Category Archives: Gene Medicine

A number of recent headlines imply a case study just published in the New England Journal of Medicine proves that gene therapy has cured sickle cell diseasea genetic disorder that incurs tremendous pain, suffering and diminished life expectancy. Here, we will unpack the significance of the researchers findings.

First, lets address why this news could be so groundbreaking to those afflicted and their loved ones.

Sickle Cell Disease is an inherited condition that causes a mutated hemoglobinthe protein within red blood cells (RBCs) that carries oxygen for delivery to vital tissues. Oxygen feeds our organs so they can stay healthy and perform their respective jobs. This Hemoglobin S (aka Sickle Hemoglobin) polymerizes on deoxygenation and rids the RBCs of their malleability. As a result, these malformed sickled cells are stiff and clump together thereby occluding vessels which in turn prompts organ damage.

Roughly 90,000 Americans have Sickle Cell Disease. (1) The natural course of the illness involves a complex cascade of events intermingled with crises often triggered by infections. Anemia is commonplace (and often profound) given these faulty cells get readily destroyed, over consumed and dont last as long as healthy RBCs. Vasoocclusive Crises result from infarction and ischemiain infants the hands and feet swell, in particular. Basically, adequate blood flow is halted wherever the obstruction takes place. Aggressive pain management and rehydration is essential.

Prophylactic antibiotics are a mainstay in an effort to stave off infection which can routinely catapult patients into a life-threatening crisis. By early childhood, they develop a functional asplenia or ineffective spleen. So, they become especially susceptible to overwhelming infection by encapsulatedbacteriahence, why vaccination for pneumococcus and the like is so important. Sepsis can result. Parvovirus can cause an aplastic crisis.

Strokes. Pulmonary infarcts with subsequent hypoxia. Acute Chest Syndrome. Gallstones. Blood transfusions are frequent. Though the blood supply is well-tested for safety, recurrent transfusion can lead to issues like iron overload, for instance. This too must be treated. The list goes on of the challenges, battles and treatment complexities these patients endure. Because fetal hemoglobin has a higher oxygen carrying capacity, a disease-modifying drug like Hydroxyurea that increases its presence is used.

Allogeneic hematopoietic stem-cell transplantation represents the only cure, but less than 18% of those with severe disease have sibling donors who are a match. (2) This is also not without great risk, though those need to be weighed against how advanced the disease. Due to such limited progress in management of this condition, this team of researchers sought to examine whether therapeutic ex vivo gene transfer into autologous hematopoietic stem cells referred to as gene therapy, may provide a long-term and potentially curative treatment for sickle cell disease. (3)

What does this mean? They took samples from the bone marrow of a patient with severe disease. The cells here provide the origins of our blood components which includes our red blood cells. This is where the problem begins in generating the sickling. A cancer drug, busulfan, was used to condition the body expected adverse effects from this occurred which resolved with standard care (e.g. anemia, low platelets, neutropenia and so on). Using a lentiviral vector, they transferred an anti-sickling gene into the patients stem cells (retrieved from the bone marrow) which get put back into the patient in the hope they will multiply and replace the cells made with the defective gene.

In a study funded in part by Bluebird Bio whose product is LentiGlobin BB305 (the antisickling gene therapy subject of this publication), the team concludes their patient had complete clinical remission with correction of hemolysis and biologic hallmarks of the disease. Furthermore, after fifteen months the antisickling protein remained high at approximately 50% and the patient had no crises or hospitalizations. Before, the patient required regular transfusions. After, all medications were stopped, no pain ones were needed, and the patient returned to full activities at school. (4)

Ongoing research is underway in a U.S. multi center, phase 1/2 clinical study. The intention is to use this gene therapy to treat those with severe sickle cell disease and another condition called beta-thalessemia. So far, in the few patients who have participated, their results seemingly support this work. Clearly, longer term follow-up and larger populations are crucial to understanding the significance of this report. Additionally, stem cell transplantation is no minor feat.

That said, for a disease that disables at such a young age, this option could be quite an extraordinary one if the success persists. ACSHs Senior Fellow in Molecular Biology, Dr. Julianna LeMieux, puts the promise of gene therapy into even greater context for this and other disease entities:"This is an incredibly promising result, even with the obvious caveat that it is only one person. Sickle Cell is a disease that is ripe for genetic advances for a few reasons. First,the gene that is affected is known andcan be replaced by the healthy variant. Also, the cells that are needed to be alteredare easily accessible inthe bone marrow. In many diseases, this is not the case. But, this one success story is incredibly encouraging for the sickle cell community and for moving the field of curing diseases using genetic editing forward."

The team proved their concept. To know if "cure" is in this gene therapy's future, much more data needs to be acquired and study be implemented. Promising with cautious optimism might be the most apt description.

Source(s):

(1) (2) (3) (4) Jean-Antoine Ribeil, M.D., Ph.D. et al. Gene Therapy in a Patient with Sickle Cell Disease. N Engl J Med. 376;848-855. March 2, 2017.

Note(s):

To learn more about "Orphan Diseases" or rare ones that afflict less than 200,000 (but in total impact 25 million Americans) and drug discovery challenges, review: Did Pompe Disease Geta New Champion in President Trump? and Pompe Disease, Newborn Screening and Inborn Errors of Metabolism.

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Did Gene Therapy Cure Sickle Cell Disease? - American Council on Science and Health

March 8, 2017 Colonies of mouse embryonic stem cells, where cell nuclei are stained in blue. The DNA from the nuclei is sequenced to infer the relative positions of genes and their switches. Credit: C. Ferrai, MDC

Cells face a daunting task. They have to neatly pack a several meter-long thread of genetic material into a nucleus that measures only five micrometers across. This origami creates spatial interactions between genes and their switches, which can affect human health and disease. Now, an international team of scientists has devised a powerful new technique that 'maps' this three-dimensional geography of the entire genome. Their paper is published in Nature.

Genes are activated to produce RNA and proteins, then switched off again when the molecules are no longer needed. Both the gene and its switches are DNA sequences, and they may lie far apart on the linear genome. This presents a challenge for the cell, because these regions usually have to be brought into contact to activate the gene.

It also creates a problem for scientists trying to understand one of the central questions in biology: how do cells decide which genes should be activated, and when? The answer will partly depend on matching every gene to its control sequences. But DNA strands are too thin to be tracked under the microscope, and even if that were possible, you'd have the vast amount of DNA in the nucleus to contend with. Imagine examining a tangle of yarn the size of the Earth in hopes of observing an encounter between individual strands.

A new technique called Genome Architecture Mapping, or GAM, now helps to identify these contacts. It involves flash-freezing tissue or cells, then cutting thin slices of individual nuclei. The tiny amount of DNA within each slice of the nucleus is then sequenced, and the team deploys a mathematical model, named SLICE, to identify 'hotspots' of increased interaction between strands. The model looks at the frequency with which different genomic regions appear in the slice to infer information about the relative positions of genes and regions called enhancers that activate them.

"An analogy might be this; if you want to understand how school children interact you might take occasional photographs of where they sit in the canteen or appear together in the playground", explains joint-lead author Ana Pombo, who began the project whilst working at the MRC London Institute of Medical Sciences (LMS) and is now based at the Berlin Institute for Medical Systems Biology, Max Delbrck Center for Molecular Medicine in the Helmholtz Association (MDC) and the Berlin Institute of Health (BIH). "If you do that many times over a month, you will begin to see a pattern in those who often sit next to each other, or who run around together while playing. These random snapshots might tell you about their social interactions."

"This is made possible by filtering out random encounters from real interactions using mathematical methods," says the joint-lead author Mario Nicodemi at the Universit di Napoli Federico II, who conceived such mathematical models and, aided by his PhD student Antonio Scialdone, developed them.

Paul Edwards, of the Hutchison/MRC Research Centre and Department of Pathology at the University of Cambridge, and Ana Pombo had the initial idea before the techniques necessary to do the experiment were available. "My research team optimised the approach, and as new technical steps came along we added them to our method," she says.

The study, which appears today in Nature, applies the method to mouse embryonic stem cells and the authors hope it will help shed light on many genes whose activity is disturbed in some very serious diseases. In some diseases, the problem lies within the sequence of a gene, but defects in regulatory regions found elsewhere in the genome can be equally dangerous and much harder to understand. The new data provides a long list of new suspects that can now be scrutinized by researchers.

Whilst previous studies have identified two-way contacts, this information does not reveal how often such contacts take place and by implication how important they might be, Pombo says: "They can spot that you and I are friends, but not how strong this friendship is relative to everyone else."

"People have been measuring two-way contacts for a long time," says Robert Beagrie, joint first author on the paper, who was a PhD student with Ana Pombo at the LMS when he collected the data for the study and is now based at the University of Oxford. "Those studies have often shown that you can have a set of different DNA elements that interact with each other in pairs. With this new approach we are able to generate a genome-wide catalogue of all the regions that we are confident interact in groups." Now, the researchers are able to reliably detect and quantify so-called 'three-way contacts' in regions of the genome that are vigorously expressed.

But perhaps the most notable advance of through GAM is that experiments are based on single cells - whether common or scarce in a tissue - and track their positions relative to each other within the tissue. Existing methods require lots of cells of the same type, which has made it difficult to study the biology and diseases of rare types. "There is huge potential for applying this in human tissue samples to catalogue contacts between regulatory regions and their target genes, and to use that to understand genetic variation and how it might alter aspects of nuclear biology," Pombo says.

Some researchers are starting to show interest in using the technique to explore what happens when retroviruses insert their DNA into the genome of a host. Cancer scientists are also keen to create DNA maps of particular areas of a tumor. "By exploiting the unique nature of GAM data, mathematical models can reliably derive such information, opening the way to identify multiple, group interactions that could play a key role in the regulation of genes," explains Nicodemi. "We can now ask whether a gene is contacted at the same time by all of its enhancers, or by each enhancer one at a time?", Beagrie says. "We know that many genes that are important for early development have multiple enhancers. But how and why they are acting to regulate genes remain unanswered questions."

Explore further: Study finds recurrent changes in DNA activate genes, promote tumor growth

More information: Robert A. Beagrie et al, Complex multi-enhancer contacts captured by genome architecture mapping, Nature (2017). DOI: 10.1038/nature21411

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A three-dimensional map of the genome - Medical Xpress

March 8, 2017 White fat stores energy, while brown fat dissipates energy by producing heat, mediated by uncoupling protein 1, or UCP1. Credit: Ray Soccio, MD, PhD, Perelman School of Medicine, University of Pennsylvania

By comparing two strains of miceone that becomes obese and diabetic on a high-fat diet and another resistant to a high-fat regimenresearchers from the Perelman School of Medicine at the University of Pennsylvania identified genome-wide changes caused by a high-fat diet.

The a team, led by Raymond Soccio, MD, PhD, an assistant professor of Medicine, and Mitchell Lazar, MD, PhD, director the Institute for Diabetes, Obesity, and Metabolism, published their findings online in the Journal of Clinical Investigation (JCI), in addition to an Author's Take video.

"We focused on the epigenome, the part of the genome that doesn't code for proteins but governs gene expression," Lazar said.

Their research suggests that people who may be genetically susceptible to obesity and type 2 diabetes due to low levels of a protein that helps cells burn fat, may benefit from treatments that ultimately increase the fat-burning molecule.

The team looked at the interplay of genes and environment in two types of white fat tissue, subcutaneous fat (under the skin) versus visceral fat around abdominal organs. The latter correlates strongly with metabolic disease. This visceral fat shows major gene expression changes in diet-induced obesity. The JCI study confirmed this relationshipand importantlyextended these findings to show that the epigenome in visceral fat also changes on a high fat diet.

Diet-induced epigenomic changes in fat cells occur at histones - proteins that package and order DNA in the nucleus, which influences gene expression - across the genome. There were also changes in the binding to DNA of an essential fat cell protein, a transcription factor called PPARgamma.

The team next treated obese mice with the drug rosiglitazone, which targets PPARgamma in fat to treat diabetes in people. "While the drug-treated obese mice were more insulin sensitive, we were surprised to see that the drug had little effect on gene expression in visceral fat," Soccio said. "This led us to look at subcutaneous fat and we discovered that this depot is much more responsive to the drug."

"These results are clinically relevant and indicate that the 'bad' metabolic effects of obesity occur in visceral fat, while the 'good' effects of rosiglitazone and other drugs like it occur in subcutaneous fat," Lazar said.

In particular, the drug-induced changes they found in subcutaneous fat reflected the phenomenon of browning, in which white fat takes on characteristics of brown fat, typically in response to cold exposure or certain hormones and drugs.

White fat stores energy, while brown fat dissipates energy by producing heat, mediated by uncoupling protein 1, or UCP1. The most interesting discovery of the study, say the authors, involves UCP1.

They showed that rosiglitazone, as expected, increases Ucp1 expression in both obesity-prone and obesity-resistant strains of mice. However, in subcutaneous fat of the obesity-resistant mice, Ucp1 expression was high even in the absence of the drug. "But the real surprise came when we looked at the offspring of obesity-resistant and obesity-prone parents, which have one of each parent's version of the Ucp1 gene," Soccio said.

Strikingly, they found that the obesity-prone mouse strain's version of the Ucp1 gene has lower expression and less PPARgamma binding than the obesity-resistant version. This imbalance shows that the obesity-prone mouse strain's Ucp1 is genetically defective, since it is less active than the other strain's version, even when both are present in the same cell nucleus.

In their final experiments, the team asked what happens when browning and Ucp1 expression are activated using rosiglitazone or exposure to cold, both environmental factors. They found that in both cases, total Ucp1 expression goes up as expected, but the obesity-prone strain's defective version of Ucp1 now reaches equal levels to the obesity-resistant strain's version.

"Importantly, we were only changing the mouse's environment with a drug or temperature, not the actual DNA sequence of the Ucp1 gene," Lazar said. "We propose that this result indicates epigenomic rescue of Ucp1 expression in subcutaneous fat cells."

The team is following up the mouse studies using human fat biopsies to figure out the exact DNA sequence differences responsible for variable Ucp1 expression, both in mice and in humans.

The relevance of this study extends even beyond UCP1 and obesity. "Many gene variants are thought to exert their effects by ultimately altering gene expression levels, and this study shows that a genetic predisposition to altered gene expression can be identified and then overcome with treatment," Lazar said. "This is the dream of precision medicine, and hopefully our study is a step in this direction."

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Study parses influence of genes and environment in metabolic disease - Medical Xpress

the Irish News

Knowing what's wrong can be a comfort the Irish News The centre, spearheaded by consultant in genetic medicine Dr Shane McKee, have been involved in the design and operation of the UK-wide Deciphering Developmental Disorders (DDD) Study since 2011. The DDD Study involves scientists sequencing the ...

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Knowing what's wrong can be a comfort - the Irish News

Researchers in the Department of Molecular and Human Genetics at Baylor College of Medicine have identified a previously unimplicated gene behind a particular form of chondrodysplasia, a skeletal dysplasia that affects cartilage formation and causes disproportionate short stature and premature osteoarthritis. The study appears in the Journal of Clinical Investigation.

Stemming from research being performed at Baylor and its genetics department as part of a systematic search for genetic causes of skeletal dysplasias, the project set out to identify the genetic driver behind Shohat type spondyloepimetaphyseal dysplasia (SEMD). It was led by Dr. Brendan Lee, professor and chair of molecular and human genetics at Baylor, and a team of researchers including project leader Adetutu Egunsola, a genetics graduate student.

SEMD is a rare type of skeletal dysplasia that impacts the development of cartilage and results in a form of dwarfism, characterized by a particular pattern of joint abnormalities, scoliosis and defects of the long bones.

Through combined whole exome sequencing and studies in zebrafish and mice, Lee and his team were able to identify a completely new gene associated with this skeletal dysplasia, DDRGK1, and discovered how it functions in cartilage. In zebrafish, for example, a DDRGK1 deficiency disrupts craniofacial cartilage development and causes a decrease in levels of the protein SOX9.

Not only did we discover the requirement of DDRGK1 in maintaining cartilage, but we also found that it to be a regulator of SOX9, which is the master transcription factor that controls cartilage formation the human skeleton, said Lee, who also holds the Robert and Janice McNair Endowed Chair in molecular and human genetics. If you do not have the SOX9 protein, you do not have cartilage it drives the production of cartilage in growth plates and joint cartilage all over the body.

The relationship between DDRGK1 and SOX9 reveals a novel mechanism that regulates chondrogenesis, or cartilage maintenance and formation, by controlling SOX9 ubiquitination, a process that controls the degradation of proteins like SOX9. Loss of the function of DDRGK1 causes this cartilage dysplasia in part via accelerated destruction of SOX9.

Studying this skeletal dysplasia resulted in the biological insight about this gene that had never been implicated in any disease condition related to the skeleton, Lee said. The future is to find out whether DDRGK1s function more globally controls ubiquitination in general and to determine how this process could be targeted for treating patients with dwarfism.

Other contributors to this work include Richard Gibbs, Adetutu T. Egunsola, Yangjin Bae, Ming-Ming Jiang, David S. Liu, Yuqing Chen-Evenson, Terry Bertin, Shan Chen and James T. Lu with Baylor, Nurit Magal with Rabin Medical Center, Annick Raas-Rothschild with Sheba-Tel Hashomer Medical Center, Eric C. Swindell with the University of Texas Graduate School of Biomedical Sciences, Lisette Nevarez and Daniel H. Cohn with the University of California, Philippe M. Campeau with the University of Montreal and Mordechai Shohat with the Sackler School of Medicine at Tel Aviv University.

This research was supported by the BCM Intellectual and Developmental Disabilities Research Center and a Program Project grant from the Eunice and Kennedy Shiver National Institute of Child Health and Human Development, the BCM Advanced Technology Cores with funding from the NIH, the Rolanette and Berdon Lawrence Bone Disease Program of Texas, the BCM Center for Skeletal Medicine and Biology and Tel Aviv University.

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Genetic driver behind rare skeletal dysplasia condition found - Baylor College of Medicine News (press release)

A French teen who underwent a first-of-its-kind procedure 15 months ago to change his DNA shows no signs of the sickle cell disease he had been suffering from. The procedure, which was performed at Necker Childrens Hospital in Paris, may offer hope to millions of patients who suffer from sickle cell disease, BBC News reported.

Sickle cell disease is a severe hereditary form of anemia, which causes patients to develop abnormal hemoglobin in red blood cells. The botched hemoglobin causes the cells to form a crescent or sickle shape, making it difficult to maneuver throughout the body. Sickle-shaped cells are less flexible, and may get stuck to vessel walls causing a blockage, which can stop blood flow to vital tissues.

Before undergoing the procedure, treatment for the unidentified teen included traveling to the hospital each month for a blood transfusion to dilute the defective blood, BBC News reported. According to the report, the excessive amount of treatment caused severe internal damage, and at age 13 he already needed a hip replacement and had his spleen removed.

In a world first, doctors at Necker Childrens Hospital removed his bone marrow and genetically altered it using a virus to compensate for the defect in his DNA responsible for sickle cell disease, BBC News reported. The results published in the New England Journal of Medicine said he no longer uses medication, and has been making normal blood for the past 15 months.

So far the patient has no sign of the disease, no pain, no hospitalization, Philippe Leboulch, professor of medicine at the University of Paris, told BBC News. He no longer requires a transfusion so we are quite pleased with that.

Doctors said the treatment will have to be repeated in other patients as the teen is the trials first, but that it does show powerful potential.

Ive worked in gene therapy for a long time and we make small steps and know theres years more work, Dr. Deborah Gill, of the gene medicine research group at the University of Oxford, told BBC News. But here you have someone who has received gene therapy and has complete clinical remission thats a huge step forward.

It was not clear how much the procedure would cost, or whether there are plans to expand to other countries.

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Doctors reverse teen's sickle cell disease with innovative gene therapy - Fox News