This month’s science round up features exciting new research findings that could lead to the development of therapeutics for treating Huntington’s disease, melanoma and Ebola. We also report on the first clinical trial using the CRISPR/Cas9 technology. You will also not want to miss our immunology section highlighting the discovery of a new immune cell type. Dive in to learn more… Happy Reading!
Huntington’s disease (HD) is an inherited and fatal neurogenerative disorder. Patients with HD experience significant weight loss and profound inanition, which is characterized as exhaustion due to lack of nourishment. It has been proposed that perturbations in amino acid metabolism may account for these effects. Researchers at the Johns Hopkins University School of Medicine previously reported that the protein responsible for making the amino acid cysteine, cystathionine gamma-lyase (CSE), is depleted in HD. In a recent study published in last week’s issue of the Proceedings of the National Academy of Sciences, the same research group further demonstrated that the master regulator of amino acid homeostasis, activating transcription factor 4 (ATF4), is dysfunctional in HD. This results in oxidative stress induced by impaired cysteine biosynthesis and transport. Using healthy control mouse brain cells and cells from mice with HD, the researchers show that this effect was indeed unique to cysteine, as ATF levels were normal in cells grown in conditions depleted of other amino acids in both healthy and HD cells. Treatment of HD cells with the antioxidant vitamin C led to the renewed ability of cells to produce ATF, and thus cysteine. Since cysteine deficiency has been reported in other diseases such as arthritis, cancer, AIDS and cardiovascular disease, these findings could also lead to therapeutic interventions for these devastating illnesses. However, the researchers caution that further research on cysteine’s role in the body is needed before its therapeutic value can be confirmed, as supplementing with too much cysteine could be harmful.
Sbodio JI et al. (2016). Transcriptional control of amino acid homeostasis is disrupted in Huntington’s disease. Proc Natl Acad Sci USA pii: 201608264 [Epub ahead of print].
The development of immune checkpoint inhibitor drugs for cancer immunotherapy has revolutionized the treatment of cancers such as advanced malignant melanoma. Approximately 20% of patients who receive ipilimumab, a monoclonal antibody that targets the checkpoint molecule CTLA-4, achieve durable responses. While this represents a significant improvement compared to historic outcomes, physician scientists have been working on strategies to increase the percentage of patients achieving long-term benefits from this immunotherapy. Researchers led by Sebastian Theurich, MD, at the University Hospital of Cologne Germany recently demonstrated that adding local peripheral treatments (LPT) such as radiotherapy, electrochemotherapy or internal radiotherapy to systemic ipilumumab treatment doubled the survival chances of patients with advanced malignant melanoma. In addition, no increases in immune-related side effects were observed. The researchers also demonstrate that combining LPT with ipilimumab is safe and effective in patients with metastatic melanoma irrespective of known risk factors or clinical disease characteristics. These findings correlate with a previous study of 29 patients with melanoma conducted in the United States. Theurich and colleagues propose that induction of antitumor immune responses is the likely underlying mechanism for the observed effects of the combination treatment strategy, however, this warrants further investigation.
Theurich S et al. Local tumor treatment in combination with systemic ipilimumab immunotherapy prolongs overall survival in patients with advanced malignant melanoma. Cancer Immunol Res doi: 10.1158/2326-6066.CIR-15-0156 [Epub ahead of print].
Barker CA et al. (2013). Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma. Cancer Immunol Res 1 92-98.
Our knowledge of innate immunology and the response to microbial infection continues to evolve at a rapid pace. The recent identification of the non T and B cell like innate lymphoid cells (ILCs), which include natural killer (NK) cells, lymphoid tissue inducer (LTi) cells and group 1-3 ILCS, challenged our understanding of the unique differences in function and characteristics of innate and adaptive immune cells. Innate immunity provides a first line of host defense against microbial pathogens. NK cells and ILC1s in particular produce large amounts of the cytotoxic cytokine interferon-gamma in response to infection. However, how these innate immune cells are primed during infection was previously unknown. New research findings from the Chinese Academy of Sciences and the West China Hospital have identified a new immune cell type called natural killer-like B (NKB) cells that provide the solution to the described unknown phenomena. These cells were shown to be distinct from NK and B cells, and differentiate from bone marrow pro-B cells. The researchers demonstrated that NKBs can activate ILC1s and NK cells to protect against microbial infection by producing IL-18 and IL-12 at an early phase of infection. This study identifies NKBs as a subpopulation of innate-like lymphocytes. Additional research will be required to further characterize these cells and their other roles in addition to their antimicrobial function.
Wang S et al. (2016). Natural killer-like B cells prime innate lymphocytes against microbial infection. Immunity 45, 131-144.
Nguyen TT and Baumgarth N (2016). Innate B cells tell ILC how it’s done. Immunity 45 8-10.
Haemophilus parasuis (Hps) is an important swine pathogen that causes Glasser’s disease, which is characterized by pneumonia, meningitis and polyserositis. There at least 15 different types of Hps strains that can be found throughout the world. Protection against Hps infection is associated with the presence of homologous antibodies in serum. However, until now, no Hps antigen that can elicit a protective immune response against all Hps strains had been identified. In a new study published in the journal Research in Veterinary Science, scientists discovered a novel immunogenic and species-specific Hps protein by screening Hps whole cell proteins using swine convalescent sera. The protein was a 52 kDa molecule identified as oligopeptide permease A (OppA). OppA elicited a specific antibody response in pigs that recovered from Hps infection. In addition, pigs immunized with recombinant OppA protein demonstrated robust serological responses. However, the antibodies were not protective against challenge infection. Since Hps infection causes serious illnesses in pigs, the identification of OppA could lead to the development of a universal species-specific vaccine against Hps infection. In addition, OppA can serve as a marker for previous systemic infection with Hps.
Macedo N et al. (2016). Immune response to oligopeptide permease A (OppA) protein in pigs naturally and experimentally infected with Haemophilus parasuis. Res Vet Sci 107, 62-67.
The CRISPR/Cas9 system is a powerful gene-editing tool. It is arguably the most revolutionary scientific discovery of the past decade. Since its discovery, it has been widely used in biomedical research. However, despite its significant potential to improve biological challenges, it has several limitations such as off-target effects and lack of easy solutions for multiplex targeting. Scientists recently addressed these limitations in a new study published in the Nucleic Acids Research journal. They have created a “toolbox” that provides a solution for easy genome editing with the ability to target multiple genes at once, while exhibiting tight temporal control and minimal off-target effects. Essentially, they developed a strategy to make the gene editing system inducible, as opposed to the constitutively active nature of the current CRISPR/Cas9 system. This resulted in minimal off-target effects. The proposed gene-editing system also contained a fluorescent marker so the researchers could track whether the editing enzyme was turned on or off in cells. To test the system, the researchers used both cancer-related cells and animal models to simultaneously deplete three cancer genes. “This new genome-editing toolbox can be used for inducible and multiple gene targeting” said Qin Yan Ph.D., corresponding author and Associate Professor of Pathology at Yale Cancer Center.
Cao J et al. (2016). An easy and efficient inducible CRISPR/Cas9 platform with improved specificity for multiple gene targeting. Nucl Acids Res doi: 10.1093/nar/gkw660 [Epub ahead of print].
The Ebola virus (EBOV) is one of the most lethal human pathogens known, as demonstrated in the global outbreak of 2014. The outbreak presented an opportunity for scientists to identify gaps in the understanding of viral pathogenesis, emphasizing the need for further research on how EBOV replicates. It is known that EBOV can successfully enter many cell types where it replicates by hijacking the host cell machinery to make its own proteins. Many of the factors that the virus co-opts are currently unknown but could represent potential targets for anti-EBOV therapeutics. Some of these factors were identified in a recent study published in the mBio journal. Scientists at Boston University, Galveston National Laboratory and the National Institutes of Health (NIH) USA demonstrated that polyamines are critical for EBOV replication. They also show that small molecule inhibitors of polyamine synthesis as well as shRNA knockdown of a polyamine pathway enzyme, spermidine, resulted in reduced EBOV replication. Blocking the function of spermidine also led to a reduction in EBOV gene expression. The pathway that involves spermidine leads to modification of a human protein that is required for EBOV to grow in cells, indicating that this protein could be a unique target for developing future Ebola therapeutics.
Olsen ME et al. (2016). Polyamines and Hypusination are required for Ebolavirus gene expression and replication. mBio 7, pii: e00882-16.
In June's science round up, we reported that a team led by Dr. Edward Stadtmauer, a physician at the University of Pennsylvania, had received approval by the US NIH on June 21, 2016 to conduct a clinical trial using the CRISPR/Cas9 system for cancer immunotherapy. However, scientists at Sichuan University’s West China Hospital in Chengdu will be the first to use CRISPR/Cas9 edited cells in humans. The research team led by Lu Yon M.D. received ethical approval from the hospital board on July 6, 2016 to test such cells in patients with lung cancer. The clinical trial is set to begin next month. The delay in the proposed clinical trial by Dr. Stadtmauer is due to the requirement for additional approval from the US Food and Drug Administration (FDA) and a university review board.
The Chinese trial will enroll patients with metastatic non-small cell lung cancer for whom prior treatments including chemotherapy and radiation therapy have been unsuccessful. Similar to the strategy proposed by Dr. Stadtmauer’s group, Dr. Yon and his colleagues will extract T cells from the blood of cancer patients, and then use the CRISPR/Cas9 technology to knock out the gene that encodes PD-1. PD-1 acts as a negative regulator of anti-tumor immunity in cancers by preventing activated T cells from attacking the cancer. Once edited, the cells will then be multiplied in the lab and re-introduced to the patient. It is noteworthy that a humanized anti-PD1 therapeutic monoclonal antibody, nivolumab, has been used successfully to treat metastatic melanoma and a clinical trial testing it in lung cancer was approved by the FDA last year. Check out this Nature News Report for more information.