Head to head narcolepsy/hypersomnia study

At the sleep research meeting in San Antonio this year, there were signs of an impending pharmaceutical arms race in the realm of narcolepsy. The big fish in a small pond, Jazz Pharmaceuticals, was preparing to market its recently FDA-approved medication: Sunosi/solriamfetol. Startup Harmony Biosciences was close behind with pitolisant, already approved in Europe. On the horizon are experimental drugs designed to more precisely target the neuropeptide deficiency in people with classic narcolepsy type 1 Read more

Anti-inflammatory approach suppresses cancer metastasis in animal models

An anti-inflammatory drug called ketorolac, given before surgery, can promote long-term survival in animal models of cancer metastasis, a team of scientists has found. The research suggests that flanking chemotherapy with ketorolac or similar drugs -- an approach that is distinct from previous anti-inflammatory cancer prevention efforts -- can unleash anti-tumor immunity. The findings, published in Journal of Clinical Investigation, also provide a mechanistic explanation for the anti-metastatic effects of ketorolac, previously observed in human Read more

I3 Venture awards info

Emory is full of fledgling biomedical proto-companies. Some of them are actual corporations with employees, while others are ideas that need a push to get them to that point. Along with the companies highlighted by the Emory Biotech Consulting Club, Dean Sukhatme’s recent announcement of five I3 Venture research awards gives more examples of early stage research projects with commercial potential. This is the third round of the I3 awards; the first two were Wow! Read more

autoimmunity

Immune ‘traffic jam’ from viral infection

Several drugs now used to treat cancer and autoimmune diseases are actually repurposed tools derived from the immune system. One of the ways these “therapeutic antibodies” work is to grab onto malignant or inflammatory cells and escort them to their doom.

Emory researchers have found that in a mouse model of chronic viral infection, a kind of traffic pileup inside the body limits how effective therapeutic antibodies can be.

The results, published this week in Immunity, have implications for biotechnology researchers who continue to refine antibodies for therapeutic purposes, as well as bolster our understanding of how chronic viral infections impair the immune system.

Researchers led by Rafi Ahmed, PhD, director of the Emory Vaccine Center, were studying mice infected by LCMV (lymphocytic choriomeningitis virus). They injected several antibodies with the goal of removing various types of immune cells from the mice.  One end of the antibody molecule is supposed to bind the target cell, while another acts as a flag for other cells to get rid of the target cell.

However, during a chronic LCMV infection, the mouse’s immune system is producing its own antibodies against the virus, which form complexes with viral proteins. These immune complexes prevented the injected antibodies from having the effect the scientists wanted, which was to deplete their target cells.

Excessive amounts of immune complexes appear to be “clogging” the Fc gamma receptors that immune cells would use to grab the antibodies bound to the target cell, says postdoctoral fellow Andreas Wieland, PhD, first author of the Immunity paper. That these immune complexes form was not news; but how much they interfere with other antibodies was, Wieland says. Fc gamma receptors were already known to be important for antibodies to be effective against influenza and HIV. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Whole exome sequencing in IBD

Last year, pediatric gastroenterologist Subra Kugathasan gave an “old fashioned” grand rounds talk at Children’s Healthcare of Atlanta’s Egleston hospital, describing a family’s struggle with a multifaceted problem of autoimmunity.

Subra Kugathasan, MD

Now the Journal of Pediatric Gastroenterology and Nutrition paper, on how the genetic alteration underlying the family’s struggles was identified, is published. Kugathasan reports that the young man at the center of the paper is scheduled for allogeneic bone marrow transplant in the United States (but not in Atlanta) in the next couple months.

The list of troubles the members of the family had to deal with is long: gastrointestinal issues and food allergies, skin irritation, bacterial + yeast infections, and arthritis. The mother and her brother were affected to some degree, as well as all three of the kids (see tree diagram). The youngest brother is the “proband”, a geneticist’s term for starting point.

As determined by whole exome sequencing, the gene responsible is FOXP3, which controls the development of regulatory T cells. These are cells that restrain the rest of the immune system; if they aren’t functioning correctly, the immune system is at war with the rest of the body, like in this family.

The genetic variant identified was new — that’s why whole exome sequencing was necessary to find it. The authors conclude:

Supporting the utility of WES [whole exome sequencing] in familial clusters of atypical IBD [inflammatory bowel disease], this approach led to a definitive diagnosis in this case, resulting in a justifiable treatment strategy of allogeneic bone marrow transplantation, the treatment of choice for IPEX [Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome].

Bone marrow transplant is a big deal; doctors are essentially wiping out the immune system then bringing it back, with several associated risks. So the decision to go ahead is not taken lightly. In general, whether bone marrow transplant — either autologous (patient donates back to self) or allogeneic (the donor is someone else) — is appropriate as a treatment for inflammatory bowel disease is still being investigated. Here, since a genetic origin is clear and there are autoimmune effects beyond the digestive system, it becomes the treatment of choice.

Posted on by Quinn Eastman in Immunology Leave a comment