Allele-Specific Suppression of Mutant Huntingtin Using Antisense Oligonucleotides: Providing a Therapeutic Option for All Huntington Disease Patients

Huntington disease (HD) is an inherited, fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The mutant protein causes neuronal dysfunction and degeneration resulting in motor dysfunction, cognitive decline, and psychiatric disturbances. Currently, there is no disease altering treatment, and symptomatic therapy has limited benefit. The pathogenesis of HD is complicated and multiple pathways are compromised. Addressing the problem at its genetic root by suppressing mutant huntingtin expression is a promising therapeutic strategy for HD. We have developed and evaluated antisense oligonucleotides (ASOs) targeting single nucleotide polymorphisms that are significantly enriched on HD alleles (HD-SNPs). We describe our structure-activity relationship studies for ASO design and find that adjusting the SNP position within the gap, chemical modifications of the wings, and shortening the unmodified gap are critical for potent, specific, and well tolerated silencing of mutant huntingtin. Finally, we show that using two distinct ASO drugs targeting the two allelic variants of an HD-SNP could provide a therapeutic option for all persons with HD; allele-specifically for roughly half, and non-specifically for the remainder.     

Systemic Hematogenous Maintenance of Memory Inflation by MCMV Infection

Several low-grade persistent viral infections induce and sustain very large numbers of virus-specific effector T cells. This was first described as a response to cytomegalovirus (CMV), a herpesvirus that establishes a life-long persistent/latent infection, and sustains the largest known effector T cell populations in healthy people. These T cells remain functional and traffic systemically, which has led to the recent exploration of CMV as a persistent vaccine vector. However, the maintenance of this remarkable response is not understood. Current models propose that reservoirs of viral antigen and/or latently infected cells in lymph nodes stimulate T cell proliferation and effector differentiation, followed by migration of progeny to non-lymphoid tissues where they control CMV reactivation. We tested this model using murine CMV (MCMV), a natural mouse pathogen and homologue of human CMV (HCMV). While T cells within draining lymph nodes divided at a higher rate than cells elsewhere, antigen-dependent proliferation of MCMV-specific effector T cells was observed systemically. Strikingly, inhibition of T cell egress from lymph nodes failed to eliminate systemic T cell division, and did not prevent the maintenance of the inflationary populations. In fact, we found that the vast majority of inflationary cells, including most cells undergoing antigen-driven division, had not migrated into the parenchyma of non-lymphoid tissues but were instead exposed to the blood supply. Indeed, the immunodominance and effector phenotype of inflationary cells, both of which are primary hallmarks of memory inflation, were largely confined to blood-localized T cells. Together these results support a new model of MCMV-driven memory inflation in which most immune surveillance occurs in circulation, and in which most inflationary effector T cells are produced in response to viral antigen presented by cells that are accessible to the blood supply.     

Females allocate differentially to offspring size and number in response to male effects on female and offspring fitness

Female investment in offspring size and number has been observed to vary with the phenotype of their mate across diverse taxa. Recent theory motivated by these intriguing empirical patterns predicted both positive (differential allocation) and negative (reproductive compensation) effects of mating with a preferred male on female investment. These predictions, however, focused on total reproductive effort and did not distinguish between a response in offspring size and clutch size. Here, we model how specific paternal effects on fitness affect maternal allocation to offspring size and number. The specific mechanism by which males affect the fitness of females or their offspring determines whether and how females allocated differentially. Offspring size is predicted to increase when males benefit offspring survival, but decrease when males increase offspring growth rate. Clutch size is predicted to increase when males contribute to female resources (e.g. with a nuptial gift) and when males increase offspring growth rate. The predicted direction and magnitude of female responses vary with female age, but only when per-offspring paternal benefits decline with clutch size. We conclude that considering specific paternal effects on fitness in the context of maternal life-history trade-offs can help explain mixed empirical patterns of differential allocation and reproductive compensation.     

The right to withdraw from controlled human infection studies: Justifications and avoidance

The right to withdraw from research without penalty is well established around the world. However, it has been challenged in some corners of bioethics based on concerns about various harms—to participants, to scientific integrity, and to research bystanders—that may stem from withdrawal. These concerns have become particularly salient in emerging debates about the ethics of controlled human infection (CHI) studies in which participants are intentionally infected with pathogens, often in inpatient settings with extensive follow-up. In this article, I provide support for preserving the right to withdraw from research without penalty and demonstrate that it is also typically justified in the specific context of CHI studies. The right is well aligned with individual freedoms outside the research setting, where autonomous individuals are permitted to engage in behaviors that will foreseeably cause them harm; where they cannot be compelled to satisfy contracts for their services, nor penalized for failure to do so; and where their behavior is not constrained by public health authorities except in extreme circumstances. These freedoms are supported by U.S. law, as well as by ethical analysis that is more globally relevant. The problems associated with the right to withdraw, however, remain. The best approach to addressing them is not to restrict the right but rather to avoid initiating research when withdrawal would be especially problematic. If research proceeds, steps can still be taken to minimize participant withdrawal without infringing the right. Investigators can avoid participant surprise through informed consent focused on a study’s most burdensome aspects and promote study completion through financial incentives. Should participants nonetheless seek to withdraw, investigators may attempt to persuade them not to do so by encouraging consideration of the range of potential harms that may result. Researchers conducting CHI studies and other research from which withdrawal might be especially problematic should prepare for the possibility of participant withdrawal, respect participant requests to withdraw without penalty, and incorporate various measures to avoid such requests.     

Cis-vaccenic acid and the Framingham risk score predict chronic kidney disease: the multi-ethnic study of atherosclerosis (MESA)

IntroductionData on the associations of fatty acids with chronic kidney disease (CKD) are sparse.Materials and methodsWe performed a cross-sectional study of 2792 men and women from the MESA cohort of African–American, Caucasian, Chinese and Hispanic adults without known cardiovascular disease. Plasma phospholipid fatty acid proportions were associated with estimated glomerular filtration rate (eGFR) and the albumin/creatinine ratio.ResultsCis-vaccenic acid (18:1n?7), adjusted for other fatty acids using multivariate logistic regression (CI: 1.0–1.4), and step-wise logistic regression (CI: 1.02–1.42), was positively associated with reduced eGFR. The Framingham Risk Score, when adjusting for fatty acid proportions and demographic factors, was positively associated with CKD as measured by the eGFR and the albumin/creatinine ratio.Discussion and conclusionsPlasma phospholipid proportions of the 18 carbon monounsaturated cis-vaccenic acid {18:1n?7}) and the Framingham Risk Score are associated with kidney function. The potential role of 18:1n?7 in the development of CKD warrants further investigation.