1) The document discusses research being conducted at Nationwide Children's Hospital on concussions and heart defects. 2) For concussions, the research aims to identify risk factors that can predict recovery outcomes in children. Preliminary findings show that about 25% of concussed children experience significant lingering symptoms. 3) For heart defects, the research shows that three types of birth defects affecting the left side of the heart - aortic valve stenosis, coarctation of the aorta, and hypoplastic left heart syndrome - may share a common molecular origin involving the NOTCH1 gene and Notch signaling pathway.

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. 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.
ResearchMagazine@NationwideChildrens.org
research | 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. 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. www.NationwideChildrens.org
− 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. 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. 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,
www.NationwideChildrens.org
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. N CH
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CH3 O CH 3
CH
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surprisingly, instead of ridding the
3
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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
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viral vector. In this case,
3
N CH3 leads to gene
that the viral vector therapy success.
the gene N
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produces
Illustration by Anthony Weiler
CH3 OH
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Oa protein
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called eGFp
being produced.
that flouresces green. OH
OH
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Tracking the Mysterious CH3
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To Dr. Walker and
his team, these findings
CH3
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CH CH3 O N
3 OH were reminiscent of studies in
CH3
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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
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the
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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
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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
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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