Therapeutic gene modulation
Encyclopedia
Therapeutic gene modulation refers the practice of altering the expression of a gene
at one of various stages, with a view to alleviate some form of ailment. It differs from gene therapy
in that gene modulation seeks to alter the expression of an endogenous gene (perhaps through the introduction of a gene encoding a novel modulatory protein) whereas gene therapy concerns the introduction of a gene whose product aids the recipient directly.
Modulation of gene expression can be mediated at the level of transcription
by artificial transcription factors or at the level of translation through RNA interference
.
is due to cells with misregulated genes, and correcting that regulation might cure the disease. For example, all cancerous cells must upregulate the enzyme telomerase
in order to become immortalized (which is the difference between benign and malignant tumours). Similarly, high cholesterol
levels could be treated by downregulating the genes involved with cholesterol biosynthesis
, while any viral infection could be mitigated by downregulating the cell surface receptor the virus uses to gain entry, so long as that receptor is not critical for the cell's survival (for example, HIV
and the receptor CXCR4
).
Of the two methods mentioned above for gene modulation, most clinical research seems to be in RNA interference (see RNA interference#Medicine). Current obstacles to this approach include its tendency to sometimes modulate other genes with sequence similarity to the target, and a difficulty in transporting exogenous RNA into cells.
There are currently no clinically approved therapies using RNAi-based therapeutics, although there are a number in clinical trials (for example, see http://www.silence-therapeutics.com/content/pipeline/overview.htm and http://clinicaltrials.gov/ct2/show/NCT00689065?term=calaa-01&rank=1).
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
at one of various stages, with a view to alleviate some form of ailment. It differs from gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
in that gene modulation seeks to alter the expression of an endogenous gene (perhaps through the introduction of a gene encoding a novel modulatory protein) whereas gene therapy concerns the introduction of a gene whose product aids the recipient directly.
Modulation of gene expression can be mediated at the level of transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
by artificial transcription factors or at the level of translation through RNA interference
RNA interference
RNA interference is a process within living cells that moderates the activity of their genes. Historically, it was known by other names, including co-suppression, post transcriptional gene silencing , and quelling. Only after these apparently unrelated processes were fully understood did it become...
.
Clinical significance
All cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
is due to cells with misregulated genes, and correcting that regulation might cure the disease. For example, all cancerous cells must upregulate the enzyme telomerase
Telomerase
Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...
in order to become immortalized (which is the difference between benign and malignant tumours). Similarly, high cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
levels could be treated by downregulating the genes involved with cholesterol biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
, while any viral infection could be mitigated by downregulating the cell surface receptor the virus uses to gain entry, so long as that receptor is not critical for the cell's survival (for example, HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
and the receptor CXCR4
CXCR4
C-X-C chemokine receptor type 4 also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene.- Function :...
).
Of the two methods mentioned above for gene modulation, most clinical research seems to be in RNA interference (see RNA interference#Medicine). Current obstacles to this approach include its tendency to sometimes modulate other genes with sequence similarity to the target, and a difficulty in transporting exogenous RNA into cells.
There are currently no clinically approved therapies using RNAi-based therapeutics, although there are a number in clinical trials (for example, see http://www.silence-therapeutics.com/content/pipeline/overview.htm and http://clinicaltrials.gov/ct2/show/NCT00689065?term=calaa-01&rank=1).
See also
- Artificial transcription factorArtificial transcription factorAn artificial transcription factor is an example of a chimeral protein, designed to target and modulate gene transcription.They are generally composed of a DNA-binding domain coupled to a modulatory domain in order to alter the expression of a particular gene...
- Antisense therapyAntisense therapyAntisense therapy is a form of treatment for genetic disorders or infections.When the genetic sequence of a particular gene is known to be causative of a particular disease, it is possible to synthesize a strand of nuc acid that will bind to the messenger RNA produced by that gene and inactivate...
- Gene therapyGene therapyGene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
- RNA interferenceRNA interferenceRNA interference is a process within living cells that moderates the activity of their genes. Historically, it was known by other names, including co-suppression, post transcriptional gene silencing , and quelling. Only after these apparently unrelated processes were fully understood did it become...