News Release

JCI online early table of contents: April 15, 2008

Peer-Reviewed Publication

JCI Journals


Clearer day for gene therapy: new vector carries big genes linked to inherited blindness

Some clinicians and researchers hope that individuals with inherited diseases (such as cystic fibrosis and recessive Stargardt disease, which causes progressive loss of sight) might one day be cured by providing them with a corrected version of their disease-causing faulty gene, i.e., by gene therapy. In gene therapy, the curative gene is packaged in an agent known as a vector, which carries the gene into cells where it is required. One of the most common vectors is derived from a virus, adeno-associated virus (AAV). However, for some diseases, such as recessive Stargardt disease, one barrier to successful gene therapy is that AAV is not able to accommodate the large size of the curative gene. New data, generated by Alberto Auricchio and colleagues, at the Telethon Institute of Genetics and Medicine, Italy, has revealed that vectors derived from a specific form of AAV known as AAV5 can accommodate large genes, including that missing in a mouse model of recessive Stargardt disease.

In the study, it was found that much larger genes could be packaged into vectors derived from AAV5 than from vectors derived from other forms of AAV. Further, it was shown that AAV5 could be used to induce cells to successfully convert the information in the large genes into protein. When AAV5 containing the mouse gene Abca4, which is the mouse correlate of the gene mutated in individuals with recessive Stargardt disease, was injected into the eye of mice lacking Abca4, improvement in the function of the eye was observed. The authors therefore concluded that vectors derived from AAV5 could be useful for treating individuals with recessive Stargardt disease.

TITLE: Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice


Alberto Auricchio
Telethon Institute of Genetics and Medicine, Naples, Italy.
Tel: 11-39-081-6132229; Fax: 11-39-081-5790919; E-mail:

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Walking on AIRE: how the G228W AIRE mutation causes disease

Individuals develop the autoimmune disease autoimmune polyglandular syndrome type 1 (APS1) if both copies of their AIRE gene are mutated such that they make no functional AIRE protein. APS1 is characterized by a specific group of symptoms, and many different mutations in the AIRE gene have been linked to this disease. Recently, individuals with a mutation known as G228W in just one copy of their AIRE gene have been identified and shown to exhibit a different pattern of symptoms to individuals with APS1. Insights into the mechanisms by which the G228W mutation causes autoimmunity have now been provided by Mark Anderson and colleagues, at the University of California, at San Francisco, Diabetes Center.

In the study, mice were engineered such that they expressed the G228W mutation. These mice were found to have a defect in a process known as negative selection, which is the process by which immune cells known as T cells that target our own organs are eliminated, such that T cells able to target the organs of the mouse escaped and caused autoimmunity. This defect occurred because the G228W mutant AIRE bound normal AIRE and sequestered it in nuclear inclusion bodies so that it could not carry out its function. As the G228W mutant AIRE was unable to prevent all normal AIRE from functioning, these data indicate that even low levels of AIRE function are insufficient to prevent autoimmunity.

TITLE: Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire


Mark S. Anderson
University of California at San Francisco Diabetes Center, San Francisco, California, USA.
Phone: (415) 502-8052; Fax: (415) 564-5813; E-mail:

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The protein KIM-1 enables kidney cells to clear up the mess made by dead cells

The clearance of dead cells is a necessary part of tissue repair after injury and scavenger cells known as macrophages have a central role in this process. However, it has been suggested that epithelial cells at the site of an injury can also perform this task, and evidence that epithelial cells in the kidney can do so has now been provided by a group of researchers at Brigham and Women's Hospital, Boston.

The protein KIM-1 (also known as TIM-1) is upregulated on the surface of injured kidney epithelial cells. In the study, it was found that upregulation of KIM-1 enabled rat, pig, and dog kidney epithelial cells to take up cells that had died by a process known as apoptosis. The uptake of the apoptotic cells, by a process known as phagocytosis, occurred after KIM-1 bound molecules on the surface of the apoptotic cells, specifically phosphatidylserine and oxidized lipoproteins. These data suggest a role for KIM-1 in repair of the lining of the kidney tubules following injury.

TITLE: Kidney injury molecule–1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells


Takaharu Ichimura
Brigham and Women's Hospital, Harvard Institute of Medicine, Boston, Massachusetts, USA.
Phone: (617) 525-5961; Fax: (617) 525-5965; E-mail:

Jeremy S. Duffield
Brigham and Women's Hospital, Harvard Institute of Medicine, Boston, Massachusetts, USA.
Phone: (617) 525-5914; Fax: (617) 525-5830; E-mail:

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ROCK solid: A key role for the protein ROCK1 in vessel wall damage

Diseases that affect the heart and/or blood vessels are known as cardiovascular diseases and they include high blood pressure (also known as hypertension), stroke, and atherosclerosis. The disease-causing changes to blood vessels in some cardiovascular diseases occur as a result of a damaging inflammatory response to blood vessel injury, and increased activity of members of the ROCK family of proteins has been linked to this process. However, several cell types are involved in the blood vessel–damaging inflammatory response to injury and it has not been determined which specific ROCK protein is involved in which specific cell type. In a new study, using mice expressing only one of the genes containing the information for making ROCK1 (Rock1+/– mice) and mice expressing only one of the genes containing the information for making ROCK2 (Rock2+/– mice), James Liao and colleagues at Brigham and Women’s Hospital and Harvard Medical School, Boston, have shown that ROCK1, and not ROCK2, mediates damaging changes to blood vessels after they have been injured by being closed off. The lack of damaging changes to blood vessels in Rock1+/– mice was associated with decreased inflammatory cell mobilization to the site of injury. Further analysis indicated that ROCK1 expression in bone marrow–derived cells, most probably inflammatory cells, was important for mediating the damaging changes to blood vessels after injury. The authors therefore concluded that ROCK1 might provide a useful target for treating inflammatory diseases of blood vessels.

TITLE: ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury


James K. Liao
Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 768-8424; Fax: (617) 768-8425; E-mail:

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‘Til death do us part: death of nerves in the gut causes intestinal disease

The nerves that control the gut form part of a network known as the enteric nervous system. Dysfunction in this system can lead to intestinal diseases such as Hirschsprung disease (also known as congenital intestinal aganglionosis), which occurs when part of the enteric nervous system is missing, meaning that the gut cannot function properly, leading to intestinal blockages and inflammation. Hirschsprung disease occurs most commonly in children born with mutations in their RET gene, but the reasons for this link have not been determined. In a new study, Hideki Enomoto and colleagues at the RIKEN Center for Developmental Biology in Kobe, Japan, have demonstrated that mice with reduced expression of the Ret gene show features of Hirschsprung disease. Disease was associated with impaired migration of precursors of enteric nerves to the gut and decreased survival of these precursor cells. If expression of the Ret gene was reduced after precursors of enteric nerves had migrated to the gut and developed into nerves, the enteric nerves that had already developed did not survive. Thus, the authors suggest that decreased Ret expression impairs the survival of both precursors of enteric nerves and enteric nerves themselves and that this cell death is potentially involved in the etiology of Hirschsprung disease.

TITLE: Diminished Ret expression compromises neuronal survival in the colon and causes intestinal aganglionosis in mice


Hideki Enomoto
RIKEN Center for Developmental Biology, Kobe, Japan.
Phone: 81-78-306-3099, Fax: 81-78-306-3089, E-mail:

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