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Sleeping Beauty Transposon

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Sharmin:
Andy, over the years I have read about chimeroplasty and the 'Sleeping Beauty Transposon' as potential cures for hemophilia, sickle cell anemia and thalassemia.  If successful this would be less complicated that gene therapy using a vector - as (from my understanding) this method would initiate a correction process in the body itself without introducing genes via a vector.  This would eliminate the use of viruses or other potentially harmful vectors as well as the need for chemotherapy in the therapy process. 
Can you shed some more light on this Andy? 

Thank you and Happy New Year,

Sharmin

Manal:
Hello Sharmin,

Could you please explain what these terms stand for????????????????????????

Happy new year to all of you

Manal

Sharmin:
Hi Manal,
Happy New Year to you!   From my understanding this form of gene therapy would be most effective and probably safest as it does not introduce foreign genetic material into the host (does not insert a beta gene for thals).  It uses a different method in which - (I believe) - it initiates process by 'sticking to the incorrect base pairs' - allowing the body to identify and correct the gene using it's own resources.   Therefore the body is able to correct the 'genetic mistake' that it has overlooked for generations.   Again I am not certain that this is exactly how the process works - I hope that Andy is able to help us out with this. 

Over the years I have always hoped that this is the form of gene therapy that will work = and soon cure our friends and family. 

Once again,
Happy New Year everyone,
Sharmin

Manal:
Thanks Sharmin a lot, this method seems really more comfortable and secure, but it is very strange that we never heard or read about it before. Anyway, I will be searching to understand more about it

Hope this would work one day,

Manal

Andy Battaglia:
Hi Sharmin,

Although early on, researchers were hopeful that this research into gene repair would quickly bear fruit, it has been very slow going. The hopes are that gene repair could cure many diseases and disorders, but with every step forward new problems have arisen. Sleeping Beauty Transposon holds much promise and it is believed it is only a matter of time before success will be seen.

The main problems associated with gene therapy are controlling the process so it works only where wanted and also developing these processes so their effects are long-lasting. A major problem has been the same problem found in previous gene therapy trials. How to control the process so it does not get out of control, leading to various cancers.

From http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1584267


--- Quote ---An alternative vector system is to use transposons as a nonviral delivery method. Transposon-based delivery systems have been shown to work in a wide variety of cell types, including stem cells [30]. In their current formulations, however, the integration events remain uncontrolled and thus may suffer the same problems of integration-based viral delivery systems. In fact, transposon-based insertions are being developed as a tool for cancer gene discovery [31]. An active but still preliminary area of research is to try to create hybrid transposases to target transposon integration to defined regions of the genome.
--- End quote ---

An extensive review of thse methods can be found at http://stemcells.alphamedpress.org/cgi/content/full/20/2/105   What can be expected?


--- Quote ---Although a number of potential obstacles remain to be addressed, e.g., transposition efficiency, epigenetic effects of transposition, and efficient delivery of transposon vectors to the nuclei of cells, the use of transposons in gene therapy appears to be inevitable. In fact, its application to stem cell biology may be significant.
--- End quote ---

Some of the risks are discussed by Dr Michael Sadelain (one of the leading researchers in the world on gene therapy and one of the main driving forces behind the upcoming gene therapy trials for thalassemia) at
http://www.nature.com/gt/journal/v11/n7/full/3302243a.html


--- Quote ---Insertional mutagenesis is an unavoidable consequence of the transposition of genetic material. Whether it involves an integrating virus, a transposable element, a replication-defective viral vector or plasmid DNA, the ectopic chromosomal integration of DNA is a mutagenic event that may disrupt chromatin or gene structure, thereby altering gene transcription, regulation and/or coding sequences. The gravest concern associated with such mutations is the risk of cell transformation...Simply put, the central question is what is the probability for any given gene therapy strategy to cause secondary malignancy?...The crucial questions are how to control the gene delivery rate effectively, so as to integrate only 1–2 vector copies per cell, and how to reduce the probability of trans-activating oncogenes, especially in stem and progenitor cells. Altogether, there are several improvements in vector design that can be developed to pre-empt gene therapy-related secondary malignancies. The challenge is to convince the medical community and the public that these auspicious safeguards work.
--- End quote ---

This article was published in 2004 and since then some convincing has taken place. Approval to commence gene therapy trials was given in 2007 and the trials will hopefully begin by June, 2008. The slow process of refining and perfecting gene repair therapies will continue, but for now it is gene therapy that is moving ahead.

I would like to add a note about Dr Sadelain. We spoke to him at the Dubai TIF conference in January, 2006 and Dr Sadelain has great confidence that the vector they have developed using the HIV virus will be both safe and effective. I realize that the sound of using the HIV virus is scary, but the virus is emptied of HIV and replaced with a working hemoglobin gene. A simple comparison is taking the passengers out of one vehicle and replacing them with new passengers. The vehicle is the same but its contents are now 100% different. I think what impressed me the most about Dr Sadelain was his confidence that his work has progressed to the point where it will successfully cure thalassemia. It may not be the only long run cure, but for now, it holds more hope than most research.

I agree that gene repair may be a better solution in the long term but until more progress is made in controlling the process, this will remain a subject of theory and further research. If you can wade through these highly technical reviews, you will see that the promise is there but that we still have a long way to go before the gene repair process is perfected.

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