EDITOR'S PICK: Gene therapy for hemophilia A mice
Hemophilia A is an inherited bleeding disease caused by a lack of the blood clotting protein Factor VIII. It had been hoped that gene therapy would provide a breakthrough in treatment, but the most common gene therapy approach has had little clinical success. However, a team of researchers, at the University of Minnesota Medical School, Minneapolis, has now developed a new approach to target genes specifically to mouse liver sinusoidal endothelial cells (the cells that are the main source of Factor VIII) and used it to provide long-term expression of Factor VIII in hemophilia A mice, markedly reducing their disease. They hope that their data might prove to be a step toward successful human clinical trials in individuals with hemophilia A.
The team, led by Betsy Kren and Clifford Steer, coated nanoparticles with hyaluron so that they targeted liver sinusoidal endothelial cells. To test the efficacy of gene delivery, the hyaluron-coated nanoparticles were engineered to contain a therapeutic gene (Factor VIII) together with a genetic element known as Sleeping Beauty, which helps the therapeutic gene insert into the genome of the targeted cells (i.e, the liver sinusoidal endothelial cells). Even 50 weeks after hemophilia A mice were injected with these nanoparticles, levels of Factor VIII in the blood were the same as in the blood of normal mice and bleeding times were also similar to those of normal mice. The authors hope that this combination of technologies, the cell-specific nanocapsule delivery system and the Sleeping Beauty genetic element, will prove to be a viable gene therapy.
TITLE: Nanocapsule-delivered Sleeping Beauty mediates therapeutic Factor VIII expression in liver sinusoidal endothelial cells of hemophilia A mice
Betsy T. Kren
University of Minnesota Medical School, Minneapolis, Minnesota, USA.
Phone: (612) 626-4255; Fax: (612) 625-5620; E-mail: firstname.lastname@example.org.
Clifford J. Steer
University of Minnesota Medical School, Minneapolis, Minnesota, USA.
Phone: (612) 624-6648; Fax: (612) 625-5620; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34332
EDITOR'S PICK: How a drug to treat acute lymphoblastic leukemia is degraded
L-Asparaginase is one of the key drugs used to treat children with acute lymphoblastic leukemia (ALL). However, some children fail to achieve therapeutic levels of L-asparaginase after receiving the drug. The mechanisms underlying such therapeutic failure are not well defined. But now, Vaskar Saha and colleagues, at the Paterson Institute for Cancer Research, United Kingdom, have found that leukemic cells from some patients with ALL express two proteins capable of degrading ASNase, one of the commercially available sources of L-asparaginase. Importantly, expression of one of these proteins, AEP, is predominantly observed in individuals with high-risk forms of ALL. By modifying one amino acid of ASNase, the authors were able to render it resistant to cleavage by AEP; however, the modified drug was not as active. The authors hope that this description of a potential mechanism to explain why some children fail to achieve therapeutic levels of L-asparaginase after receiving ASNase will enable optimization of L-asparaginase therapy to the benefit of children with ALL.
TITLE: A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase
Paterson Institute for Cancer Research, Manchester, United Kingdom.
Phone: 44-161-446-3094; Fax: 44-161-446-3092; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37977
ONCOLOGY: Learning about antitumor immune responses from human patients
Insight into antitumor immune responses can be gained by studying the small number of individuals with small cell lung cancer (SCLC) that develop the neurologic disorder Hu paraneoplastic neurologic syndrome. SCLC cells express the protein HuD, which is normally only expressed by nerve cells, and the presence of an immune response against HuD correlates with improved prognosis for individuals with SCLC. However, in a small number of patients, the immune response against HuD on the cancer cells attacks nerve cells expressing HuD, leading to neurologic symptoms. It has been proposed for many years that immune cells known as CD8+ T cells contribute to disease in Hu patients, but no one has been able to detect these cells. However, Robert Darnell and colleagues, at The Rockefeller University, New York, have now identified, in Hu patients, HuD-specific CD8+ T cells and determined one potential explanation for why they have been so difficult to detect.
In the study, the HuD-specific CD8+ T cells detected in Hu patients were of two types: normal CD8+ T cells that produce the molecule IFN-gamma and kill cells expressing their target (in this case HuD); and atypical CD8+ T cells that produce the molecules IL-13 and IL-15 and cannot kill HuD-expressing cells. Further analysis revealed that SCLC cells produce factors that skew CD8+ T cells to the atypical type, leading the authors to suggest that SCLC might evade antitumor immune responses by skewing tumor-targeted CD8+ T cells to the nonkilling type.
TITLE: Patients with lung cancer and paraneoplastic Hu syndrome harbor HuD-specific type 2 CD8+ T cells
Robert B. Darnell
The Rockefeller University, New York, New York, USA.
Phone: (212) 237-7460; Fax: (212) 327-7109;
View the PDF of this article at: https://www.the-jci.org/article.php?id=36131
OPHTHALMOLOGY: When development of the eye fails to give clear sight
Masaru Inatani and colleagues, at Kumamoto University Graduate School of Medical Sciences, Japan, have provided new insight into the development of the anterior chamber of the mouse eye, the fluid-filled space inside the eye that lies between the iris and the cornea. The clinical relevance of this information lies in the fact that failure of the anterior chamber to develop causes developmental glaucoma.
In the study, failure of the anterior chamber to develop was caused by a lack of the molecule HS in mouse neural crest cells. Specifically, the characteristics of the mice resembled the form of human developmental glaucoma known as Peters anomaly. Signaling induced by the molecule TGF-beta-2 was disturbed in the neural crest cells lacking HS; this altered expression of the proteins Foxc1 and Pitx2. Mutations in the genes responsible for generating these two proteins are known to cause developmental glaucoma. These data indicate that HS is required for proper formation of the anterior chamber of the mouse eye from neural crest cells and lead the authors to suggest that modulation of HS levels might cause developmental glaucoma.
TITLE: Heparan sulfate deficiency leads to Peters anomaly in mice by disturbing neural crest TGF-beta-2 signaling
Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Phone: 81-96-373-5247; Fax: 81-96-373-5249; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38519
BACTERIOLOGY: Clearing pneumococcal bacteria from the upper airways
The bacterium Streptococcus pneumoniae can be found in the upper airways (the nose, mouth, and throat) of most children. When living in the upper airways, S. pneumoniae is harmless. However, if the bacteria are carried to other sites, they cause disease, for example ear infections and life-threatening pneumonia. Long-term studies have shown that the upper airways of children do not continuously harbor S. pneumoniae. Rather, it is a cycle of bacterial clearance followed by recolonization, with little known about how the bacteria are cleared. However, Jeffrey Weiser and colleagues, at the University of Pennsylvania School of Medicine, Philadelphia, have now identified a cellular immune mechanism by which mice clear S. pneumoniae from their upper airways.
In the study, they found that efficient clearance of S. pneumoniae from the upper airways of mice that had not been previously colonized by the bacteria required immune cells known as Th17 cells (CD4+ T cells that secrete the soluble factor IL-17). Further analysis indicated that these cells were required to sustain the recruitment of other immune cells known as monocyte/macrophages, which effectively cleared the pneumococcal bacteria. The authors suggest these data provide a new model for immune-mediated clearance of S. pneumoniae from the upper airways.
TITLE: Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice
Jeffrey N. Weiser
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-3511; Fax: (215) 573-4856; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=36731
GENE THERAPY: Selecting genetically modified cells in rhesus macaques
Transplanting individuals with genetically modified hematopoietic stem cells has been considered a viable gene therapy approach to treat a number of diseases. One major limitation to this approach is the low efficiency of gene transfer into the target cells. Including a drug resistance gene in the viral vector containing the therapeutic gene has been suggested as a way to overcome this limitation. Andre Larochelle and colleagues, at the NIH, Bethesda, have now tested this hypothesis in rhesus macaques using the gene MGMT*, which confers resistance to the drugs O6-benzylguanine and temozolomide.
In the study, when rhesus macaques were transplanted with hematopoietic progenitor cells genetically modified to carry MGMT* and a fluorescent protein, there was a transient increase in cells expressing the fluorescent protein after treatment with O6-benzylguanine and temozolomide. However, there was no long-term selection of genetically modified cells. Despite the lack of long-term effects, these data should have clinical impact. For example, the observation that rhesus macaques transplanted with cells modified to express MGMT* were able to receive increasing doses of temozolomide without toxic consequences might provide benefit to individuals with malignant brain tumors that require temozolomide dose intensification.
TITLE: In vivo selection of hematopoietic progenitor cells and temozolomide dose intensification in rhesus macaques through lentiviral transduction with a drug resistance gene
National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 451-7139; Fax: (301) 496-8396; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37506
DEVELOPMENT: 'Notch'ing up our understanding of embryonic heart development
Congenital heart disease can be caused by mutations in either the JAGGED or NOTCH genes. Jonathan Epstein and colleagues, at the University of Pennsylvania, Philadelphia, have now provided new insight into the role of Jagged-Notch signaling in heart development in mice, defining a potential cellular explanation for forms of congenital heart disease linked to JAGGED and NOTCH mutations.
In the study, genetic manipulation of the region of the developing mouse embryo that gives rise to the right ventricle of the heart (the second heart field) such that it either lacked Jagged1 (a molecule that binds Notch, initiating signaling) or expressed an inhibitor of the Notch signaling pathway led to abnormal development of the heart. Further, inhibition of Notch in the second heart field affected the development of neighboring tissues; for example, abnormal migration of cardiac neural crest cells was observed. Further analysis revealed a molecular explanation for the heart defects: decreased expression of the Fgf8 and Bmp4 genes. The authors therefore suggest that altered Notch-Jagged signaling within the second heart field might underlie forms of congenital heart disease linked to JAGGED and NOTCH mutations.
TITLE: Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development
Jonathan A. Epstein
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 898-8731; Fax: (215) 573-2094; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38922
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