01. Gene therapy Boulikas.pdf - Gene therapy & Molecular Biology

This field is in its infancy; however, animal studies
showed that treatment of obese persons is one of the future
prospects of gene therapy. Adenovirus-mediated transfer
of the mouse leptin cDNA in the ob/ob mouse (which is
genetically deficient in leptin and exhibits both an obese
and a mild non-insulin-dependent diabetic phenotype)
resulted in dramatic reductions in both food intake and
body weight, as well as the normalization of serum insulin
levels and glucose tolerance (Muzzin et al, 1996). Thus,
transfer of the leptin gene can correct the obese and
diabetic phenotypes in the adult ob/ob mice; these studies
also provided confirming evidence that the control in body
weight may be critical in the long-term management of
non-insulin-dependent diabetes mellitus in obese patients.
Infusion of a recombinant adenovirus containing the
rat leptin cDNA under control of the CMV promoter to
Wistar rats (8 ng/ml for 28 days) made them
hyperleptinemic; these animals exhibited a 30-50%
reduction in food intake and gained only 22 g over the
experimental period versus 115-132 gained by control
animals. Body fat was absent and plasma triglycerides and
insulin levels were significantly lower in hyperleptinemic
compared to control rats (Chen et al, 1996).
On the contrary, delivery of the rat neuropeptide Y
(NPY) cDNA with AAV and Sendai virosomes into the rat
hypothalamic para-ventricular nucleus increased body
weight and food intake for 21 days (Wu et al, 1996).
XLII. Profile of Biotech companies: the
big race
Boulikas: An overview on gene therapy
126
Research and drug development in Biotech Industry
have played and continue to play an important role in
advancing molecular medicine. A number of
Biotechnology Companies sponsor ongoing gene therapy
Clinical Trials led by Genetic Therapy Incorporated (part
of Novartis, Gaithersburg, MD) with the phase III trial in
glioblastoma.
Biotech Companies have the expertise and resources in
large scale production, regulatory affairs, and clinical
development to take off the basic science of gene therapy
into the skies of commercialization and clinical trials. This
is more evident in USA where strong bridges between the
academia and industry have been established and
numerous biotechnology companies dedicated to gene
therapy have been founded. As of 1997 Europe lags some
3 to 5 years behind USA in translating basic science into
commercial technology; however, European
Pharmaceutical Companies have invested $1.4 billion in
the American gene and cell therapy industry (compared
with a modest $140 million investment from USA biotech
firms to European partners). It is certain that both USA
and Europe will ultimately benefit from the successful
gene therapy development (Martin, 1997).
Table 8 gives a glimpse of the role of Biotech Industry
in drug discovery related to gene therapy and the clinical
trials sponsored.
Table 8. Biotech companies and drug development related to genes or cancer targeting
Company Drug/Gene type Goal/Disease Status of drug development
(end of 1997)
Calydon (San Francisco, CA) Prostate cancer gene therapy Preclinical trials
Canji/Schering-Plough (San
Diego, CA)
Canji/Schering-Plough (San
Diego, CA)
p53 to restore p53-mediated
tumor suppression or
apoptosis
RB to restore RB-mediated cell
cycle arrest
Colon with hepatic
metastases(#131); prostate
(#148)
Bladder(#140), non-small cell
lung cancer (#156), lung,
ovarian, and liver cancers
Phase I
Early clinical trials
Cell Genesys, Inc CC49-Zeta T cell receptor Colorectal carcinomas
expressing the tumorassociated
antigen, TAG-72
(#110)
Phase I /II
Cell Genesys, Inc CD4-zeta Chimeric Receptor HIV (#85, 116) Phase I-II
Chiron Corporation (Emerville HIV-1IIIB envelope protein HIV Phase I
& San Diego CA)
(#108)
IDUN Pharmaceutical (San
Diego, CA)
bcl-2 inhibition Preclinical trials
Incyte Pharmaceuticals (Palo
Alto, CA)
Gene sequence databases License access to database for
drug discovery to different
companies