A Path Toward Potential Treatment of Hemoglobinopathies

Blood from a patient with sickle cell disease, a form of hemoglobinopathy. Image credit: CDC/Sickle Cell Foundation of Georgia

Blood from a patient with sickle cell disease, a form of hemoglobinopathy. Image credit: CDC/Sickle Cell Foundation of Georgia

Hemoglobinopathies, such as sickle cell disease (SCD) and thalassemia, represent an emerging public health challenge, with 14 million children worldwide expected to be born with SCD in the next 40 years. Current supportive treatment plans require a variety of intensive techniques, including regular blood transfusions and antibiotics, but Takahiro Maeda, MD, PhD, and his colleagues are investigating a new therapeutic avenue that would benefit a wide patient population.

When the fetal-type hemoglobin gene is repressed soon after birth, mutations in the subsequently induced adult-type hemoglobin gene lead to hemoglobinopathies. One promising approach is to “re-activate” healthy fetal-type hemoglobin (HbF) production. Currently, the BCL11A protein is the only truly validated repressor of HbF. In their preclinical study of the gene repression mechanism, the researchers found that the DNA binding protein LRF (Leukemia/Lymphoma Related Factor) represses expression of HbF independently of BCL11A. These findings are published in Science.

“Our study may provide additional opportunities for therapeutic targeting in the treatment of hemoglobinopathies, including the development of new HbF reactivation therapies,” said Maeda.

Paper cited: Masuda T et al. “Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin” Science DOI: 10.1126/science.aad3312


How We Shape Our Gut Microbiome

E. coli (pictured here) is one of the many species of bacteria commonly found in the human gut.

E. coli (pictured here) is one of the many species of bacteria commonly found in the human gut. Image credit: CDC/Janice Haney Carr

The human gut is home to trillions of microbes that can influence metabolism, immunity and a wide variety of diseases, but how a host controls and shapes its microbiome has largely been a mystery. In a study published in Cell Host & Microbe, investigators from BWH report that a host’s fecal microRNAs – short, snippets of RNA that can regulate gene expression – may influence the composition of the gut microbiome. This discovery points the way toward new strategies for manipulating the microbiome to treat disease.

The researchers characterized microRNAs found in the fecal matter of mice and humans, tracing them back to two specific kinds of cells found in the gut. They also found that transplanting microRNAs into a mouse model of colitis could restore gut microbiota, suggesting potential therapeutic applications for microRNAs.

“Our findings identify a novel strategy for the manipulation of the microbiome to improve the health of a host,” said senior study author Howard Weiner, MD, co-director of the Ann Romney Center for Neurologic Diseases at BWH. “We are optimistic that it will one day be possible to administer microRNAs as therapeutic compounds to improve health and treat disease.”

Paper cited: Liu S et al. “The Host Shapes the Gut Microbiota via Fecal microRNA” Cell Host & Microbe DOI: 10.1016/j.chom.2015.12.005


Investigating long-term risks from infection in very pre-term infants

Woodward_RRFor babies who are born very early there is always the worrying risk of infection. Although the effects of infection on these children’s development during the first two years of life has been investigated, almost nothing is known about how these children fare over the longer term, particularly in terms of important outcomes such as school achievement and mental health. In a study published in The Journal of Pediatrics, BWH investigators report on the neurodevelopmental outcomes – including  motor development, behavioral and emotional adjustment and cognitive delay – for VPT babies who have been followed from birth through age 9, and find that risks of later neurodevelopmental problems were confined only to those infants where there was biologically confirmed evidence of infection, and even then these risks were relatively modest, offering some reassurance for parents. Findings also suggest that MRI scans may help predict neurodevelopmental outcomes for those who had neonatal infections.

By studying school age children, the researchers were able to more thoroughly assess educational achievement, mental health and other measures than previous studies that have been conducted which have primarily focused on just early motor and cognitive skills. After accounting for other neonatal factors, the researchers found a modest increase in risk of severe motor impairment, ADHD and IQ delay among children who had been diagnosed with neonatal infections (this increased risk was not seen among those with suspected but unconfirmed cases of infection).

The researchers found that they were able to use MRI scans taken when a baby had reached full term to detect neurologic abnormalities and predict later neurodevelopmental outcomes. Study finding help shed light on the potential biological pathway that lead to neurodevelopmental impairment after infection, and could also allow clinicians and developmental specialists to intervene earlier to help these higher risk infants and their parents.

“Our study suggests that for very pre-term infants who have had a confirmed infection, it is important to that we initiate developmental support services in the hospital as well ensure that infants and their families receive follow-up and early intervention services that will help minimize longer term risks and ideally help them toward recovery,” said Lianne Woodward, PhD, of BWH’s Department of Pediatric Newborn Medicine. “It also highlights the importance of doing everything clinically possible to prevent the risk of infection early in life, to lower neurodevelopmental risk later.”

Paper cited: Rand K et al. “Neonatal Infection and Later Neurodevelopmental Risk in the Very Pre-Term Infant.” The Journal of Pediatrics. DOI: 10.1016/j.jpeds.2015.11.017


Early Weight Gain and Childhood High Blood Pressure

pressurecuffThe prevalence of high blood pressure in children and adolescents is on the rise and is commonly associated with other cardiovascular risk factors as well as obesity, which underscores the importance of identifying what factors play a role in elevated blood pressure early in life. Both low birth weight and rapid early childhood weight gain are associated with future high blood pressure, but there has been limited research that explores the timing of weight gain in infancy and childhood as it relates to blood pressure later in life, and little is known regarding the role that linear (length/height) growth plays.

Researchers led by Mandy B. Belfort, MD, a BWH neonatologist and senior author of a new paper that explores the link between timing of early weight gain and childhood high blood pressure, studied nearly 1,000 participants in Project Viva, an ongoing U.S. pre-birth cohort, and examined the connection between body mass index and length/height change during four early life age intervals – birth–6 months, 6 months–1year, 1–2years, and 2–3years—with blood pressure during mid-childhood (6–10-years-old), and evaluated whether these relationships differed by birth size. Researchers found that gains in body mass index during birth–6 months and 2–3years were associated with higher systolic blood pressure (0.81 [95% CI: 0.15, 1.46] and 1.61 [95% CI: 0.33, 2.89] mmHg respectively). The study is published in Hypertension.

“Our findings suggest that more rapid gain in body mass index during the first 6 postnatal months and in the preschool years may lead to higher systolic blood pressure in mid-childhood, regardless of size at birth. Strategies to reduce accrual of excess adiposity during early life may reduce mid-childhood blood pressure, which may also impact adult blood pressure and cardiovascular health,” the authors write.

Paper cited: Perng W et al. “Early Weight Gain, Linear Growth, and Mid-Childhood Blood Pressure.” Hypertension DOI: 10.1161/HYPERTENSIONAHA.115.06635