26 research outputs found
Lentiviral-Mediated Gene Therapy Results in Sustained Expression of β-Glucuronidase for up to 12 Months in the Gus mps/mps
Gene therapy for Parkinson's disease: recent achievements and remaining challenges
Gene therapy is the use of nucleic acids as
drugs. Thus, ways had to be developed to deliver this
new generation of drugs to target tissues. Various viral
and non-viral vectors have been engineered to carry
potentially therapeutic nucleic acids into diseased organs
or target cells. The brain offers a particular challenge for
gene delivery to its constituent cells: it is encased by the
skull, separated from the general circulation by the blood
brain barrier, and made up of mostly non-dividing cells.
The skull limits direct injection of vectors into the brain,
the blood brain barrier inhibits the easy entry of vectors
injected into the bloodstream, and post mitotic target
cells restrict what type of vector can be used to deliver
genes to the brain. We will discuss the main challenges
faced by gene delivery to the brain, i.e. immune
responses to the delivery vectors and therapeutic
transgenes and length of duration of the therapy
specifically as applied to Parkinson's disease. We will
also discuss therapeutic strategies, which could be
implemented to treat Parkinson's disease, and the models
in which they have been tested
Gene therapy strategies for intracranial tumours, glioma and pituitary adenomas
Intracranial tumours such as brain gliomas
and pituitary adenomas pose a challenging area of
research for the development of gene therapy strategies,
both from the point of view of the severity of the
diseases, to the physiological implication of gene
delivery into the central nervous system and pituitary
gland. On the one hand, brain gliomas are very
malignant tumours, with a life expectancy of six months
to a year at the most after the time of diagnosis, in spite
of advances in treatment modalities which involve
chemotherapy, surgery and radiotherapy. Gene therapy
for these tumours is therefore a very attractive
therapeutic modality which due to the severity of the
disease is already in clinical trials. On the other hand,
pituitary tumours are usually benign, and in most cases,
treatment is successful. Nevertheless, there are some
instances, especially with the macroadenomas and some
invasive tumours in which treatment fails. Gene therapy
strategies for these adenomas therefore needs to progress
substantially in terms of safety, adverse side effects and
physiological impact on the normal pituitary gland
before clinical implementation.
In this paper, we will review gene delivery systems
both viral and non-viral and several therapeutic
strategies which could be implemented for the treatment
of these diseases. These include cytotoxic approaches
both conditional and direct, immune-stimulatory
strategies, anti-angiogenic strategies and approaches
which harness pro-apoptotic and tumour suppressor gene
targets. We will also review the models which are
currently available in which these gene therapy
strategies can be tested experimentally.
This new therapeutic modality holds enormous
promise, but we still need substantial improvements both
from the delivery, efficacy and safety stand points before
it can become a clinical reality
The effects of benzodiazepines on basal and isoproterenol-stimulated N-acetyltransferase activity by the rat pineal gland, in vivo and in vitro
Antiglioma Immunological Memory in Response to Conditional Cytotoxic/Immune-Stimulatory Gene Therapy: Humoral and Cellular Immunity Lead to Tumor Regression
Purpose: Glioblastoma multiforme is a deadly primary brain cancer. Because the tumor kills due to recurrences, we tested the hypothesis that a new treatment would lead to immunological memory in a rat model of recurrent glioblastoma multiforme. Experimental Design: We developed a combined treatment using an adenovirus (Ad) expressing fms-like tyrosine kinase-3 ligand (Flt3L), which induces the infiltration of immune cells into the tumor microenvironment, and an Ad expressing herpes simplex virus-1-thymidine kinase (TK), which kills proliferating tumor cells in the presence of ganciclovir. Results: This treatment induced immunological memory that led to rejection of a second glioblastoma multiforme implanted in the contralateral hemisphere and of an extracranial glioblastoma multiforme implanted intradermally. Rechallenged long-term survivors exhibited anti-glioblastoma multiforme-specific T cells and displayed specific delayed-type hypersensitivity. Using depleting antibodies, we showed that rejection of the second tumor was dependent on CD8(+) T cells. Circulating anti-glioma antibodies were observed when glioblastoma multiforme cells were implanted intradermally in naive rats or in long-term survivors. However, rats bearing intracranial glioblastoma multiforme only exhibited circulating antitumoral antibodies upon treatment with Ad-Flt3L + Ad-TK. This combined treatment induced tumor regression and release of the chromatin-binding protein high mobility group box 1 in two further intracranial glioblastoma multiforme models, that is, Fisher rats bearing intracranial 9L and F98 glioblastoma multiforme cells. Conclusions: Treatment with Ad-Flt3L + Ad-TK triggered systemic anti-glioblastoma multiforme cellular and humoral immune responses, and anti-glioblastoma multiforme immunological memory. Release of the chromatin-binding protein high mobility group box 1 could be used as a noninvasive biomarker of therapeutic efficacy for glioblastoma multiforme. The robust treatment efficacy lends further support to its implementation in a phase I clinical trial. (Clin Cancer Res 2009;15(19):6113-27