Adipocytes as a vehicle for ex vivo gene therapy: Novel replacement therapy for diabetes and other metabolic diseases

Kuroda, Masayuki; Bujo, Hideaki; Aso, Masayuki; Saitō, Yasushi

doi:10.1111/j.2040-1124.2011.00133.x

Cited by 11 publications

(10 citation statements)

References 82 publications

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“…20 Enzyme replacement therapy for human congenital LCAT efficiency is still under development. 21 Our case report provides encouraging evidence to suggest that restoration of LCAT activity in patients with LCAT deficiency could induce resolution of the abnormal lipid deposition.…”

Section: Discussionmentioning

confidence: 57%

Nephrotic Syndrome Caused by Immune-Mediated Acquired LCAT Deficiency

Takahashi

Hiromura²,

Tsukida³

et al. 2013

Journal of the American Society of Nephrology

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Lecithin-cholesterol acyltransferase (LCAT) is an enzyme involved in maintaining cholesterol homeostasis. In familial LCAT deficiency (FLD), abnormal lipid deposition causes renal injury and nephrotic syndrome, frequently progressing to ESRD. Here, we describe a 63-year-old Japanese woman with no family history of renal disease who presented with nephrotic syndrome. The laboratory data revealed an extremely low level of serum HDL and undetectable serum LCAT activity. Renal biopsy showed glomerular lipid deposition with prominent accumulation of foam cells, similar to the histologic findings of FLD. In addition, she had subepithelial electron-dense deposits compatible with membranous nephropathy, which are not typical of FLD. A mixing test and coimmunoprecipitation study demonstrated the presence of an inhibitory anti-LCAT antibody in the patient's serum. Immunohistochemistry and immunofluorescence detected LCAT along parts of the glomerular capillary walls, suggesting that LCAT was an antigen responsible for the membranous nephropathy. Treatment with steroids resulted in complete remission of the nephrotic syndrome, normalization of serum LCAT activity and HDL level, and disappearance of foam cell accumulation in renal tissue. In summary, inhibitory anti-LCAT antibody can lead to glomerular lesions similar to those observed in FLD.

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Section: Discussionmentioning

confidence: 57%

Nephrotic Syndrome Caused by Immune-Mediated Acquired LCAT Deficiency

Takahashi

Hiromura²,

Tsukida³

et al. 2013

Journal of the American Society of Nephrology

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“…2,4 To prevent renal failure in patients with FLD, replacement therapy with recombinant enzyme is currently being developed. [5][6][7][8] Alternatively, we are developing a long-lasting gene therapy by transplantation of human LCAT genetransduced autologous adipocytes. 7,9 Recombinant LCAT (rLCAT) secreted by the LCAT gene-transduced adipocytes corrected abnormal HDL subpopulations in sera of FED patients in vitro.…”

mentioning

confidence: 99%

“…[5][6][7][8] Alternatively, we are developing a long-lasting gene therapy by transplantation of human LCAT genetransduced autologous adipocytes. 7,9 Recombinant LCAT (rLCAT) secreted by the LCAT gene-transduced adipocytes corrected abnormal HDL subpopulations in sera of FED patients in vitro. 10 LCAT catalyzes the esterification of cholesterol with acyl groups hydrolyzed from phospholipids, predominantly on HDL particles.…”

mentioning

confidence: 99%

Lipoprotein Subfractions Highly Associated With Renal Damage in Familial Lecithin:Cholesterol Acyltransferase Deficiency

Kuroda

Holleboom

Stroes

et al. 2014

ATVB

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Objective-In familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD), deposition of abnormal lipoproteins in the renal stroma ultimately leads to renal failure. However, fish-eye disease (FED) does not lead to renal damage although the causative mutations for both FLD and FED lie within the same LCAT gene. This study was performed to identify the lipoproteins important for the development of renal failure in genetically diagnosed FLD in comparison with FED, using high-performance liquid chromatography with a gel filtration column. Approach and Results-Lipoprotein profiles of 9 patients with LCAT deficiency were examined. Four lipoprotein fractions specific to both FLD and FED were identified: (1) large lipoproteins (>80 nm), (2) lipoproteins corresponding to large lowdensity lipoprotein (LDL), (3) lipoproteins corresponding to small LDL to large high-density lipoprotein, and (4) to small high-density lipoprotein. Contents of cholesteryl ester and triglyceride of the large LDL in FLD (below detection limit and 45.8±3.8%) and FED (20.7±6.4% and 28.0±6.5%) were significantly different, respectively. On in vitro incubation with recombinant LCAT, content of cholesteryl ester in the large LDL in FLD, but not in FED, was significantly increased (to 4.2±1.4%), whereas dysfunctional high-density lipoprotein was diminished in both FLD and FED. Conclusions-Our novel analytic approach using high-performance liquid chromatography with a gel filtration column identified large LDL and high-density lipoprotein with a composition specific to FLD, but not to FED.

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“…Clinical experience has demonstrated that aspirated fat is a suitable autologous tissue transplantation source for the correction of tissue defects in plastic and reconstructive surgery with minimal risk. [64][65][66] Adipose tissue is well vascularized and reported to be an important endocrine and secretory organ, [67][68][69][70] which may provide a cell-based gene therapy with efficient systemic delivery of therapeutic proteins 71) (Fig. 2).…”

Section: Adipocytes As Potential Target Cells For Developing Ex Vivo mentioning

confidence: 99%

A Novel Approach to the Treatment of Plasma Protein Deficiency: <i>Ex Vivo</i>-Manipulated Adipocytes for Sustained Secretion of Therapeutic Proteins

Kuroda

Saitō²,

Aso³

et al. 2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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Despite the critical need for lifelong treatment of inherited and genetic diseases, there are no developmental efforts for most such diseases due to their rarity. Recent progress in gene therapy, including the approvals of two products (Glybera and Strimvelis) that may provide patients with sustained effects, has shed light on the development of gene therapy products. Most gene therapy products are based on either adeno-associated virus-mediated in vivo gene transfer to target tissues or administration of ex vivo gene-transduced hematopoietic cells. In such circumstances, there is room for different approaches to provide clinicians with other therapeutic options through a variety of principles based on studies not only to gain an understanding of the pathological mechanisms of diseases, but also to understand the physiological functions of target tissues and cells. In this review, we summarize recent progress in gene therapy-mediated enzyme replacement and introduce a different approach using adipocytes to enable lifelong treatment for intractable plasma protein deficiencies.

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Adipocytes as a vehicle for ex vivo gene therapy: Novel replacement therapy for diabetes and other metabolic diseases

Cited by 11 publications

References 82 publications

Nephrotic Syndrome Caused by Immune-Mediated Acquired LCAT Deficiency

Nephrotic Syndrome Caused by Immune-Mediated Acquired LCAT Deficiency

Lipoprotein Subfractions Highly Associated With Renal Damage in Familial Lecithin:Cholesterol Acyltransferase Deficiency

A Novel Approach to the Treatment of Plasma Protein Deficiency: <i>Ex Vivo</i>-Manipulated Adipocytes for Sustained Secretion of Therapeutic Proteins

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