Five Steps for Gene Therapy to Work and Five Reasons for Problems
- From: J <nswex@nalid;no>
- Date: Tue, 19 Feb 2008 04:32:15 -0500
http://www.cancermonthly.com/blog/2007/12/cancer-gene.html
Five Steps for Gene Therapy to Work and Five Reasons for Problems
After a virus (i.e. viral vector) has been genetically engineered to carry
the normal human gene there are five basic steps for this therapy to
potentially work : 1) Target cells such as the patient?s liver or lung
cells must be infected with the viral vector; 2) The viral vector must
unload its payload of genetic material containing the ?normal? human gene
into the target cells; 3) The gene must make its way into the cells and
nuclei; 4) The infected cells must become normal and produce functional
(i.e. normal) protein product; 5) the functional protein should stop or
slow the disease process.
Current gene therapy has not proven very successful in clinical trials for
a number of reasons. First, it can be difficult to ensure that steps one
through five above work consistently and reliably. In addition, there are
other inherent problems:
* First, to be a permanent cure for a disease, the genes introduced by
gene therapy must be long-lived and stable. Often, they are not.
* Second, the immune system is designed to attack invaders like
viruses regardless of whether they carry helpful genes.
* Third, viral vectors can create toxicity and immune and inflammatory
responses. (You may recall the avoidable death of 18-year-old Jesse
Gelsinger who participated in a gene therapy trial for ornithine
transcarboxylase deficiency (OTCD). He died from multiple organ failures
four days after starting the treatment. His death is believed to have been
triggered by a severe immune response to the adenovirus carrier virus.)
* Fourth, once inside the patient, the viral vector could potentially
revert to its previous ?wild type? form and cause disease.
* And lastly, many diseases, especially cancers, have a number of gene
mutations. Multigene disorders are especially difficult to treat
effectively using gene therapy because all these challenges would be
multiplied by the number of genes targeted.
Mutation May Not Equal Cancer
But there may be a more universal reason why gene therapy will not cure a
disease like cancer. Many of these so-called mutations found in cancer
cells can also be found in healthy cells and it is becoming less clear
whether DNA mutations are actually the sole cause of disease. Research
over the past few years suggests that it is not.
The cause of diseases like cancer may actually be due in whole or in part
to epigenetic modifications which are potentially reversible changes in
gene function that occur without a change in DNA sequence (genotype).
According to researchers at Johns Hopkins, ?It is increasingly apparent
that cancer development not only depends on genetic alterations but on an
abnormal cellular memory, or epigenetic changes, which convey heritable
gene expression patterns critical for neoplastic initiation and
progression.?(1) Researchers from McGill University concur, ?Cancer growth
and metastasis require the coordinate change in gene expression of
different sets of genes. While genetic alterations can account for some of
these changes, many of the changes in gene expression observed in cancer
are caused by epigenetic modifications.?(2)
In other words, epigenetic changes which are outside the genetic code and
are due to how the gene is expressed, not the hard-wiring of the genetic
sequence or code itself, are being identified with carcinogenesis.
1. Ting AH, et al., The cancer epigenome?components and functional
correlates. Genes Dev. 2006 Dec 1;20(23):3215-31
2. Szyf M., Targeting DNA methylation in cancer. Bull Cancer. 2006 Sep
1;93(9):961-72
.
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