Gene therapy finally gets its day!

DNA vaccine and Gene therapy techniques are si...

DNA vaccine and Gene therapy techniques are similar. (Photo credit: Wikipedia)

It is finally real.  One very specific form of gene therapy has been approved by the European drug authorities.  Actually, China has allowed some forms of gene therapy since 2003, but regulatory authority in Chinese Healthcare is not as rigorous as other countries.

What exactly constitutes gene therapy.  It is a form of treatment for any disease in which a defective gene is replaced by a functional gene through a very a specific protocol.  Simply injecting genes or using gold particle coated with gene(s) (units of DNA which code for a protein) is not enough.  Genes must be delivered into cells through certain vehicles before they can work properly.  Viruses make excellent carriers of genes because of their unique properties of 1) infecting cells and 2) getting gene products to be converted into protein products in an efficient manner.

The US and other countries with active medical research capabilities have been certainly keen to adopt gene therapy in the past.  However, as of date, there are currently NO gene therapy approved protocols/nor products in the US.  Why?  In 2000-2001 the entire human genome was sequenced and we technically at least know all the genes that humans have.  So, the issue of the gene itself is solved (theoretically).  The problem is in the delivery.  How do we get cells (and the right cells in fact) to take up the genes and most importantly convert the gene into a useful product?

That is where viruses come in.  The most useful and somewhat safe viral system developed so far is something called the adenovirus.  This virus will infect human cells and allow the inserted gene to be converted into useful protein product.  Also importantly, the virus itself does not insert the gene into the human genome.  In this way the new gene does not disrupt the existing genes or DNA material that is inside the cell.

Sounds good.  So what the problem?  Well all viruses are pathogens.  That means that part of the definition of a virus is that it infects human and has the potential to cause an infection.  Secondly, even if it has been modified extensively, it is still a virus and thus a foreign entity or organism.  One fundamental tenant of the human immune system is that foreign proteins or entities are immunoreactive.  Thus, the human immune system can mount an aggressive  response.  That response is normal, but can actually kill the patient if strong enough.  In fact, that is exactly what happened in a very well publicized gene therapy trial for a teenage boy with a very rare disease (ornithine transcarbamylase deficiency) in 1999, who was killed after mounting a huge immune response against the viral carrier of the gene being replaced.  There have been a number of other accidents and failures to various gene therapy trials and the US regulatory authorities have been extremely cautious to grant approval of any new forms of gene therapy.

There are over 2000 different types of diseases which are potentially treatable with gene therapy.   Generally any deficiency in which a single gene is responsible can be treated with gene therapy.  All one technically has to do is make sure that the cell type which carries and produced the defective gene (like the gene responsible for the disease cystic fibrosis) and use gene therapy with a corrected version of the gene that is targeted to that cell using some kind of modified virus.  The gene needs to be produced over a long time in order to be effective as a treatment.  In the case of this newly approved gene therapy by the company called uniQure Glybera allows for the expression of the new gene that codes for a lipid processing enzyme that is deficient in the patient receiving the treatment.  The gene is introduced into the muscle tissue with an adenoviral associated virus (AAV).  As the virus does not insert the gene into the human genome itself the gene only lasts in the nucleus of the cells for as long as 12 weeks and seems to minimize the diseases for almost two years.  This new therapy relied on a AAV that has been modified to be non-pathogenic, thus not causing disease.  So, the parts of the virus that causes disease has been removed, the the parts that allows the virus to act like the virus has been kept (e.g. the viral coat proteins).  Only one case of fever (often a result of immune reaction) has been reported so far, thus this new viral vector may indeed hide itself from recognition by the immune system.

So, finally gene therapy gets its share of the limelight.  Generally, it takes one successful trial of a certain drug class (in this case gene therapy using AAV) to get other agencies to approve that therapy or to get the same agency to approve of use of that therapy in different disease.  In clinical trials at the moment is this type of gene therapy for Parkinson’s disease and others.  So, who knows this approval for this one disease may point the way to more approval for other countries and other diseases where single gene replacement is curative.

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Dr. C

The new human genome!

A slight mutation in the matched nucleotides c...

A slight mutation in the matched nucleotides can lead to chromosomal aberrations and unintentional genetic rearrangement. (Photo credit: Wikipedia)

So this week, in over 30 different journals, a detailed study was reported on the nature of the over 3 billion nucleotides (the fundamental building blocks of genes and thus of DNA) that make up the human genome.  In the turn of this century, the human genome was completely sequenced (identified at the nucleotide level).  At that time it was thought that only 1.5% of those 3 billion plus nucleotides were functional and directly coded for proteins.  Much of the remaining 98.5% of the human DNA material in all of our chromosomes where thought to be junk DNA, thus serving little to no function.

However, this has been challenged greatly by new studies published this week suggested that as much as 80% of all the DNA in our cells are functional.  They define functional as the following: nucleotides that do not code for proteins but that does for RNA that is not translated in proteins (but can be regulatory in nature), nucleotides that themselves bind proteins, or nucleotides that affect the shape of the DNA in one way or another.  Thus is a far cry from the thought that most of the genome in our bodies is junk.

What does this mean in the real world and will it revolutionize medicine and science. It certainly means that labs all around the world working on their favorite gene or gene location will pay a lot more attention to sequences outside of the traditional gene unit (usually includes, enhancer, promoters and the introns and exons of the genes themselves).  More and more data will probably come out from labs on novel regulatory mechanisms from far away gene sequences and so on.  However, clinically t is doubtful that this new finding will bear any direct relevance to treatment and disease.  Just as the impact of the human genome was rather weak after the initial wave of euphoria, this too will pass.

Human genome

Human genome (Photo credit: Wikipedia)