9 Gaucher's disease: studies of gene transfer to haematopoietic cells

Barranger, John A.; Rice, Erin; Dunigan, James T.; Sansieri, C; Takiyama, Nobuaki; Beeler, M.; Lancia, Jody K.; Lucot, S.; Scheirer-Fochler, S.; T, Mohney; Swaney, William; Bahnson, Alfred; Ball, Edward D.

doi:10.1016/s0950-3536(97)80039-x

Cited by 30 publications

(11 citation statements)

References 11 publications

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“…Potential therapeutic strategies currently undergoing investigation include gene therapy, using a viral vectormediated approach, and pharmacologic substrate deprivation (through inhibition of GL1 synthesis) [35,36].…”

Section: Managementmentioning

confidence: 99%

Bone and joint complications related to Gaucher disease

2000

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There is a broad spectrum of Gaucher disease-related skeletal complications, ranging from asymptomatic osteopenia to osteonecrosis (of the shoulders and hips) with secondary degenerative joint disease. Characterization of the pattern and severity of bone involvement in the individual patient requires the application of conventional and advanced radiographic techniques. The introduction of enzyme replacement therapy (ERT) for this inborn error of glycosphingolipid metabolism has focused great interest in determining the nature and extent of the bone responses with this mode of treatment. The multifactorial etiology of the bone complications necessitates a multifaceted approach, combining pharmacologic strategies with physical therapy and orthopedic intervention. As bone disease can lead to chronic pain and debility with a resultant adverse impact on quality of life, it is important that patients be monitored closely and that early intervention with ERT prior to established bone disease (infarction and fibrosis) be considered.

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Section: Managementmentioning

confidence: 99%

Bone and joint complications related to Gaucher disease

2000

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“…Studies of human CD34 cells were carried out to evaluate their potential use in a gene therapy approach to Gaucher disease and trials in humans were initiated. 121,122 Unhappily progress has been erratic and new clinical trials in patients with Gaucher disease are not yet on the horizon. However, based on a new murine model of type 1 Gaucher disease and using low-risk conditioning regimens (non-myeloablative doses of busulfan) there have been encouraging data that only a low level of normal or gene-corrected cells with engraftment can induce a beneficial therapeutic outcome.…”

Section: Conclusion: Hopes For the Futurementioning

confidence: 99%

Review of the safety and efficacy of imiglucerase treatment of Gaucher disease

Elstein¹

2009

BTT

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Abstract:Most patients who suffer from symptomatic Gaucher disease will benefit from enzyme replacement therapy (ERT) with imiglucerase. The safety profile is excellent, only a small percentage of those exposed developing antibodies; similarly, very few patients require pre-medication for allergic reactions. Within 3 to 5 years of imiglucerase therapy, best documented at doses of 30 to 60 units/kg/infusion, hepatosplenomegaly can be expected to be reduced so that the liver volume will be maintained at 1 to 1.5 times normal (30% to 40% reduction from advent of ERT) and spleen volume to 2 to 8 times normal (50% to 60% reduction from advent of ERT). For anemic and thrombocytopenic patients, with 2 to 5 years of imiglucerase, hemoglobin levels are expected to be 11 g/dL for women and children and 12 g/dL for men; and platelet counts in patients with an intact spleen, depending on the baseline value, should approximately be doubled. Bone crises and bone pain but not irreversible skeletal damage will improve in most patients. Nonetheless, some features and some symptomatic patients apparently do not respond equally well and/or perhaps inadequately. The benefit for patients with the neuronopathic forms is primarily in improved visceral and hematological signs and symptoms. There are still several unresolved issues, the high per-unit cost being an important one, which have spurred the development of biosimilar enzymes as well as chaperone therapies currently in clinical trials.

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“…With the preclinical murine and human studies completed, three gene therapy clinical trials [Barranger et al, 1997;Schuening, 1997;Dunbar et al, 1998] were initiated for Gaucher disease, and a total of ten patients have been studied thus far. The trial by Dunbar et al [1998] consisted of three adult type I Gaucher patients, for which peripheral blood stem cells were used for two patients, and bone marrow for the third.…”

Section: Gene Transfer For Glucocerebrosidasementioning

confidence: 99%

“…An immediate twofold increase in enzyme level was detected, but there was no engraftment of transduced cells. The trial by Barranger et al [1997] studied four type I patients, who underwent G-CSF mobilization of peripheral blood stem cells, and the CD34 þ cells were transduced by centrifugation. The average transduction efficiency was 20%, and the enzyme activity of the transduced cells increased ten-fold.…”

Section: Gene Transfer For Glucocerebrosidasementioning

confidence: 99%

Hematopoietic stem cell gene therapy for inherited bone marrow disorders: Past accomplishments and continued challenges

Becker

2002

J. Cell. Biochem.

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From the time that the genes encoding the defective proteins were cloned for a number of inherited diseases, it became a goal to correct those conditions by restoring the normal gene and thereby, its product. For the inherited disorders affecting the blood and its progenitor cells, the hematopoietic stem cells were the ideal target cells for gene transfer, because the normal gene would then be transferred to all of the progeny cells, theoretically for the lifetime of the recipient. However, the tasks of isolating the hematopoietic stem cells, introducing the new genes in such a manner as to preserve engraftment of the manipulated cells, and achieving long-term gene expression, have not been straightforward in the clinical trial setting, although there has been moderate success for cells in vitro, and in murine studies. With the report of clinical efficacy of gene transfer in children with X-linked severe combined immunodeficiency disease, the dream of clinical gene transfer to hematopoietic cells has become a reality. But there are still significant impediments remaining for a number of diseases. The innovations of introduction of synthetic receptors that confer growth advantage, the use of lentiviral vectors with increased stem cell transduction efficiency, and the addition of modified promoter/enhancer sequences to augment and preserve gene expression may bring wider success to gene therapy clinical trials for bone marrow disorders in the near future.

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9 Gaucher's disease: studies of gene transfer to haematopoietic cells

Cited by 30 publications

References 11 publications

Bone and joint complications related to Gaucher disease

Bone and joint complications related to Gaucher disease

Review of the safety and efficacy of imiglucerase treatment of Gaucher disease

Hematopoietic stem cell gene therapy for inherited bone marrow disorders: Past accomplishments and continued challenges

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