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Gene therapy, though in its infancy, is set to revolutionise
the treatment of disease over the next few decades. There
are many vector systems available for use and each has its
own particular properties. The choice of which vector to
use could therefore be a critical factor in achieving a
successful outcome.
In this third article in the series on gene therapy, editors
from R&Dfocus
have compiled a who's who of viral vectors in development,
their properties, and the companies involved and linked
them to potential applications in disease areas.
|
Vector
systems and their properties
|
|
Vector
|
Properties
|
Companies
involved
|
| Adenovirus |
-
Episomal
- High transduction efficiency
- Infects replicating and non-replicating cells
- Elicits an immune response
- Insert capacity 8-36kb |
Aventis,
Canji (Schering-Plough), GenVec,Genzyme, Incyte, Onyx,
Transgene |
| Adeno-associated
virus |
-
Integrates genome into specific region on human chromosome
19
- Low immunogenicity
- No associated disease w Infects both dividing and
non-dividing cells
- Limited insert capacity of ~5kb |
Avigen,
Cell Genesys, Targeted Genetics |
| Herpesvirus |
-
Large insert capacity
- Broad host range
- Infects dividing and non-dividing cells |
BioVex,
Cantab, NeuroVir |
| Liposomes/Naked
DNA |
-
No limit to the size of genes that can be delivered
- Low immunogenicity
- Poor levels of gene transfer |
ALZA,
The Liposome Company, Valentis, Vical |
| Retrovirus |
-
Non-pathogenic in humans
- Stably transduces dividing but not non-dividing cells
- Inserts genome into host cell's DNA
- Long term expression
- Insert capacity of 8kb
- Inactivated by human Complement |
Cell
Genesys, Oxford Biomedica |
Source:
R&Dfocus
The
Adenovirus:
One of
the most widely used and studied gene therapy vectors, the
adenovirus vector is currently the vector of choice for
many researchers, and is being used in three Phase III cancer
trials. However, following the recent
death in a different trial using an adenovirus vector,
questions have been raised about the safety of using these
vectors due to their immunogenicity.
In cancer trials, an immune response directed against the
tumour could be advantageous, but for long-term gene expression
in hereditary disorders this becomes significant.
The development of 'gutless' adenoviral vectors may remove
the immunogenicity issue. However, the downside is that
the genome is expressed episomally, leading to dilution
of the gene in a dividing cell population.
Where long-term expression is required, stable integration
of the therapeutic gene into the host cell DNA is essential
so that the information can be passed down to daughter cells.
Relevant vector systems being investigated include retroviruses,
adeno-associated viruses and herpesviruses.
Adeno-associated virus:
Adeno-associated virus (AAV) vectors are under evaluation
for several indications, and data from preclinical studies
looks promising, with gene expression continuing for over
two years in a study by Avigen. Phase I/II trials are being
conducted with Avigen in haemophilia B patients,
and with Targeted Genetics in cystic fibrosis patients.
Phase I trials are also being conducted with Collateral
Therapeutics for the treatment of congestive heart failure.
The main downfall of these vectors is their low insert capacity;
however, recent studies have indicated the possibilities
of splitting the expression cassette into two separate vectors
to double the insert capacity of the system.
Herpes Simplex virus:
Initial toxicity problems associated with the herpes virus
(HSV) vectors have been overcome and these vectors are being
developed for many indications. For the treatment of cancer,
BioVex and NeuroVir are developing HSV vectors that can
selectively replicate in cancer cells.
BioVex is also developing HSV vectors to express neurotrophic
factors for Parkinson's disease or antigens to induce
an immune response against cancer or chronic infectious
diseases such as hepatitis and HIV.
Cantab is using its proprietary disabled infectious single
cycle (DISC) HSV technology in Phase II trials for the delivery
of antigens for genital herpes, and is also considering
using the technology for the delivery of genes for the treatment
of cancer.
Retroviruses:
Oxford Biomedica is conducting Phase I/II trials with macrophages
transduced ex vivo with a retrovirus expressing genes, such
as cytochrome P450, under the control of hypoxia response
elements as a potential therapy for solid tumors.
Cell Genesys is also using retroviral vectors to transduce
T cells for treatment of HIV-infection and clinical trials
are being conducted in Europe and the USA. Retroviruses
from INSERM have successfully been used to deliver the gamma-c
gene for the treatment of severe combined immunodeficiency-X1
(SCID) in infants in France.
The main limitation of the original retroviral vectors is
the inability to infect non-dividing cells, such as neurones.
Vectors are, therefore, being developed from the lentivirus
genus of retrovirus, which can infect non-dividing cell
populations. At present, no clinical trials have been initiated
using these vectors; however, preclinical evaluation for
a variety of disorders such as Parkinson's disease and haemophilia
is ongoing.
Concerns have been raised regarding the development of lentiviral
vectors based on HIV, such as those in development with
Cell Genesys, but these have no scientific basis at present.
Oxford Biomedica is the other force behind the development
of lentivirus vectors, using the equine infectious anaemia
virus strain.
A glimpse in the crystal ball:
Naked DNA, TRANSPORTAN, and liposomes may all play their
part in the future development of gene therapy. Additionally,
lentiviral vectors could be the most exciting recent development
- but they still have to be clinically tested. New vectors
are being developed all the time, for example, baculovirus
vectors have recently been used for mammalian gene transfer
by Eurogene.
Vector choice depends on the properties required to treat
the target disease,
as there is no 'universal' vector system that meets the
requirements for all indications.
The rapid advancements being made in current vector design
acknowledge the fact that some or even all of the above
vectors may fall by the wayside as the search for the 'universal'
vector system, the gene therapy holy grail, continues.
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