We don't need no dystrophin

Researchers from Harvard Medical School and the Brazilian Universidade de Sao Paulo have discovered a gene variant that could counteract the effects of mutant dystrophin. The team had previously reported on two dogs that had normal life span and functional muscles despite the complete absence of dystrophin. In the current work, they used genomics techniques to identify the gene that protected the animals from muscular dystrophy. They showed that increased expression of the gene Jagged1, which regulates the key developmental protein Notch, appeared to be the critical protective factor in those animals. The team concluded that "these results suggest that Jagged1 may be a new target for DMD therapeutic efforts in a dystrophin-independent manner, which will complement existing approaches." Their work appeared in the Nov. 12, 2015, online issue of Cell.

High-frequency blood stem cell editing

Researchers from the University of Southern California and Sangamo Biosciences Inc. have reported they were able to modify blood stem cells with high efficiency by combining electroporation of zinc finger nuclease (ZFN) mRNA with adeno-associated virus 6 (AAV6) delivery of template DNA for repair. CRISPR may be all the rage, but ZFNs are the more clinically advanced technology and, for now, the more precise editors. However, not all cells are easily edited using ZFN technology, and editing blood stem cells has to date been inefficient enough to hamper clinical translation of the technology. In their experiments, the authors showed they were able to edit the CCR5 and AAVS1 loci of blood stem cells that expressed the markers of primitive cells at frequencies of 17 percent and 26 percent, respectively. The authors concluded that AAV6 vectors "provide a means of broadening the application of genome engineering for the treatment of human diseases of the blood and immune systems." They published their results in the Nov. 9, 2015, issue of Nature Biotechnology.

More coronaviruses on the way

Scientists at the University of North Carolina have studied a severe acute respiratory syndrome coronavirus (SARS-CoV)-like virus that is currently circulating in Chinese horseshoe bat populations, and concluded it is indicative of "a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations." Coronaviruses are hard to study because they do not replicate in mice. However, it is possible to study their spike protein, which is the key to their ability to infect mammalian cells, by combining it with a mouse-adapted backbone. The authors created such a chimeric virus and found that it could "efficiently use multiple orthologs of the SARS receptor . . . replicate efficiently in primary human airway cells and achieve in vitro titers equivalent to epidemic strains of SARS-CoV. Additionally, in vivo experiments demonstrate replication of the chimeric virus in mouse lung with notable pathogenesis." If that is not enough bad news, "evaluation of available SARS-based immune-therapeutic and prophylactic modalities revealed poor efficacy." The work appeared in the Nov. 9, 2015, online issue of Nature Medicine.

Deciphering MRSA's double whammy

Infection with methicillin-resistant Staphylococcus aureus (MRSA) is a bigger problem than infection with sensitive strains for two reasons. MRSA is resistant to first-line antibiotics, and even when treated with appropriate antibiotics, it causes worse disease than sensitive strains. Now, a team at Cedars-Sinai Medical Center has discovered that those two phenomena are linked. The team showed that the gene that confers resistance to beta-lactamase antibiotics such as penicillin and methicillin also affects the cross-linking of peptides in the bacterial cell wall. The net effect was that MRSA induced an inflammatory response, including high levels of interleukin 1-beta. The authors concluded that "such an altered innate inflammatory response could lead to increased immunopathology and might contribute to the noted difference in morbidity between MRSA and drug-sensitive S. aureus infections." The work appeared in the Nov. 11, 2015, online issue of Cell Host & Microbe.

Gene therapy for Batten disease

Scientists at the Children's Hospital of Philadelphia have shown that they were able to improve the symptoms of Batten disease in dogs through the use of gene therapy to the epithelial cells that line the brain ventricles. Batten disease is one of the lysosomal storage disorders and is caused by lack of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1). TPP1 is a soluble enzyme, and so the authors investigated whether it would spread through the brain if it was synthesized in the ventricle lining. They found that such gene therapy was successful at leading to the expression of TTP1 that spread throughout the brain and spinal cord, and the treated dogs had delayed symptoms and a longer life span than untreated controls. The authors concluded that their study "highlights the utility of [gene therapy] of ventricular lining cells to accomplish stable secretion of recombinant protein for broad distribution in the central nervous system and therapeutic benefit." They reported their results in the Nov. 12, 2015, issue of Science Translational Medicine.

By Anette Breindl, Senior Science Editor