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JCI online early table of contents: March 15, 2010

JCI Journals

EDITOR'S PICK: Targeted gene therapy beneficial to mice with spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by progressive muscle wasting and weakness. The severity of the disease varies between individuals, with the clinical spectrum ranging from early infant death to normal adult life with only mild weakness. Currently, there are no effective therapies. As SMA is caused by mutations in the SMN1 gene that result in a lack of SMN protein, gene therapy provides one possible treatment strategy. Marco Passini and colleagues, at Genzyme Corporation, Framingham, now provide hope that this therapeutic approach might one day be possible by showing that in a severe mouse model of SMA they can substantially improve muscle strength, coordination, and locomotion by injecting the gene-carrying therapeutic directly into the brain and spinal cord of newborn mice.

TITLE: CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy

Marco A. Passini
Genzyme Corporation, Framingham, Massachusetts, USA.
Phone: 508.270.2033; Fax: 508.271.4776; E-mail:

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EDITOR'S PICK: Sealing the deal to block heart failure in dogs with muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy characterized by rapid progression of muscle degeneration that eventually leads to death. However, due to advances in palliative respiratory care, heart failure is now emerging as a leading cause of death, and there are currently no effective therapies for this fatal clinical consequence of DMD. But now, DeWayne Townsend and colleagues, at the University of Minnesota, Minneapolis, have found that chronic infusion of membrane-sealing poloxamer blocks advanced heart disease in the golden retriever muscular dystrophy model of DMD. Further analysis provided a mechanistic basis for the beneficial effect of poloxamer: it restored the compliance of heart muscles from the dystrophic dogs to normal. The authors therefore suggest that membrane-sealant therapy could provide a new approach to treating DMD heart disease.

TITLE: Chronic administration of membrane sealant prevents severe cardiac injury and ventricular dilatation in dystrophic dogs

DeWayne Townsend
University of Minnesota, Minneapolis, Minnesota, USA.
Phone: 612.625.6873; Fax: 612.625.5149; E-mail:

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PARASITOLOGY: Cancer drug beneficial in models of infectious disease

Drugs known as receptor tyrosine kinase inhibitors (RTKIs) are routinely used to treat several forms of cancer, but whether they could be used to effectively treat infectious diseases has not been determined. Paul Kaye and colleagues, at York University, United Kingdom, have now started to address this question, showing that the cancer drug sunitinib maleate (which is an RTKI) blocks several symptoms of disease in mouse models of visceral leishmaniasis, a neglected tropical disease caused by the parasites Leishmania donovani and Leishmania infantum.

In the study, although sunitinib maleate treatment alone prevented the development of several symptoms of visceral leishmaiasis, it did not cause a reduction in tissue parasite burden. However, sequential administration of sunitinib maleate and a conventional antileishmanial drug led to effective parasite clearance with ten-fold less of the conventional drug than normally required to achieve this effect. The authors therefore suggest that using an RTKI prior to administration of conventional antileishmanial drugs might be clinically useful in the treatment of visceral leishmaniasis.

TITLE: Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice

Paul M. Kaye
University of York, York, United Kingdom.
Phone: 44.1904.328840; Fax: 44.1904.328844; E-mail:

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TUMOR IMMUNOLOGY: Why immune and conventional therapies combine to kill tumors

Approaches to harness the immune system as a treatment for cancer are being developed because conventional therapies often do not eradicate disease. However, most cancer immunotherapies tested in the clinic so far have not been very effective, although recent data indicate that they are tremendously beneficial when combined with conventional cancer chemotherapeutics. A team of researchers, led by Dmitry Gabrilovich, at the H. Lee Moffitt Cancer Center and Research Institute, Tampa, has now uncovered a mechanism by which cancer immunotherapies mediate a potent antitumor effect in mice when combined with conventional chemotherapeutics. They believe that their data provide strong rationale for a combination approach to the treatment of advanced cancers.

In the study, a variety of cancer immunotherapeutic approaches (specifically several cancer vaccines and an adoptive T cell transfer approach) were tested in mice in combination with several commonly used chemotherapeutic drugs. It was found that the chemotherapeutic drugs made tumor cells more susceptible to killing by immune cells known as CTLs, suggesting that small numbers of CTLs can provide a potent antitumor effect in the presence of commonly used chemotherapeutic drugs.

TITLE: Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice

Dmitry I. Gabrilovich
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Phone: 813.745.6863; Fax: 813.745.1328; E-mail:

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ONCOLOGY: Possible new drug target for head and neck cancers

Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer; it is the name given to a group of cancers that includes cancer of the mouth. While the prognosis for all patients with HNSCC is not good, it is substantially worse for those whose cancer has already spread (metastasized) to their lymph nodes by the time they are diagnosed. Identifying the molecules involved in promoting metastasis therefore provides potential new targets for drugs that might prevent the spread of cancer to new sites. A team of researchers, led by Sumin Kang and Jing Chen, at the Winship Cancer Institute of Emory University, Atlanta, has now generated several lines of evidence that suggest that the protein RSK2 might be a potential target for such drugs.

In the study, two of the key lines of evidence highlighting the potential of RSK2 as a therapeutic target were the observations that expression of RSK2 correlated with metastatic progression in patients with HNSCC and that decreasing RSK2 expression substantially reduced the metastatic potential of HNSCC cells in a xenograft mouse model of HNSCC. The authors therefore conclude that RSK2 is involved in the programming of HSNCC cells to become metastatic and that this makes it an ideal target for drugs that might prevent the spread of cancer to new sites.

TITLE: p90 ribosomal S6 kinase 2 promotes invasion and metastasis of human head and neck squamous cell carcinoma cells

Sumin Kang
Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.
Phone: 404.778.1880; Fax: 404.778.4755

Jing Chen
Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.
Phone: 404.778.5274; Fax: 404.778.5520; E-mail:

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INFLAMMATION: Repairing damaged tissues: the role of hematopoietic stem/progenitor cells

Hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) are the source of circulating blood cells. They have also been suggested to have a role in tissue repair at sites of inflammation. Using two mouse models of sterile inflammation, Israel Charo and colleagues, at the Gladstone Institute of Cardiovascular Disease, San Francisco, have determined that HSCs/HPCs are recruited to sites of inflammation, where they promote tissue repair, and that their expression of the protein CCR2 is crucial for their ability to be recruited.

In the study, one observation of particular interest, given that the most common form of acute liver failure in the developed world is acute acetominophen (paracetamol) overdose, administration of normal HSCs/HPCs, but not those lacking CCR2, accelerated the repair of liver damage induced by acetominophen in mice. The authors hope that further defining the molecular mechanisms controlling the recruitment of HSCs/HPCs to sites of inflammation will provide a framework for developing cell-based therapies for organ damage.

TITLE: CCR2 mediates hematopoietic stem and progenitor cell trafficking to sites of inflammation in mice

Israel F. Charo
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
Phone: 415.734.2000; Fax: 415.355.0960; E-mail:

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IMMUNOLOGY: New insight into the mechanisms by which the protein RAG2 functions

Genetic mutations that impair the function of the protein RAG2 can cause severe combined immunodeficiency (SCID) or Omenn syndrome (OS), an immune deficiency condition closely related to SCID. By analyzing a panel of genetic mutations that affect the PHD domain of RAG2 and cause either SCID or OS, Patricia Cortes and colleagues, at Mount Sinai School of Medicine, New York, have provided new insight into the mechanisms by which RAG2 functions. Specifically, they found that the PHD domain of RAG2 is crucial for regulating the function of the entire RAG2 protein. These data provide a potential explanation for why the immune deficiency caused by some point mutations that affect the PHD domain of RAG2 is more profound than that caused by mutations that result in deletion of the entire PHD domain.

TITLE: Analysis of mutations from SCID and Omenn syndrome patients reveals the central role of the Rag2 PHD domain in regulating V(D)J recombination

Patricia Cortes
Mount Sinai School of Medicine, New York, New York, USA.
Phone: 212.659.9443; Fax: 212.849.2525; E-mail:

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