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Feasibility of Gene Therapy for Late Neuronal Ceroid Lipofuscinosis
Dolan Sondhi, PhD;
Neil R. Hackett, PhD;
Robin L. Apblett, BA;
Stephen M. Kaminsky, PhD;
Robert G. Pergolizzi, PhD;
Ronald G. Crystal, MD
Arch Neurol. 2001;58:1793-1798.
ABSTRACT
Late infantile neuronal
ceroid lipofuscinosis is a progressive childhood neurodegenerative
disorder characterized by intracellular accumulation of autofluorescent
material resembling lipofuscin in neuronal cells. This report
summarizes the new therapies under consideration for late infantile
neuronal ceroid lipofuscinosis, with a focus on strategies for in vivo
gene therapy for the retinal and central nervous system manifestations
of the disease.
INTRODUCTION
Late infantile neuronal ceroid lipofuscinosis (LINCL; Batten
disease) manifests between the ages of 2 and 4 years with seizures,
ataxia, myoclonus, impaired vision, and delayed speech as the primary
symptoms. The disease is characterized by cerebral and cerebellar
atrophy, with progressive loss of neurons and retinal cells. The
central nervous system (CNS) and retinal cells show characteristic
autofluorescent curvilinear lysosomal storage bodies. The main
component of this storage material is the mature form of subunit c of
mitochondrial adenosine triphosphate synthetase, suggesting a defect in
the turnover of this protein. Afflicted children develop blindness and
become chair bound by the age of 4 to 6 years, with death by the age of
8 to 12 years.1
Late infantile neuronal ceroid lipofuscinosis is caused by
mutations in the CLN2 (ceroid lipofuscinosis, neuronal 2)
gene, a 6.7–kilo-base pair (kbp) gene with 13 exons and 12
introns mapped to 11p15 (Figure 1, A). The gene expresses 2.5- and 3.5-kbp messenger RNA
transcripts.1 Three mutations account for most cases of
LINCL, including an intron G C transversion in the invariant AG
of the 3' splice junction of intron 5; an exon 6 CT causing a
premature stop; and an exon 10 GC missense mutation.2
The CLN2 gene product is tripeptidyl peptidase I (TPP-I), a
lysosomal enzyme that progressively removes groups of 3 amino acids
from the amino terminus of proteins (Figure 1, B). Tripeptidyl
peptidase I is normally secreted into the extracellular
milieu in a "pro–TPP-I" form that is then taken up via 2
mannose-6-phosphate high-affinity receptors, and shunted to lysosomes.
The secreted pro–TPP-I protein is enzymatically inactive, but when
acidified in the lysosomes it is autocatalytically converted to its
active form.1, 3
NEW TREATMENT OPTIONS FOR LINCL
The goal of therapy for LINCL is to deliver active TPP-I to CNS and
retinal cells in a sufficient amount and in time to prevent the cell
loss. Theoretically, this goal could be achieved by enzyme augmentation
therapy, allogeneic stem cell transplantation, and various forms of
gene therapy. These strategies are all based on the concept that the
pro–TPP-I protein is taken up via mannose-6-phosphate receptors on
both the producer and the neighboring cells.4, 5 The late
emergence of an LINCL phenotype associated with mild mutations of
the CLN2 gene suggests that a therapy that would provide 5%
to 10% of normal intracellular TPP-I activity would be sufficient to
prevent progression of LINCL.2
It is uncertain what duration of therapy will be needed to impact
the clinical phenotype. Because LINCL is a hereditary disorder, it has been assumed that
therapy must be continuous. However, because the clinical phenotype is
not manifested until the age of 2 to 4 years, effective
clearance of this material might "reset the clock" and delay
progression of the disease, ie, transient augmentation of
extracellular pro–TPP-I levels may provide protection of CNS
and retinal cells for a few years. Contrary to this view is
the hypothesis that TPP-I has critical functions other than the
degradation of proteins accumulating in lysosomes, ie, the accumulation
of metabolic by-products is not central to disease pathogenesis. This
question will likely not be answered until clinical studies are carried
out, but for now, it is prudent to have continuous augmentation of
extracellular pro–TPP-I levels (and, hence, active intracellular
TPP-I) in the target tissues as the highest priority.
Enzyme augmentation therapy is a strategy in which
purified, recombinant pro–TPP-I would be infused into affected
individuals. In addition to the challenge of producing and purifying
the recombinant protein, the blood-brain barrier precludes effective
TPP-I therapy for the CNS from being administered systemically. This
could be circumvented by direct intracerebral administration of
recombinant pro–TPP-I, but this is a difficult challenge given the
diffuse nature of the CNS disease and the requirement for continuous
augmentation.
Allogeneic stem cell therapy is based on the knowledge that bone
marrow–derived stem cells can differentiate into blood monocytes that
migrate to the brain to further differentiate into microglial
cells.6 For LINCL, stem cell transplantation from a
matched or partially matched donor would theoretically provide a cell
source in the CNS for the normal TPP-I protein. It is unlikely,
however, that this approach will work. In addition to the risk of
long-term immunosuppression therapy, one attempt with stem cell therapy
was unsuccessful in correcting the CNS pathology in a patient with
LINCL, and the CNS abnormalities of mice with a related lysosomal
storage disease are not corrected by stem cell therapy administered in
the postnewborn period.7, 8
Gene therapy entails delivery of the CLN2 complementary DNA
(cDNA) to the target tissues as the source of TPP-I. Theoretically, if
the transferred CLN2 cDNA persists and continues to express
TPP-I, there would be a continual local supply of the therapeutic
protein. There are several approaches to consider for gene therapy for
LINCL.
Systemic administration of autologous, genetically modified cells
involves ex vivo modification of CD34+ stem cells (bone
marrow or blood) to express the CLN2 cDNA and intravenous
administration of those modified cells to the patient. This strategy
has the same logic as allogeneic therapy, but would not require
long-term immunosuppression, and by using a strong constitutive
promoter, the differentiated microglial cells would theoretically
express large amounts of TPP-I. Unfortunately, gene transfer to
CD34+ cells in humans has been successful only in
conditions with positive selection pressure in vivo for the infused,
transduced stem cells.9 This, together with the low rate of
migration of monocytes into the CNS, diminishes the chances of success
for this strategy.
Transplantation of genetically modified cells directly to the CNS has
the advantage of ensuring high levels of local production of TPP-I.
Most experimental systems have used autologous fibroblasts or
allogeneic fetal neurons as the cells to be modified and
transplanted.10, 11 In addition to the social/political
issues that may limit the use of fetal cells, this approach is not
easily applicable to LINCL because of the diffuse nature of the CNS
disease, requiring multiple sites of administration. This approach also
has the risk of transplanting a large number of cells to a closed
space. This safety issue, the challenge of obtaining large numbers of
genetically modified autologous cells, and the necessity for ex vivo
manipulation assign a low priority to this approach.
In vivo gene therapy is a strategy in which the CLN2 cDNA
would be directly delivered to cells throughout the CNS and retina,
enabling the modified cells to produce TPP-I. This direct approach is
the strategy most likely to succeed. The major challenge for in vivo
gene therapy is whether the available gene transfer vectors can modify
cells in the target tissues to produce sufficient amounts of TPP-I in
the appropriate anatomic regions to stabilize and/or reverse the
disease.
IN VIVO GENE THERAPY FOR LINCL: VECTORS AND EXPERIMENTAL STUDIES
Given the biological challenge and the available technology, we
conclude that in vivo gene therapy is the most viable short-term option
for treating the CNS and retinal manifestations of LINCL. Before
discussing the practical aspects of initiating human gene therapy
trials, it is useful to review the technology available to accomplish
this and the experience of in vivo gene therapy in relevant models.
Gene Transfer Vectors
To efficiently transfer a gene to the nucleus of target cells of the
CNS and retina, it is necessary to put the gene in a "vector," a
carrier that helps to circumvent biological barriers to nucleic acid
internalization to the nucleus, where it can use the normal cellular
machinery to transcribe the exogenous gene. Viral gene transfer vectors
capitalize on the property of viruses to efficiently transfer their
genome to the nucleus of cells. These vectors are designed to be
"replication deficient" by removal of critical genetic information.
A viral gene vector used to treat LINCL would have the addition of
an "expression" cassette containing the TPP-I cDNA controlled by an
appropriate promoter. There are 3 types of gene transfer vectors,
adeno-associated virus (AAV), lentivirus (LV), and adenovirus (Ad),
that have the biological characteristics appropriate for effective in
vivo gene transfer for LINCL. Other vectors do not fit the needs of
this clinical target (nonviral vectors have low efficiency and
transient gene transfer/expression, murine retroviruses have low
transduction efficiency in vivo and require target cells to be
proliferating to transfer genes to the nucleus, and human herpes
simplex virus has not been proved to be sufficiently safe for this
application).
Adeno-associated viruses are small nonenveloped icosahedral
parvoviruses with a 4.7-kbp single-stranded DNA genome.12
All viral genes in AAV vectors are replaced by an expression cassette,
leaving intact essential cis elements, including the inverted
terminal repeats, the DNA packaging signal, and the replication
origin.13 Adeno-associated vectors are effective in
long-term gene transfer to14 the CNS and
retina,15 and there is a good safety record in humans using
AAV serotype 2.
Lentiviruses are a family of complex retroviruses that include the
human immunodeficiency viruses. Lentivirus gene transfer vectors have
the useful features of retroviral vectors (efficient integration in the
chromosome, absence of viral genes from the genetic information
transferred, and limited host responses to the vector), and the
important added ability to infect nondividing cells such as those found
in the CNS.16, 17, 18 However, there are concerns about the
safety of LV vectors, given the serious nature of the human diseases
attributable to members of this family.
Adenoviruses are nonenveloped icosahedral viruses with a
double-stranded 36-kbp DNA genome that causes transient mild infections
of the upper respiratory tract and intestine.19 Deletion of
essential genes, typically E1, renders Ad replication deficient and
leaves room for insertion of an expression cassette.20 Most
clinical experience with Ad vectors is with serotype 5. Because the Ad
genome does not replicate or integrate into the genome, and these
vectors initiate antivector host responses, Ad vectors mediate only
transient expression. Because the brain is partially immunoprivileged,
transgene expression from Ad vectors may persist for longer periods in
the CNS than in other tissues. The critical questions for use of Ad for
LINCL are as follows: (1) How long and at what levels is the
protein expressed? (2) At a therapeutic dose, is readministration
possible and at what intervals? (3) If expression of the
CLN2 gene can clear storage granules and prevent neuronal
death, how long does the enzyme persist and how quickly do storage
granules reaccumulate?
Following the death of a patient involved in a clinical trial
using an Ad vector at the University of Pennsylvania, Philadelphia, in
late 1999, there have been safety concerns about the intravascular use
of high doses of Ad vectors.21 However, extensive
assessment of the record by the Food and Drug Administration and the
National Institutes of Health has shown that Ad is well tolerated at
moderate doses, if administered directly to the
target.22, 23
Lessons From Experimental Models
There is no animal model for LINCL. However, data from other
experimental models support the use of AAV, LV, and Ad vectors to treat
the CNS and retinal manifestations of LINCL. Most relevant are the
data from mice with mucopolysaccharidosis (MPS) VII
(ß-glucuronidase deficiency or Sly syndrome, a related lysosomal
disorder). Mice with MPS VII are characterized by the
accumulation of storage granules in CNS neurons and photoreceptor
cell degeneration24, 25 (untreated, these mice live 5
months). Like TTP-I, ß-glucuronidase is normally secreted
and taken up by neighboring cells using the mannose-6-phosphate
receptor pathway. Studies of mice with MPS VII have established the
following principles: (1) direct gene transfer to the CNS is required
for correction of the storage defect in the adult
brain8, 26, 27, 28; (2) there is cross correction, with
transplantation of wild-type cells correcting mutant cells over an area
much greater than the region of transplantation29; and (3)
AAV, LV, and Ad vectors can reverse storage and behavioral defects
after direct CNS administration.30, 31, 32, 33, 34
Summary
Adeno-associated virus, LV, and Ad vectors appear to be suitable to
treat the CNS and retinal manifestations of LINCL.
HUMAN GENE THERAPY FOR LINCL: PRACTICAL CONSIDERATIONS
The objective of clinical gene therapy trials for LINCL is to
reverse the progress of the disease. Whether this can be achieved using
current technology is not known, but if the preclinical efficacy and
toxicology studies are sufficiently robust to support a clinical trial,
the available scientific evidence, together with an overwhelming
medical need for this rare, universally fatal disorder for which there
is no therapy, strongly argues that resources should be devoted toward
this end. The following are practical considerations to achieve this
goal.
Vectors
Comparing the biological characteristics of the vectors,
their known safety profiles, and theoretical risks with the biological
features of LINCL, we conclude that the priorities for vector
development for clinical use should be as follows: AAV is greater than
LV, which is greater than Ad. Adeno-associated virus merits the highest
priority because LINCL is a hereditary disorder, and there is good
experimental evidence that AAV can mediate gene transfer with long-term
expression in the CNS and retina. While LV has many of the same
characteristics, it has to be given a lower priority because there is
far less experience with LV compared with AAV in human trials, and
because of the theoretical safety issue of using a vector partially
derived from human immunodeficiency virus 1 genetic elements.
There are some drawbacks to AAV that should be considered. If there is
overexpression of gene (or gene product), it could be toxic and cannot
be switched off (unless a genetic "switch" is built into the
vector). Some AAV genomes may integrate inappropriately, with
the theoretical risk of inducing malignancy. Intravenous administration
of an AAV vector expressing ß-glucuronidase to neonatal mice with MPS
VII resulted in long-term survival, but many of the treated mice later
developed hepatocellular carcinoma.35 The origin of the
hepatocellular carcinoma may be a consequence of the underlying
pathology of the mice with MPS VII, rather than of the AAV vector
therapy.
While Ad vectors may only provide transient expression, if the
abnormal lysosomal storage is fundamental to the loss of neurons in
patients with LINCL, then transient (1-2 weeks) expression of the
CLN2 cDNA in the CNS may provide sufficient TPP-I to clear the
storage granules and "set the clock back," delaying the morbidity
in children with LINCL by years. This concept, plus human safety
data for Ad vector administration to the CNS for glioma,36
suggests that Ad vectors should be developed for possible clinical use,
albeit at a lower priority.
Expression Cassette
For gene therapy of LINCL, the expression cassette will be the
CLN2 human cDNA controlled by an active promoter. With the
knowledge that gene transfer technology can only deliver genes to a
limited percentage of cells in a target, the requirement to deliver the
CLN2 protein product in a diffuse fashion argues that
high-level constitutive expression is necessary, ie, regardless of the
vector used, the assumption of cross correction of neighboring cell
types makes production of a high level of TPP-I protein of paramount
consideration. Examples of such promoters include the Rous sarcoma
virus long terminal repeat, the cytomegalovirus early/intermediate
promoter/enhancer, and the chicken ß-actin promoter with
cytomegalovirus enhancer.36, 37, 38
Administration
There are 3 possible routes of delivery of vectors to the CNS:
intravascular, intrathecal, or intracranial. For the retina, the vector
can be administered directly to the subretinal or the vitreal space.
Theoretically, intravascular or intrathecal delivery could be used, but
the substantial technology (intravascular) and doses (intrathecal)
required for these strategies when balanced against the urgent clinical
need for a therapy suggest this should be a low priority. The most
direct approach to administration of vectors to the CNS is direct
injection into the brain parenchyma. The requirement for diffuse
administration necessitates injection into several sites, something
achieved only with multiple burr holes. It is unknown how many of these
will be required without knowing the diffusion characteristics of the
vector and the TPP-I protein in the CNS of a large experimental animal.
This variable is governed by the volume injected (a buffered sugar-salt
solution is used as a vehicle for the vector) and by the diffusion
characteristics of the vector in the target tissue. Because the CNS is
a closed space, there is a limit to the volume that can be administered
per unit time. A reservoir could be used to slowly administer the
vector, but this will require studies of safety and vector stability,
and their use may be associated with a risk of infection. Despite the
diffuse nature of LINCL, there are some CNS regions (eg, the cortex
and the cerebellum) that may play a dominant role in the
phenotype; these areas might be the primary
targets for the initial studies. Alternatively, the vector could be
administered repetitively. This has the advantage of being able to
assess each single administration for adverse events before proceeding,
but assumes that host defenses against the vector will not limit the
safety and effectiveness of repeated administration.
For the retina, the most common effective procedure for vector
administration is a single injection through a sclerotomy into the
subretinal space.39, 40 Alternatively, the vector can be
administered with a single injection through the front of the eye, to
the vitreous, or continuing through the vitreous into the superior
subretinal space.40
Dose Response
The administration of a gene transfer vector has the potential of
inducing toxicity from the vector and/or transgene product. Because the
CNS and retina may be sensitive to such adverse events, it would be
prudent to limit the intensity and spatial distribution of any toxicity
by initiating a gene transfer trial to these sites with low doses of
the vector, and to administer the vector to a limited (local) region of
the brain or to one eye. The development of gene therapy for LINCL
must balance ethical issues (eg, using a low dose may not be
efficacious for this fatal disorder) against safety issues (eg,
persistent high-dose vector expression causing toxicity). If
a conservative approach is taken using a low dose and/or administration
to a limited region of the brain, the only solution is to consider
readministration (if possible) after sufficient time passes to assess
the toxicity from the first administration.
Repeat Administration
For most drugs, repeat administration is the norm. However, for
LINCL, each administration to the CNS will require burr holes.
Systemic immunity against a viral vector may preclude effective gene
transfer on readministration, and host defenses against the vector may
induce inflammation that may be unacceptable. Despite the fact that the
CNS is a partially immunoprotected site, we predict that repeated
administration of viral vectors to the CNS and retina may be safe but
may not be progressively efficacious.41
Preclinical Data
Without the availability of a suitable model for LINCL, critical
preclinical studies must address the following issues: (1) Will the
TPP-I product diffuse throughout the brain in sufficient levels to
provide efficacy? (2) What toxic effects are associated with
administration of the vector at doses within and above the range likely
to be used in the clinical studies? For each vector and each site,
these studies need to be carried out with naive and antivector
immune-positive animals, and with single and repeat administration. As
another assessment of toxicity, the creation of transgenic mice with
the CLN2 cDNA will be useful to know if there is a phenotype
associated with overexpression.
Regulatory and Ethical Issues
In the context that LINCL is a rare, fatal disease, it may be
necessary to develop gene therapy for it by compressing the studies
into a combined phase 1, 2, and 3 study that simultaneously assesses
safety and efficacy parameters. The initial human studies will likely
require a lower than therapeutic dose. While local delivery will be the
safest way to start, it will likely not treat all aspects of the CNS
disease. Furthermore, the parameters that measure clinical outcome in
the CNS are relatively insensitive and may provide little information
about the efficacy of gene transfer, ie, CLN2 gene therapy
studies in humans involving small numbers of patients may yield
ambiguous data in posttherapy tests. Depending on the final
inclusion/exclusion criteria, there will be a limited number of
patients eligible for the therapeutic development pathway. There is an
ethical dilemma regarding the recruitment of children with far advanced
disease, but restrictive inclusion/exclusion criteria could radically
reduce the number of available subjects for a trial. Because families
are highly motivated to participate in a gene therapy trial for
LINCL, clear consent materials will be necessary, as will
provisions for extensive discussions before and during the study.
SUMMARY
There are many unanswered questions that will require assessment before
proposing a clinical gene therapy trial for LINCL. Many decisions
will require data generated from experimental animals. Objective,
quantitative parameters will need to be developed before assessment of
subjects with LINCL in a gene therapy protocol can be achieved.
However, there is sufficient information available to conclude that if
our assumptions regarding the biology are correct, the resources are
available, and the regulatory climate is supportive, it is rational to
initiate the preclinical safety and toxicity studies directed toward
mounting clinical trials for the CNS and retinal manifestations of
LINCL.
AUTHOR INFORMATION
Accepted for publication April 23, 2001.
This study was funded in part by Nathan's Battle Foundation,
Indianapolis, Ind.
We thank R. Boustany, MD, K. Wisniewski, MD, PhD, N. Zhong,
MD, M. Sands, PhD, P. Lobel, PhD, P. Gutin, MD, M. Souweidane, MD, F.
Marshall, MD, J. Bennet, MD, PhD, P. Leopold, PhD, and R. Zalaznick,
BA, for helpful discussions and advice; and B. Charlot, T.
Virgin-Bryan, and N. Mohamed, MPH, for preparation of the manuscript.
From the Institute of Genetic Medicine and Belfer Gene Therapy Core
Facility, Weill Medical College of Cornell University, New York, NY.
Corresponding author and reprints: Ronald G. Crystal, MD, Institute of
Genetic Medicine, Weill Medical College of Cornell University, 515 E
71st St, Suite 1000, New York, NY 10021 (e-mail: geneticmedicine{at}med.cornell.edu).
REFERENCES
| |
1. Williams RE, Gottlob I, Lake BD, Goebel HH, Winchester BG, Wheeler RB. CLN 2: classic late infantile NCL. In: Goebel HH, Mole SE, Lake BD,
eds. The Neuronal Ceroid Lipofuscinoses (Batten
Disease). Amsterdam, the Netherlands: IOS Press;
1999:37-54.
2. Sleat DE, Gin RM, Sohar I, et al. Mutational analysis of the defective
protease in classic late-infantile neuronal ceroid lipofuscinosis, a
neurodegenerative lysosomal storage disorder. Am J Hum Genet. 1999;64:1511-1523.
FULL TEXT
|
ISI
| PUBMED
3. Sleat DE, Donnelly RJ, Lackland H, et al. Association of mutations in a
lysosomal protein with classical late-infantile neuronal ceroid
lipofuscinosis. Science. 1997;277:1802-1805.
FREE FULL TEXT
4. Neufeld EF, Fratantoni JC. Inborn errors of mucopolysaccharide
metabolism. Science. 1970;169:141-146.
FREE FULL TEXT
5. Taylor RM, Wolfe JH. Cross correction of ß-glucoronidase deficiency
by retroviral vector-mediated gene transfer. Exp Cell Res. 1994;214:606-613.
FULL TEXT
|
ISI
| PUBMED
6. Krivit W, Sung JH, Shapiro EG, Lockman LA. Microglia: the effector cell
for reconstitution of the central nervous system following bone marrow
transplantation for lysosomal and peroxisomal storage diseases. Cell Transplant. 1995;4:385-392.
FULL TEXT
|
ISI
| PUBMED
7. Lake BD, Steward C, Oakhill A, Wilson J, Perham TG. Bone marrow
transplantation in late infantile Batten disease and juvenile Batten
disease. Neuropediatrics. 1997;28:80-81.
ISI
| PUBMED
8. Sands MS, Barker JE, Vogler C, et al. Treatment of murine
mucopolysaccharidosis type VII by syngeneic bone marrow transplantation
in neonates. Lab Invest. 1993;68:676-686.
ISI
| PUBMED
9. Cavazzana-Calvo M, Hacein-Bey S, de Saint BG, et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science. 2000;288:669-672.
FREE FULL TEXT
10. Kordower JH, Freeman TB, Snow BJ, et al. Neuropathological evidence of
graft survival and striatal reinnervation after the transplantation of
fetal mesencephalic tissue in a patient with Parkinson's disease. N Engl J Med. 1995;332:1118-1124.
FREE FULL TEXT
11. Taylor RM, Wolfe JH. Decreased lysosomal storage in the adult MPS VII
mouse brain in the vicinity of grafts of retroviral vector–corrected
fibroblasts secreting high levels of ß-glucuronidase. Nat Med. 1997;3:771-774.
FULL TEXT
|
ISI
| PUBMED
12. Berns KI, Giraud C. Biology of adeno-associated virus. Curr Top
Microbiol Immunol. 1996;218:1-23.
ISI
| PUBMED
13. Carter B. Adeno-associated virus and adeno-associated virus vectors for
gene delivery. In: Smyth Tempelton N, Lasic DD, eds. Gene
Therapy. New York, NY: Marcel Dekker Inc; 2000:41-59.
14. McCown TJ, Xiao X, Li J, Breese GR, Samulski RJ. Differential and
persistent expression patterns of CNS gene transfer by an
adeno-associated virus (AAV) vector. Brain Res. 1996;713:99-107.
FULL TEXT
|
ISI
| PUBMED
15. Bennett J, Maguire AM, Cideciyan AV, et al. Stable transgene expression
in rod photoreceptors after recombinant adeno-associated virus-mediated
gene transfer to monkey retina. Proc Natl Acad Sci U S A. 1999;96:9920-9925.
FREE FULL TEXT
16. Akkina RK, Walton RM, Chen ML, Li QX, Planelles V, Chen IS. High-efficiency gene transfer into CD34+ cells with a human
immunodeficiency virus type 1–based retroviral vector pseudotyped with
vesicular stomatitis virus envelope glycoprotein G. J Virol. 1996;70:2581-2585.
ABSTRACT
17. Naldini L, Blomer U, Gallay P, et al. In vivo gene delivery and stable
transduction of nondividing cells by a lentiviral vector. Science. 1996;272:263-267.
ABSTRACT
18. Reiser J, Harmison G, Kluepfel-Stahl S, Brady RO, Karlsson S, Schubert M. Transduction of nondividing cells using pseudotyped defective
high-titer HIV type 1 particles. Proc Natl Acad Sci U S A. 1996;93:15266-15271.
FREE FULL TEXT
19. Shenk T. Adenoviridae: the viruses and their replication. In: Fields B, Knipe D, Howley PM, eds. Virology. Philadelphia, Pa:
Lippincott-Raven Publishers; 1996:2111-2148.
20. Hackett NR, Crystal RG. Adenovirus vectors for gene therapy. In: Smyth
Tempelton N, Lasic DD, eds. Gene Therapy. New York, NY: Marcel
Dekker Inc; 2000:17-40.
21. Sorelle R. Human gene therapy: science under fire. Circulation. 2000;101:e9023-e9024. Available at:
http://circ.ahajournals.org/cgi/content/full/101/12/e9023. Accessed
August 8, 2001.
22. Harvey B-G, Maroni J, O'Donoghue KA, et al. Safety of local delivery
of low and intermediate dose adenovirus gene transfer vectors to
individuals with a spectrum of comorbid conditions. Hum Gene
Ther. In press.
23. Office of Recombinant DNA Activities. Safety Reports and Adverse Events for Human Gene Transfer Protocols Recombinant DNA Advisory Committee Meeting, December 8-10, 1999. NIH/ORDA. Available at:
http://www4.od.nih.gov/oba/rac/minutes/1299rac.pdf. Accessed August
8, 2001.
24. Birkenmeier EH, Barker JE, Vogler CA, et al. Increased life span and
correction of metabolic defects in murine mucopolysaccharidosis type
VII after syngeneic bone marrow transplantation. Blood. 1991;78:3081-3092.
FREE FULL TEXT
25. Lazarus HS, Sly WS, Kyle JW, Hageman GS. Photoreceptor degeneration and
altered distribution of interphotoreceptor matrix proteoglycans in the
mucopolysaccharidosis VII mouse. Exp Eye Res. 1993;56:531-541.
FULL TEXT
|
ISI
| PUBMED
26. Gao C, Sands MS, Haskins ME, Ponder KP. Delivery of a retroviral vector
expressing human ß-glucuronidase to the liver and spleen decreases
lysosomal storage in mucopolysaccharidosis VII mice. Mol Ther. 2000;2:233-244.
FULL TEXT
|
ISI
| PUBMED
27. Ohashi T, Watabe K, Uehara K, Sly WS, Vogler C, Eto Y. Adenovirus-mediated gene transfer and expression of human
ß-glucuronidase gene in the liver, spleen, and central nervous system
in mucopolysaccharidosis type VII mice. Proc Natl Acad Sci U S
A. 1997;94:1287-1292.
FREE FULL TEXT
28. Watson GL, Sayles JN, Chen C, et al. Treatment of lysosomal storage
disease in MPS VII mice using a recombinant adeno-associated virus. Gene Ther. 1998;5:1642-1649.
FULL TEXT
|
ISI
| PUBMED
29. Skorupa AF, Fisher KJ, Wilson JM, Parente MK, Wolfe JH. Sustained
production of ß-glucuronidase from localized sites after AAV vector
gene transfer results in widespread distribution of enzyme and reversal
of lysosomal storage lesions in a large volume of brain in
mucopolysaccharidosis VII mice. Exp Neurol. 1999;160:17-27.
FULL TEXT
|
ISI
| PUBMED
30. Bosch A, Perret E, Desmaris N, Heard JM. Long-term and significant
correction of brain lesions in adult mucopolysaccharidosis type VII
mice using recombinant AAV vectors. Mol Ther. 2000;1:63-70.
FULL TEXT
|
ISI
| PUBMED
31. Bosch A, Perret E, Desmaris N, Trono D, Heard JM. Reversal of pathology
in the entire brain of mucopolysaccharidosis type VII mice after
lentivirus-mediated gene transfer. Hum Gene Ther. 2000;11:1139-1150.
FULL TEXT
|
ISI
| PUBMED
32. Davidson BL, Brooks AI, Stein CS, et al. Correction of cellular
pathology and behavioral deficits in adult ß-glucuronidase–deficient
mice after FIV vector–mediated gene transfer to brain [abstract]. Mol Ther. 2000;1:A688.
33. Stein CS, Ghodsi A, Derksen T, Davidson BL. Systemic and central
nervous system correction of lysosomal storage in mucopolysaccharidosis
type VII mice. J Virol. 1999;73:3424-3429.
FREE FULL TEXT
34. Frisella WA, O'Connor LH, Vogler CA, et al. Intracranial injection of
recombinant adeno-associated virus improves cognitive function in a
murine model of mucopolysaccharidosis type VII. Mol Ther. 2001;3:351-358.
FULL TEXT
|
ISI
| PUBMED
35. National Institutes of Health. Safety considerations in the use of AAV vectors in gene transfer clinical trials. Paper presented at: Fourth National Gene Transfer Safety Symposium; March 7, 2001; Rockville, Md.
36. Trask TW, Trask RP, Aguilar-Cordova E, et al. Phase I study of
adenoviral delivery of the HSV-tk gene and ganciclovir
administration in patients with current malignant brain tumors. Mol Ther. 2000;1:195-203.
FULL TEXT
|
ISI
| PUBMED
37. Yoon SO, Lois C, Alvirez M, Alvarez-Buylla A, Falck-Pedersen E, Chao MV. Adenovirus-mediated gene delivery into neuronal precursors of the
adult mouse brain. Proc Natl Acad Sci U S A. 1996;93:11974-11979.
FREE FULL TEXT
38. Yukawa H, Takahashi JC, Miyatake SI, et al. Adenoviral gene transfer of
basic fibroblast growth factor promotes angiogenesis in rat brain. Gene Ther. 2000;7:942-949.
FULL TEXT
|
ISI
| PUBMED
39. Ali RR, Sarra GM, Stephens C, et al. Restoration of photoreceptor
ultrastructure and function in retinal degeneration slow mice by gene
therapy. Nat Genet. 2000;25:306-310.
FULL TEXT
|
ISI
| PUBMED
40. Lau D, McGee LH, Zhou S, et al. Retinal degeneration is slowed in
transgenic rats by AAV-mediated delivery of FGF-2. Invest
Ophthalmol Vis Sci. 2000;41:3622-3633.
FREE FULL TEXT
41. Harvey BG, Leopold PL, Hackett NR, et al. Airway epithelial CFTR mRNA
expression in cystic fibrosis patients after repetitive administration
of a recombinant adenovirus. J Clin Invest. 1999;104:1245-1255.
ISI
| PUBMED
SECTION EDITOR: IRA SHOULSON, MD
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