation pathways, including the N-glycosylation pathway, viaphosphomannomutase (PMM2); excess Man-6-P is catabolized by the residual MPI activity (Scheme 1). Patients on this therapy survive and lead a normal life without obvious side effects (2).

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Mannose metabolic pathway. Man, mannose; Glc, glucose; HK, hexokinase; MPI, phosphomannose isomerse; PMM2, phosphomannomutase2; GDP-Man, GDP-mannose; Dol-P-Man, dolichol phosphate mannose; LLO, lipid linked oligosaccharide.

To model MPI-CDG and follow the effects of mannose therapy, we previously knocked out the single Mpigene in mice, leading to death at embryonic day 11.5 (E11.5) due to abnormalities in both placenta and the embryo. Mannose could not rescue because Man-6-P accumulates to toxic levels, limiting ATP and inhibiting several glycolytic enzymes (3). However, because patients with MPI-CDG have residual enzymatic activity, hypomorphic mice would offer a more patient-relevant model than would a complete Mpi knockout (KO). Here, we describe a viable, hypomorphic mouse line containing a patient-derived mutation that reduced enzymatic activity and altered mannose metabolism, as predicted. While a minority of mutant embryos died in utero, surprisingly, adolescent and adult mice had none of the expected symptoms reported in patients with MPI-CDG; these Mpi-deficient mice had a subclinical phenotype. However, if dams consumed mannose during pregnancy, most of the Mpi hypomorphic embryos died, and nearly half of the survivors were born with severe ocular defects. The combination of reduced enzymatic activity and the increased mannose load altered its metabolic flux, leading to Man-6-P accumulation in the eyes.

Mannose is widely used as a “natural” treatment for urinary tract infections; this seemingly innocuous sugar may have a negative effect for some pregnant women. While the frequency of MPI-CDG is unknown, women at risk for having subsequent MPI-CDG children who intend to take mannose as a “prenatal therapy” may inadvertently cause other side effects.

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GIOSTAR: Worldwide Network of Stem Cell Hospital and Research Centers

(ED NOTE: There is no other area of Healthcare that sorely need both healthcare worker education, and patient education, than the field of Stem Cells; there seems to be an unlimited source of promise, and an area that needs continuing research to mine this tremendous promise.  This entire post is taken from the website of this organization.  The San Diego office is a Research Center)

Global Institute of Stem Cell Therapy and Research (GIOSTAR), headquartered in San Diego, California (U.S.A.), was formed with the vision to provide stem cell based therapy to aid those suffering from degenerative or genetic diseases around the world.

We are the leaders in developing cutting edge stem cell based technology, supported by leading scientists with the pioneering publications in the area of stem cell biology. Our primary focus is to discover and develop a cure for human diseases with innovative and unique stem cell based therapies and products. Regenerative medicine promises treatment for those diseases previously regarded as incurable. GIOSTAR’s ultimate aim is to maintain its leadership in the field of stem cell science and to continue developing affordable stem cell based therapy for those in need.

In July 2011, GIOSTAR inaugurated the world’s first dedicated stem cell treatment hospital at Ahmedabad, Gujarat, India. This is a 125-bed state of the art facility with the most advanced on-site stem cell laboratory.

GIOSTAR has an ability to treat several devastating Immunological diseases and Blood related diseases. These include Diabetes Type I, Lupus, Multiple Sclerosis, Crohns, Vasculitis, Scleroderma, Myasthenia Gravis, Sickle cell anemia, Leukemia, Lymphoma, Thalassemia and developing the therapies for Alzheimer’s, Autism, Anti-Aging Treatments, Parkinson’s, , Cancer, Heart and Retinal Degeneration, Amyyotrophic Lateral Sclerosis, Neuropathy, Osteoarthritis, Paralysis, Strokes, Spinal Cord Injuries, Skin Burns and Spinal Muscular Atrophy (SMA).

GIOSTAR is in process of opening dedicated stem cell treatment hospitals in Asia, Middle East, Africa, North and South America and Europe. The proposed facilities will be developed with the international support from public and private sectors grants and investments to provide stem cell based therapy for those suffering from degenerative or genetic diseases.

GIOSTAR uses autologous and allogeneic adult stem cells transplant to treat patients, following the highest medical standards.

GIOSTAR is leading the most advanced research to use embryonic stem (ES) cells and Induced Pluripotent Stem (IPS) cells to develop new therapies for clinical use.

GIOSTAR is a coalition of esteemed and illustrious scientific minds in the field of genetic and stem cell science. For over 15 years GIOSTAR team of scientists and clinicians have been involved in the development and utilization of stem cell based clinical protocols related to stem cell transplants.

The GIOSTAR team includes international leaders in the field of embryonic stem (ES) cells and Induced Pluripotent Stem (IPS) cells research and technologies. GIOSTAR team is the first in demonstrating the significance of ES cell use for the development of therapies for several degenerative diseases related to tissue and organs. The publications of these therapies have been thoroughly investigated and documented by many noted journals of medicine. GIOSTAR cutting-edge Stem Cell science will be used to treat qualified patients on needed basis.

GIOSTAR is using three kinds of stem cells : adult stem cell, human embryonic stem cell and Induced Pluripotent cells. The adult stem cell technology is well developed and being used regularly in clinical practice. Our clinicians are licensed to treat the patients using autologous (their own) and allogeneic (from others) adult stem cells for certain diseases. We are the leading private organization, which has state of art excellence in extraction of stem cell from a human body and use it for therapy. Our clinicians are treating the patients regularly using adult stem cells since 2000. GIOSTAR is leading the most advanced research to use embryonic stem (ES) cells and Induced Pluripotent Stem (IPS) cells to develop new therapies for clinical use.

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