Production and characterization of human induced pluripotent stem cell line (PUMCi002-A) from a Krabbe patient related control to study disease mechanisms associated with GALC mutation

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Abstract

<p class="first" id="d100500e99">A KD-control human induced pluripotent stem cells (iPSCs) line (PUMCi002-A) was generated from dermal fibroblasts of a Krabbe patient's father with a c.461C>A mutation in Galactocerebrosidase (GALC) gene. The pluripotency, in vitro differentiation potential and karyotype stability of generated iPSC line were analyzed and confirmed. This cell line can be exploited as a control iPSC line to better understand the mechanisms involved in GALC-associated Krabbe disease and provide plausible new therapeutic directions. </p>

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Molecular genetics of Krabbe disease (globoid cell leukodystrophy): diagnostic and clinical implications.

D Wenger, M Rafi, P Luzi (1997)

Galactocerebrosidase (GALC) is a lysosomal beta-galactosidase responsible for the hydrolysis of the galactosyl moiety from several galactolipids, including galactosylceramide and psychosine. The deficiency of this enzyme results in the autosomal recessive disorder called Krabbe disease. It is also called globoid cell leukodystrophy (GLD), because of the characteristic storage cells found around cerebral blood vessels in the white matter of affected human patients and animal models. Although most patients present with clinical symptoms before 6 months of age, older patients, including adults, have been diagnosed by their severe deficiency of GALC activity. More than 40 mutations have been identified in patients with all clinical types of GLD. While some mutations clearly result in the infantile type if found homozygous or with another severe mutation, it is difficult to predict the phenotype of novel mutations or when mutations are found in the heterozygous state. A high incidence of polymorphic changes on apparent disease-causing alleles also complicates the interpretation of the effects of mutations. The detection of mutations has greatly improved carrier identification among family members and will permit preimplantation diagnosis for some families. The molecular characterization of the naturally occurring mouse, dog, and monkey models will permit their use in trials to evaluate different modes of therapy.

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Krabbe disease: One Hundred years from the bedside to the bench to the bedside.

David Wenger, Mohammad Rafi, Paola Luzi (2016)

This Review summarizes the progress in understanding the pathogenesis and treatment of Krabbe disease from the description of five patients in by Knud Krabbe until 2016. To determine the cause of this genetic disease, pathological and chemical analyses of tissues from the nervous systems of patients were performed. It was determined that these patients had a pathological feature known as globoid cell in the brain and that this consisted partially of galactosylceramide, a major sphingolipid component of myelin. The finding that these patients had a deficiency of galactocerebrosidase (GALC) activity opened the way to relatively simple diagnostic testing with easily obtainable tissue samples, studies leading to the purification of GALC, and cloning of the GALC cDNA and gene. The availability of the gene sequence led to the identification of mutations in patients and to the current studies involving the use of viral vectors containing the GALC cDNA to treat experimentally naturally occurring animal models, such as twitcher mice. Currently, treatment of presymptomatic human patients is limited to hematopoietic stem cell transplantation (HSCT). With recent studies showing successful treatment of animal models with a combination of HSCT and viral gene therapy, it is hoped that more effective treatments will soon be available for human patients. For this Review, it is not possible to reference all of the articles contributing to our current state of knowledge about this disease; however, we have chosen those that have influenced our studies by suggesting research paths to pursue. © 2016 Wiley Periodicals, Inc.

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Sendai Virus-Based Reprogramming of Mesenchymal Stromal/Stem Cells from Umbilical Cord Wharton's Jelly into Induced Pluripotent Stem Cells.

Cristian Miere, Liani Devito, Dusko Ilic (2016)

In an attempt to bring pluripotent stem cell biology closer to reaching its full potential, many groups have focused on improving reprogramming protocols over the past several years. The episomal modified Sendai virus-based vector has emerged as one of the most practical ones. Here we describe reprogramming of mesenchymal stromal/stem cells (MSC) derived from umbilical cord Wharton's Jelly into induced pluripotent stem cells (iPSC) using genome non-integrating Sendai virus-based vectors. The detailed protocols of iPSC colony cryopreservation (vitrification) and adaption to feeder-free culture conditions are also included.