ASGT Press Release
For Immediate Release
November 27, 2001 |
Contact: Fintan R. Steele,
Ph.D.
Fax: 646-935-3742 |
This is the press release for the December 1, 2001, issue of Molecular
Therapy (Volume 4, Number 6), the journal of the American Society
of Gene Therapy (ASGT). Molecular Therapy is owned and copyrighted
by the ASGT, and published monthly by Academic Press.
This information is not embargoed (see embargo policy below). Please
cite Molecular Therapy as the source of this information. If you
want to be removed from this list, please respond to this email. If you
wish to have someone else added, please respond with the email address
to be included in future releases. All questions should be directed to
the Editor (contact information below).
PDF files of these articles are available for reporting purposes only,
and only to direct recipients of this email.
A major safety issue confronting the use of human gene therapy is the
possibility of germ-line transmission of the introduced gene. Is it possible
to treat a human being with gene therapy and not have that treatment be
carried to succeeding generations? Two papers in this issue of Molecular
Therapy address this question directly for two commonly used gene
therapy vectors, and suggest that the risk is extremely small.
In the first study, a group of researchers led by Katherine High of the
Children's Hospital of Philadelphia looked for germline transmission following
intramuscular or intraarterial (hepatic) injection of recombinant adeno-associated
virus (AAV) in males from four different animal species (mouse, rat, rabbit
and dog). The researchers demonstrate conclusively that, in these animal
models, risk of AAV germline transmission is vanishingly small.
Robert Braun of the University of Washington and his collaborators describe
experiments in another paper that try to determine the risk of adenovirus
transmission. The researchers injected an adenovirus carrying a reporter
gene hooked up to a germ cell-specific promoter directly into the heart
ventricles of mice and subsequently monitored possible germ cell expression
of the reporter gene. Despite this substantial "challenge,"
the researchers determined that the chance of vertical germline transmission
as well as insertional mutagenesis is "highly unlikely."
(It should be noted that recent news reports relate that in an ongoing
clinical AAV-based trial for hemophilia that vector could be detected
in the semen of one patient for up to seven weeks following treatment.
However, the source of this positive test remains uncertain: All the animal
data to date would suggest that it is highly unlikely to be the result
of vector-bearing germ cells.)
- Arruda, et al. (2001). Lack of germline transmission of vector sequences
following systemic administration of recombinant AAV-2 vector in males.
- Mol. Ther. 4: 586-592. Peters, et al. (2001). Absence of germline
infection in male mice following intraventricular injection of adenovirus.
Mol. Ther. 4: 603-613.
Introduction of a missing gene may provide a critical missing protein,
but may also set off an immune response to a "new" protein,
thus defeating the therapeutic purpose of gene therapy. This is a particular
concern in such diseases as muscular dystrophy, where the immune system
is already on "high alert," marked by a large number of infiltrating
macrophages in necrotic muscle. Although it is possible to suppress the
immune system, this is not optimal for many reasons.
Jeffrey Chamberlain of the University of Washington and his collaborators
present data that support the hypothesis that targeted delivery of transgenes
expressed in a tissue-specific manner (muscle, in this case) can evade
the immune response, even in dystrophic muscle. Using an adenovirus vector
containing a muscle-specific promoter and a reporter gene, the researchers
demonstrate that they could obtain high levels of protein expression with
minimal immune response in mdx (muscular dystrophy) mice.
Thus, a combination of targeted vector and tissue specific gene control
may overcome the immune response problems seen in other studies, and provide
a robust gene therapy approach to muscular dystrophy as well as other
tissue-directed interventions.
- Hartigan-O'Connor, et al. (2001). "Immune evasion by muscle-specific
gene expression in dystrophic muscle." Mol. Ther. 4: 525-533.
The availability of the human genome sequence has allowed scientists
to identify, among many other riches, the molecular causes of many inner
ear diseases that cannot be treated by current therapies. However, there
are few animal models of these human diseases to test gene therapies.
Mice are particularly attractive for the development of such models, given
their genetics and history of laboratory use. Unfortunately, the mouse
inner ear is very small, complicating surgical approaches used to perform
gene transfer. However, in this issue of Molecular Therapy, Yehoash
Raphael of the University of Michigan and a group of international researchers
provide both a methodological approach and a proof of concept that demonstrates
that gene transfer to the vestibular system and cochlea is possible without
compromising hearing. Although still a technically difficult feat, the
researchers' ability to successfully transfer adenovirus-mediated reporter
genes to the mouse inner ear via either cochleostomy (which disturbs cochlear
function but gets the gene into the sensory epithelium of the cochlea)
or canalostomy (which preserves cochlear function and efficiently targets
the inner ear) should spur more research into gene therapy treatments
for the growing number of known inner ear disorders.
- Kawamoto, et al. (2001). 'The functional and structural outcome of
inner ear gene transfer via the vestibular and cochlear fluids in mice."
Mol. Ther. 4: 575-585.
Editor-in-Chief Inder Verma argues for a more concerted and coherent response
to the threat of bioterrorism.
Betsy Nabel (NIH) reflects on the recent loss of Jeff Isner and outlines
his legacy to gene therapy.
Phillip Factor of Northwestern University reviews the use of gene therapy
for treating acute disease, an application of the technology which was
not originally envisioned, but which has gained growing interest.
EMBARGO POLICY:
Molecular Therapy considers the embargo lifted upon editorial
acceptance of a manuscript (i.e., the decision of the editor to accept
a manuscript following successful peer review and revision). We make every
effort to have manuscripts published electronically before print. Manuscripts
still under review should not be reported as being published in Molecular
Therapy.
Fintan R. Steele, Ph.D.
Editor, Molecular Therapy
Executive Editor, Genomics
Academic Press
15 E. 26th St. 15th Floor
New York, NY 10010
212-592-1023 phone
646-935-3742 fax
fsteele@acad.com
http://authors.elsevier.com/JournalDetail.html?PubID=622922&Precis=DESC
http://www.academicpress.com/genomics
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