A P u b l ic At i o n o f T he R es e aR c h I nsT I T u T e aT naT I o nw I d e c h I l d Re n’s h ...
sPRING/suMMeR 2009

research is dedicated to the
mission of informing and inspiring                    Table of Contents
Genetics of Heart Defects

neural development,
Classifying Concussions
Research on the Road
  THe effeCTs Of BRAIN AGe                                                Dr. Yeates says that in a m...
N                                                                                                                     CH
reSearch Magazine Issue 4
reSearch Magazine Issue 4
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reSearch Magazine Issue 4


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This biannual publication, reSearch, is dedicated to the mission of informing and inspiring readers by highlighting scientific performance at The Research Institute at Nationwide Children's Hospital.

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reSearch Magazine Issue 4

  1. 1. research A P u b l ic At i o n o f T he R es e aR c h I nsT I T u T e aT naT I o nw I d e c h I l d Re n’s h o sp I Tal Genetics of Heart Defects Might a Defective Signaling Pathway Lead to Left-Sided Heart Malformations? feature Stories • Genetics of Heart Defects • Classifying Concussions • Disarming Killer T Cells • Bypassing the Brain’s Barrier
  2. 2. sPRING/suMMeR 2009 research is dedicated to the mission of informing and inspiring Table of Contents readers by highlighting scientific performance at The Research Institute at Nationwide Children’s Hospital. This publication is produced biannually by the Marketing and Public Relations Department at Nationwide Children’s Hospital. fe at ure s 4 Genetics of Heart Defects Molecular proof that three distinct cardiac defects share an origin le a deRs hIp 8 Classifying Concussions The Research Institute at Risk factors help predict how concussed kids will recover nationwide children’s hospital John a. Barnard, Md 12 Tracking the Mysterious Death of Killer T Cells President Could a mechanism for silencing immunity improve the outcome of viral lauren o. Bakaletz, phd gene therapy? Vice President, Basic Sciences Research Kelly Kelleher, Md, Mph Vice President, Health Services Research 14 Bypassing the Brain’s Barrier A new strategy evades a biological obstacle to gene therapy success william e. smoyer, Md Vice President, Clinical and Translational Research e xt ras Grant Morrow III, Md Medical Director 7 A Home to National Clinical Trials daniel R. Mann Nationwide Children’s Hospital has been selected to join two new clinical Vice President, Research Administration 14 and Operations research trial networks, a designation bestowed only to preeminent Katherine s. Milem research facilities in the nation Injection of a gene therapy virus, President, Research Business Services AAV9, successfully bypassed the blood 11 Research on the Road brain barrier and targeted neurons, the carriers of electrical signals in the research New mobile research lab targets hard-to-reach participants nervous system, and astrocytes, the Writer and editor most abundant cells in the nervous Melissa hamilton 16 Technology in Practice system. Neurons that were successfully Art Director A risk-assessment technology developed at Nationwide Children’s is Tanya Bender infected by AAV9 are shown in yellow; helping physicians and patients communicate more effectively infected astrocytes are teal. Photographers Brad smith ON THe COveR The finding that AAV9 efficiently enters dan smith Kim L. McBride, MD, examines Notch protein distribution throughout the interior and on the nervous system after injection into Manager, Research Communications the surface of a cell. New research shows that changes in Notch signaling could promote the bloodstream provides potential for Jan arthur heart defects. new therapies and could lead to better Contact us at understanding of neurological disease. research | 3
  3. 3. Genetics of Heart Defects PROOf THAT THRee DIsTINCT CARDIAC DefeCTs sHARe AN ORIGIN Knowing that LVOT malformations share a common molecular mechanism is a big step forward… – DR. K I M L . MC B R I De valve stenosis, coarctation of the aorta seARCHING fOR A GeNeTIC LINK Families with at least two members with and hypoplastic left heart syndrome. Since Dr. McBride’s group has established an LVOT malformation were included Although all three conditions involve that there is a strong and complex genetic in the study and each underwent the left side of the heart, a molecular component to LVOT malformations, their echocardiography to assess for any similarity between the three defects had focus is now to pinpoint the genes behind structural heart abnormalities. After not yet been identified. the disorders. Using a variety of study analyzing DNA markers from these designs for gene mapping, the team is families, researchers found evidence for During the study, which appears in analyzing the pattern of inheritance of linkage to three chromosomes for the Human Molecular Genetics, 91 patients with selected genes in signaling pathways combined LVOT malformations and for LVOT malformations had their DNA important in cardiac development. the disorders individually. screened for mutations in NOTCH1, a gene that has been linked to an aortic Most recently, they conducted the first- These data provide the initial phase valve condition and that is part of a ever study to “gene hunt” among families for gene identification of these LVOT signaling pathway involved in multiple with multiple LVOT malformations, malformations, a basic-science discovery Like a windstorm that leaves one household Despite the myriad of mutations that could be responsible for each of the LVOT developmental processes. These patients’ grouping the malformations together as that could be translated into improved DNA was then compared to that of 216 though they were one disorder. “Grouping patient care. “Identifying a specific without power, another with downed trees malformations, faculty members at The people without LVOT malformations. the individual malformations together as gene also now holds hope for eventually Research Institute are discovering that the one disease allowed us to greatly increase and a third with roof damage, scientists are most telling explanation of disease devel- Results showed that NOTCH1 gene the ability to map the locations of the providing better risk counseling for families,” said Dr. McBride. opment could be revealed by studying the mutations are present in some individuals finding that congenital heart conditions can have disorders together as a group. with aortic valve stenosis, coarctation responsible genes,” said Dr. McBride. differing effects, yet stem from a common “Clinicians traditionally thought of of the aorta and hypoplastic left heart syndrome. With the help of Dr. Susan biological event. these heart defects as separate entities,” said Kim L. McBride, MD, principal Cole, assistant professor in the College of Biological Sciences at The Ohio State investigator in the Center for Molecular University, several of these mutations 1) Notch1 protein distribution THe MysTeRy Of LefT-HeART the first few days of life, many newborns and Human Genetics at The Research (green) as it appears normally, MAlforMAtionS were shown to affect Notch pathway with an LVOT malformation, especially Institute. “More recent views have throughout the cell interior and Congenital cardiovascular malformations signaling in the cell. This suggests that those with hypoplastic left heart grouped them together based on findings on the cell surface. are among the most common birth Notch signaling plays a vital role during syndrome, will die. from cardiac developmental biology, cardiovascular development and relatively 2) Distribution of mutant defects in the United States. One group observations of clustering in families, Notch1 protein (green) trapped Presumably, these defects arise when minor changes may promote LVOT 1) 2) of heart defects known as left ventricular and our own previous work on near the cell’s nucleus (blue). the inner lining of the heart or aorta defects. “These findings support our outflow tract obstruction (LVOTO) inheritance analysis.” develops improperly, but the basic, previous idea that these defects may malformations arise from obstruction of CONsequeNCes Of A TRAPPeD PROTeIN disease-causing mechanisms remain LINKeD By A MOLeCuLAR share a common developmental blood flow through the developing left How could minor changes in the Notch protein sequence promote heart defects? unclear. Scientists believe they are likely MeCHANIsM pathogenesis,” said Dr. McBride. “They ventricle and aorta. These malformations Recent research has shown that some mutations in the NOTCH1 gene affect a complex mix of defects in one or more Research conducted by Dr. McBride and also emphasize the hereditary nature of include aortic valve stenosis, coarctation where the protein appears in the cell, trapping it and making it non-functional. genes, chromosomal abnormalities and colleagues reveals, for the first time, a these defects and explain why one can of the aorta and hypoplastic left heart possibly environmental exposures. common molecular mechanism for aortic find individuals in the same family with syndrome. Without major surgery during different forms of LVOT malformations.” 4 | research research | 5
  4. 4. neural development, plasticity and Regeneration They’re skeletal Muscle Biology and Consulting exercise physiology Our Experts N ationwide Children’s has been selected to join two new clinical research trial networks, one through the Muscular Dystrophy Association and the other through the Cystic Fibrosis Foundation. This designation is bestowed only host Interactions with to preeminent research facilities in Bacterial pathogens the nation. Clinical trial networks bring together clinical research centers throughout the nation to Collaborative research between Kim L. McBride, MD, and Susan Cole, PhD, are revealing new information about how pediatric heart centralize and standardize the some heart defects develop. network research process. sCIeNTIfIC TRANsLATION Dr. McBride also collaborates with better view of our target,” said Dr. Faculty members at Nationwide THROuGH CLINICAL clinical faculty at Nationwide Children’s McBride. “Knowing that LVOT Children’s also serve on more than collAborAtion including surgeons who provide heart malformations share a common Blood cancers 40 study sections of national review In order to progress toward gene tissue samples donated by patients during molecular mechanism is a big step panels across a full range of pediatric discovery, Dr. McBride’s team must cardiac surgery. “It would be impossible forward, as it allows us to more maintain the clinical collaborations to conduct this research without the effectively focus our efforts, provides Gastrointestinal cell health topics. Section members are that have been so vital in their present teamwork of our on-site surgeons the first clues to the underlying and Molecular Biology considered experts in their field and research. While Dr. McBride’s team because the tissue samples are too fragile pathogenesis, and hopefully will allow assess the scientific and technical utilizes animal models during their to be shipped from one location to improved genetic counseling for affected merit of research conducted by studies, no existing animal models another,” said Dr. McBride. “It also helps families.” their peers. precisely mimic LVOT malformations. that we are able to collaborate with Further reading: McBride KL, Riley MF, Zender This is why much of their research doctors who are leaders in the treatment GA, Fitzgerald-Butt SM, Towbin JA, Belmont JW, directly involves real-life patient samples. Cole SE. NOTCH1 mutations in individuals with of hypoplastic left heart syndrome.” left ventricular outflow tract malformations reduce ligand-induced signaling. Hum Mol Genet. 2008 Sep The complex nature of this translational Ultimately, the genetic information 15;17(18):2886-93. Web exclusive work necessitates close collaborations with a variety of skilled people including obtained by Dr. McBride and his McBride KL, Zender GA, Fitzgerald-Butt SM, Faculty members at nationwide To view a full list of national colleagues may result in genetic tests a genetic counselor who recruits patients to identify at-risk pregnancies early and Koehler D, Menesses-Diaz A, Fernbach S, Lee K, Towbin JA, Leal S, Belmont JW. Linkage analysis of children’s serve on more than 40 study review panels that include experts from Nationwide Children’s left ventricular outflow tract malformations (aortic and families, obtains detailed medical and family histories and collects blood help develop unique treatments and improved surgical techniques. valve stenosis, coarctation of the aorta, and hyp- sections of national review panels across Hospital, visit us online at oplastic left heart syndrome). Eur J Hum Genet. 2009 for lab studies. This information then “Although we are at the beginning of our a full range of pediatric health topics. − keyword search: panels. becomes part of an extensive clinical hunt for the causes of these devastating database that serves as a repository for heart malformations, we now have a scientific study. 6 | research research | 7
  5. 5. Classifying Concussions Although these mild brain injuries are common among children, Yet, additional research suggests there might be more at work. Dr. Yeates says that not all concussions should be treated equally. “Given the amount of time kids spend with their parents and “There is often an assumption that all mild head injuries are the in the family setting, it seems possible that these are factors RIsK fACTORs HeLP PReDICT HOW CONCusseD KIDs WILL ReCOveR same, that all concussions are the same. But, conventional in recovery,” said Dr. Yeates. “Is it the injury that accounts for definitions of concussion and mild head injury actually encompass post-concussive symptoms? Or is it other factors like how the a wide range of severity,” he said. family copes or how the child reacts? What we’re finding is that it’s both.” This wide range of severity can range from injuries that lead to a 20-minute loss of consciousness and obvious lesions on brain One of Dr. Yeates’ studies examined how family burden and imaging, to those that only involve feeling foggy, without being parent distress following a child’s mild traumatic brain injury unconscious, and no findings on neuroimaging. Yet the level related to post-concussive symptoms. Overall, the results were of severity is not the only determinant of patient outcome. “It’s encouraging, suggesting that family burden and parental distress clear clinically that some kids with brain injuries do surprisingly following mild traumatic brain injury is typically limited. How- well and others do very poorly,” said Dr. Yeates. “Although there ever, data suggested that children’s post-concussive symptoms is a relationship between how severe an injury is and how kids shortly after a minor injury may be a more powerful source of do, there is a lot of variability,” he said. post-injury family burden and distress than the injury itself. WHeN CONCussION syMPTOMs LINGeR In conjunction with the University of Cincinnati, Dr. Yeates’ In an effort to clarify risk factors related to concussion outcomes, team is examining a potential intervention that uses a web-based Dr. Yeates and colleagues recently examined nearly 200 children tool to teach families and children with severe traumatic brain with concussion and followed them for a year. The study, which injury better problem-solving and communication skills as a way appears in Pediatrics, revealed that while most kids had few prob- of reducing the parents’ distress and indirectly improving the lems, one out of every four experienced significant post-concussive children’s outcomes. “Our research suggests that it is important symptoms, some of which never fully resolved. “There is a group to do family-centered care, not just because it sounds like it is of kids that are at risk and do seem to be able to continue to have the nice thing to do, but because it actually makes a difference these symptoms even up to a year after their injury,” said Dr. Yeates. in how kids recover,” he said. Still, he says this study is not cause for alarm. In reality, it provides reassurance for parents of kids who suffer first-time concussions because more often than not children recover fully A within a short amount of time. Despite this, the study also shows that kids who are at risk because their concussions are more Keith O. Yeates, PhD well-known, albeit unfortunate story among Dr. Keith Yeates’ family is that he toppled down severe need to be monitored for a longer period of time as their the stairs in a mobile baby walker during childhood. Although he was not evaluated for head symptoms may last longer. trauma, the fall left him with two prominent black eyes, which Dr. Yeates assumes were the result of a basilar skull fracture. However, physicians aren’t always able to predict who will have long-term issues. While symptoms like headaches, fatigue and The clinical neuropsychologist and director of the Center for Biobehavioral Health at The irritability can all be signs that a concussion is lingering, there is Research Institute cites this childhood tale as a personal example of how head trauma and its no test to show when a child has fully recovered. potentially long-lasting effects are not so easily identified. Dr. Yeates believes classifying concussions as high-risk or low-risk Fortunately, his almost 20 years of clinical and research experience at Nationwide Children’s Hospital is helping may help physicians determine which patients need special atten- to reverse this reality. By studying brain development and outcomes of brain injury, Dr. Yeates and his team are tion. “We’re trying to understand the factors that relate to recovery.” working to help physicians and families understand risk factors associated with traumatic brain injury and their expected outcomes. INjuRy seveRITy PLus fAMILy DyNAMICs As previously indicated, one recovery-related factor seems to be In relation to concussions, one of the most common childhood head injuries, researchers are learning that severity of injury. Results from the aforementioned study showed multiple physical and psychosocial factors play a role in how children will recover. Medical imaging techniques such as MRI help clinicians determine that children whose concussions resulted in a loss of consciousness, the severity of injury by revealing brain abnormalities related to CHARACTeRIsTICs Of CONCussION disorientation or post-traumatic amnesia, or an abnormal MRI were trauma. Injury severity is one of the many recovery-related factors A concussion is a mild injury to the brain caused by a blow to the head. It’s estimated that more than a half more likely to have symptoms that persisted. that Dr. Yeates’ team is examining in order to help classify million kids in the United States go to the hospital each year with this injury, an average of a kid per minute, concussions as high- or low-risk. every minute of every day. 8 | research research | 9
  6. 6. Research on the Road THe effeCTs Of BRAIN AGe Dr. Yeates says that in a more severe diffuse injury that tends to Research has also revealed that age is an important factor related involve large regions of the brain, young kids actually don’t recover to recovery. When it comes to brain injury, kids shouldn’t be as quickly or as completely compared to older children. More compared to adults. research is needed to find out if the effects of mild traumatic brain NeW MOBILe ReseARCH LAB TARGeTs injuries are also more pronounced for younger children. HARD-TO-ReACH PARTICIPANTs Consider this: Several studies that have focused specifically on D adults with mild traumatic brain injury indicate that the presence The vulnerability of age is why it is important to investigate emographics are an important The mobile lab is currently being used to of the APOE ε4 allele, a genetic risk factor, is associated with the effects that brain injuries have on aptitudes developed measure for ensuring that research extend Dr. Reynolds’ impulsivity research, poorer neurobehavioral outcomes. However, after conducting a during childhood, such as social skills. An ongoing study in findings are generalizable to large which focuses on how specific impulsive similar study in children with this allele, Dr. Yeates and col- the Center for Biobehavioral Health is focused on social populations. How can researchers increase behaviors are involved in an adolescent’s ability leagues found that the APOE ε4 allele is not consistently related outcomes related to traumatic brain injury. “A lot of traumatic a study’s demographic scope when it’s to stop or reduce smoking. Initial “on-the-road” to the outcomes of mild traumatic brain injury in children. brain injury research has focused on kids’ cognitive skills, but logistically difficult for a wide variety of data collection began in January 2009 in the the things that are most troublesome to kids and to their families people to participate? Ohio Appalachia region. Despite the fact that childhood brain injury needs to be evaluat- have to do with how kids do behaviorally and socially,” said Dr. ed differently than similar injuries in adults, Dr. Yeates says there They can go the distance. Plans call for the mobile lab to be used Yeates. “If you look at long-term predictions of how people turn are more important age groups to compare. “There has been a for the next 10 to 15 years in studies by out as adults, their social relationships as kids are better In an effort to improve sampling and to reach lot of research in age-related differences in outcomes and the additional researchers, including research predictors of quality of life than school performance is.” target populations, Center for Biobehavioral most significant difference isn’t between school-aged kids and on parent safety practices and impulsivity adults. It is between preschool children and older children.” To aid in both cognitive and social development following brain Health Principal Investigator Brady Reynolds, and another focused on depression and teen injury, investigators in the Center for Biobehavioral Health, in PhD, has developed a “research lab on smoking. “The opportunities for research conjunction with the University of Oregon, also are studying wheels.” This mobile lab is fully equipped are endless,” says Dr. Reynolds. No Way to Play the outcomes of a school transition program that alerts schools when kids are coming back with traumatic brain injury, and to conduct studies off-site, in rural areas where participant recruitment is difficult. KIDs ARe COMPeTING TOO sOON providing the school with appropriate resources. AfTeR CONCussIONs A MODeL Of BRAIN ReCOveRy A study from the Center for The identification of risk factors that help to predict how Injury Research and Policy at patients will recover from brain injury, and a better understanding The Research Institute found that of how kids are affected post-injury, could change the way 41 percent of student athletes across 100 US high schools who physicians and families deal with all-too-common concussions. The findings could also help inform models of recovery in other Inside the Mobile Lab diseases that can affect the central nervous system, such as suffered a concussion returned to Every aspect of the mobile research lab was care- childhood cancer or prematurity. play too soon, against guidelines fully designed and strategically planned to utilize Yet Dr. Yeates notes that as important prediction and aftercare space and protect privacy during data collection. set by the American Academy of are, methods of prevention should not be overlooked. “The Neurology. In girl’s volleyball and PRIvATe BATHROOM biggest difference we could make in terms of disability and boy’s basketball and baseball, Space to collect urine samples to test for biomarkers. death for kids in the US would be doing a better job of more than half of the concussed Such tests are more reliable than personal reports preventing injury.” when measuring levels of cigarette smoking. players returned to play before Further reading: Yeates KO, Taylor HG, Rusin J, Bangert B, Dietrich A, Nuss fully recovered. K, Wright M, Nagin DS, Jones BL. Longitudinal trajectories of postconcussive COMPuTeR CeNTeR symptoms in children with mild traumatic brain injuries and their relationship to A place for participants to complete specially- acute clinical status. Pediatrics. 2009 Mar; 123 (3): 735-43. designed research tasks. Web exclusive Ganesalingam K, Yeates KO, Ginn MS, Taylor HG, Dietrich A, Nuss K, Wright For “Concussion Tips and M. Family burden and parental distress following mild traumatic brain injury in INTeRvIeW sPACe children and its relationship to post-concussive symptoms. J Pediatr Psychol. 2008 Symptoms: What Every Parent A private room used during one-on-one data Jul;33(6):621-9. Should Know,” visit us online at collection. Moran LM, Taylor HG, Ganesaligam K, Gastier-Foster JM, Frick J, Bangert B, Dietrich A, Nuss KE, Rusin J, Wright M, Yeates KO. Apolipoprotein E4 as a OuTDOOR AWNING − keyword search: concussion. predictor of outcomes in pediatric mild traumatic brain injury. J Neurotrauma. 2009 Feb 18. [Epub ahead of print] Provides shelter for conducting research or recruiting outside the lab. 10 | research research | 11
  7. 7. N CH CH3 CH3 O CH 3 CH CH3 OH N CH3 O CH surprisingly, instead of ridding the 3 O CH3 H 4. CH3 OH O cell of the foreign protein, killer O 2. 1. scientists deliver presence of the green N T cells receive a mysterious fluorescence, which can The immune system recognizes eGFp as foreign CH3 death signal and begin a “gene” to the leg muscle 3. CH3 of a mouse model using aCH be observed by the OH and killer T cells invade to destroy green to die. Their death naked eye, confirms muscle cells. CH3 H viral vector. In this case, 3 N CH3 leads to gene that the viral vector therapy success. the gene N N CH3 successfully delivered OH produces Illustration by Anthony Weiler CH3 OH H O the gene and that the Oa protein H desired protein is called eGFp being produced. that flouresces green. OH OH CH3 CH3 O O CH CH3 CH3 O O Tracking the Mysterious CH3 N CH3 CH3 To Dr. Walker and his team, these findings CH3 O Death of Killer T Cells CH CH3 O N 3 OH were reminiscent of studies in CH3 OH N CH CH3 humans infected with the hepatitis C CH3 O virus. Dr. Walker’s team discovered that the NeW ReseARCH Is sHOWING THAT GeNe THeRAPy DOes NOT evADe THe O CH3 OH CH3 killer T cells lost the ability to destroy tissues they IMMuNe sysTeM, As ORIGINALLy BeLIeveD. RATHeR, GeNe THeRAPy suCCess recognized as foreign and ultimately died, a process that N ReLIes ON THe DeATH Of IMMuNe-sysTeM-ACTIvATeD KILLeR T CeLLs. CH3 has been observed in N liver of humans persistently infected with the CH3 CH3 CH3 OH CH3 the hepatitis C virus. CH3 W hat if your immune system could be switched on and “Some of these pathogenic adversaries have learned to use these Like an aircraft dropping needed supplies, scientists hope N that N A CH OH BALANCING ACT DeLICATe N N off as needed to fight disease? immune switches to gain an advantage during infection, said CH3 vectors can be used to deliver the body’s missing genes. OHHCH C 3 These studies indicate that the balance between success and failure 3 CH3 OH Christopher M. Walker, PhD, director of the Center for Vaccine OH However, one potentially important barrier to this success in gene therapy is considerably more tenuous than first thought, Although this scenario might seem suitable for a OHdramatic screenplay, in reality, scientists are edging closer to and Immunity at The Research Institute. “The hepatitis C virus could be the immune system. “Therapeutic proteins produced in relying on death of armed killer T cells. Unraveling mechanisms is an example. It can exploit one of the off switches to impair diseased tissues differ from those inherited by the patient and so of killer T cell death may hold the key to treatment of diseases as understanding how immunity is switched on and off during viral, immunity in many infected people, resulting in life-long they may be viewed as foreign and threatening by the immune diverse as chronic virus infection, in the case of hepatitis C, and bacterial and parasitic infection. infection with the virus and greatly increased risk of serious system,” said Dr. Walker. success in gene therapy for inherited genetic diseases like muscular liver diseases like cirrhosis and cancer.” dystrophy or hemophilia B. Killer CD8 T cells are the most threatening component of the In an effort to improve the health of patients infected with the immune system. These white blood cells were designed by nature “It is surprising how two lines of research for diseases that appeared hepatitis C virus, Dr. Walker and his team are searching to “out- to destroy infected tissues and to interrupt production of new so dissimilar have converged in our laboratory,” said Walker. smart” this pathogen and switch immunity back on. As is often the viruses. In gene therapy this normally beneficial response could “Understanding the switches that lead to programmed death of case in research, this work has recently led Dr. Walker’s laboratory lead to disaster. T cells could at once allow us to restore immunity in a serious in an unexpected and important new direction, one that could have infectious disease like hepatitis C, and turn immunity off where it groundbreaking implications for gene therapy. A DesIRABLe fAILeD IMMuNe ResPONse is not wanted in gene therapy.” Yet, disaster may not be inevitable. GeNe-CARRyING vIRuses Moreover, this research serves as a reminder that current gene Once considered futuristic, it is now possible to manipulate Remarkably, foreign proteins can be produced for a lifetime in therapy strategies involve a delicate balancing act with host some simple viruses to deliver human genes. Through complex, mouse models without interference from the immune system. For immunity. “As these findings indicate, cellular immune responses technology-assisted processes, scientists remove the disease-causing many years it was thought that these therapeutic proteins were should also be considered as a potential risk to the success of genes from a simple virus and use the pathogen’s protective coating ignored by killer T cells, but recent studies by Dr. Walker’s team gene transfer when using viral vectors,” said Dr. Walker. to package the functional human gene. challenge this logic. Delivery of an AAV vector to leg muscles of Further reading: Velazquez VM, Bowen DG, Walker CM. Silencing of T mice did result in long-term production of the therapeutic protein, lymphocytes by antigen-driven programmed death in recombinant adeno- Known as viral gene therapy vectors, these manipulated viruses have but instead of being ignored the protein engaged the immune associated virus vector-mediated gene therapy. Blood. 2009 Jan 15;113(3):538-45. been shown to cure genetic diseases in animals and are now being system. Killer T cells even infiltrated the treated muscle, but failed tested in humans. A common example is the adeno-associated virus in their mission to remove the muscle cells producing the (AAV), which has been converted to treat inherited diseases including therapeutic protein. Christopher M. Walker, PhD cystic fibrosis, arthritis, muscular dystrophy and hemophilia. 12 | research research | 13