Fighting HIV Evolution with an Evolved Therapeutic Agent: Phase I Dose Escalation Clinical Trial of a Potent Broadly Neutralizing Human Antibody

In previous commentaries (http://dev-evmedreview.pantheonsite.io/?p=1863; http://dev-evmedreview.pantheonsite.io/?p=837; http://dev-evmedreview.pantheonsite.io/?p=385), I have discussed the critical role of extensive B-cell and immunoglobulin gene evolution in generating broadly neutralizing antibodies for HIV-1.  Of course, the unprecedented magnitude of antibody evolution necessary to achieve potent neutralization of a high percentage of HIV strains reflects the unprecedented evolutionary plasticity of HIV that originates in both high mutation and recombination rates for the HIV genome (Korber et al., 2001).  A new study by Caskey et al. (Nature, 2015) from the Nussenzweig Laboratory reports results for a first-in-human dose escalation phase I clinical trial of a human monoclonal antibody (mAb) specific for the HIV envelope (env) protein. (more…)

Altered Androgen Receptor Ligand Specificity in Prostate Cancer Cells Treated with an Androgen Biosynthesis Inhibitor

Carcinomas of the prostate are the most common cancers affecting men and a leading cause of male cancer deaths in the United States (CDC web site, Cancer Prevention and Control).  Given the unique association of the prostate with males, it makes sense that prosate carcinoma cells are often dependent for continued growth and proliferation on signaling by the androgen receptor, as andogens are primarily associated with physiological effects critical for male sexual development.  Therefore, therapies aimed at inhibiting either androgen synthesis or androgen receptor function make great sense. In a recent paper by Chen et al. (2014), Steven Balk and colleagues demonstrate that treatment of castration-resistant prostate cancer with a drug (abiraterone) that inhibits the production of androgens can select for mutant androgen receptors (AR) that more effectively recognize and get activated by a non-androgen. (more…)

Potentially Positive Therapeutic Applications of Mutations Negatively Affecting Gene Product Function

Altshuler and colleagues (Nature Genetics, 2014) recently reported a study of about 150,000 individuals representing five different ancestral groups in which they identified twelve low-frequency variants of the gene SLC30A8 through either genomic sequencing or genotyping.  These variants are all predicted to truncate the gene product (ZnT8), a protein involved in zinc transport in beta cells in the islets of Langerhans.  In beta cells, zinc is involved for insulin packaging and secretion.

Of particular interest, carriers possessing one or another of these loss-of-function mutations appeared to be at lower risk from type 2 diabetes (T2D).  Averaging over the different variants, these alleles provided an approximately 65% lower risk of T2D. (more…)

Evolved Genetic Variation as a Guide to the Evolution of Therapy

In a previous post (http://evomed.org/?p=1034), I discussed a study from Stuart Orkin’s lab that illustrated the exploitation of genetic variants that influence a disease-related phenotype to design a possible therapy for a murine version of sickle cell disease.  Increased fetal hemoglobin expression had been demonstrated to diminish the severity of sickle cell disease in mice, as is true also in humans.  Orkin and colleagues showed that eliminating a gene (BCL11A) that mediated decreased fetal hemoglobin expression, thereby achieving increased fetal hemoglobin expression, improved hematologic parameters in mice that serve as a model of sickle cell disease.  They speculated about the prospects for developing therapeutic agents that could inhibit BCL11A function and thereby facilitate fetal hemoglobin expression thereby decreasing adult hemoglobin expression and the manifestations of sickle cell disease.

Another example (more…)

A comeback for antibiotic cycling?

Christiane Goulart and Miriam Barlow and colleagues have published an important study in this month’s PLOS One entitled “Designing Antibiotic Cycling Strategies by Determining and Understanding Local Adaptive Landscapes.

Because of the growing problem of antibiotic resistance, antibiotic cycling has been proposed as a strategy to preserve antibiotic susceptibility of disease-causing microbes. Unfortunately, these efforts have largely been disappointing. In 2004 Carl Bergstrom argued that antibiotic cycling was likely to be ineffective in the hospital setting, based on a computational approach informed by natural selection. At that time, Bergstrom left open the possibility that a cycling regime could work, but he warned that the theoretical underpinnings of such an approach had not been demonstrated.

Goulart, Barlow and colleagues have satisfied that precondition with their compelling recent study. (more…)