Gene Therapy

[NightSwim]

Anyone know of any good articles on gene therapy? The concept of it fascinates me. It seems like the ultimate cure for chronic genetic disorders, similar to the way creating a vaccine for infectious diseases is ideal to stopping mortality and morbidity.

Any chance we see it in our lifetime?? The problem is finding a way to get the fixed genes into the DNA of cells with mutated genes. No one's been able to do this yet, right? If researchers found a way to do this, we would almost immediatly be able to cure single mutated gene diseases like Cystic Fibrosis, right?

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[vc7777]

http://content.nejm.org/cgi/content/short/361/25/2483

 

[vc7777]

http://www.wired.com/wiredscience/2009/09/colortherapy/

For those w/o NEJM access...

 

[NightSwim]

http://content.nejm.org/cgi/content/short/361/25/2483

Just read it. This review article is optimistic. It reviews a study where the investigators inject a recombinant virus into the cone photoreceptors of monkeys in order to restore the gene that causes color blindness to its normal form. It worked too, although they don't know the safety-profile of performing this injection. At the end of the review article, the author says that reprogramming diseased genes is very possible, at least in the situation of color blindness. Pretty amazing.

Anyone else want to chime in? Other articles?

 

[kami333]

Couple that I've recently read:

Expression of Dog Microdystrophin in Mouse and Dog Muscles by Gene Therapy
http://www.ncbi.nlm.nih.gov/pubmed/20179674

Vectors and delivery systems in gene therapy
http://www.ncbi.nlm.nih.gov/pubmed/15795707

Design and Packaging of Adeno-Associated Virus Gene Targeting Vectors
http://www.ncbi.nlm.nih.gov/pubmed/10775597

Tailoring the AAV vector capsid for gene therapy
http://www.ncbi.nlm.nih.gov/pubmed/19052631


It's fun stuff, looks very promising in the next ~10years.

 

[NightSwim]

Couple that I've recently read:

Expression of Dog Microdystrophin in Mouse and Dog Muscles by Gene Therapy
http://www.ncbi.nlm.nih.gov/pubmed/20179674

Vectors and delivery systems in gene therapy
http://www.ncbi.nlm.nih.gov/pubmed/15795707

Design and Packaging of Adeno-Associated Virus Gene Targeting Vectors
http://www.ncbi.nlm.nih.gov/pubmed/10775597

Tailoring the AAV vector capsid for gene therapy
http://www.ncbi.nlm.nih.gov/pubmed/19052631


It's fun stuff, looks very promising in the next ~10years.

NICE. This should keep me busy for a while.

 

[echolalia16]

I actually do clinical gene therapy research for treatment for prostate and pancreatic cancer. We're also working on brain cancer but I don't know if it will ever make it into the clinic.

http://www.ncbi.nlm.nih.gov/pubmed/17406342

Look up anything by Freytag SO in pubmed. Most of it is gene therapy related.

 

[gte770m]

There are so many articles on it that you can just google it and you are bound to come across several good review articles.

Personally, from what I have seen in my studies as a biomedical engineering major in grad school, I am not sure how viable it will be. It could be a workable option in limited cases with direct injections in high dose, but the delivery problem in general seems almost impossible to overcome. There are so many treatments that seem viable in small-scale lab experiments, but the systemic delivery problem seems to rule out almost all of them...(antisense oligonucleotides and siRNA being two prominent examples that are not delivering on their promises) Maybe I'm being too pessimistic...

 

[TooMuchResearch]

Do your own homework, OP

 

[tungsten87]

they've already used gene therapy to treat non X-linked SCID which is caused by a deficiency in adenosine deaminase, which causes through a few feedback loops causes deficiency in nucleotide biosynthesis. I believe they use retroviral vectors to deliver the ADA gene.

also, I had a molecular pharmacology class in undergrad and one of the papers we studied was by a man named Niu who was working on a STAT3 analog that would compete with the wt STAT3 for dimerization, thus inhibiting cellular proliferation in certain types of cancers that are dependent on cytokine signaling.

http://cancerres.aacrjournals.org/cgi/content/abstract/59/20/5059

 

[tungsten87]

There are so many articles on it that you can just google it and you are bound to come across several good review articles.

Personally, from what I have seen in my studies as a biomedical engineering major in grad school, I am not sure how viable it will be. It could be a workable option in limited cases with direct injections in high dose, but the delivery problem in general seems almost impossible to overcome. There are so many treatments that seem viable in small-scale lab experiments, but the systemic delivery problem seems to rule out almost all of them...(antisense oligonucleotides and siRNA being two prominent examples that are not delivering on their promises) Maybe I'm being too pessimistic...

this is where I think nanotech and synthetic RNA apatamers will come into play. targeted delivery with little to no chance of eliciting an immune response. we are currently able to use antibodies conjugated to liposomes/nanoparticles that are filled with certain small molecule drugs to target certain tissues/cancers but these synthetic antibodies often act as immunogens and thus are taken out by the immune system. but yes i agree, targeted delivery and avoiding the immune system are probably the two biggest challenges standing in the way of successful gene therapy.

 

[NightSwim]

Do your own homework, OP

Working on it. Obviously I knew I could do my own pubmed/google search. I was hoping people would recommend articles they liked on gene therapy, and I was also hoping to stimulate discussion. So far so good, but I haven't had time yet to read enough of these articles. I should have been more clear about my intentions.

 

[muhali3]

People have also died from gene therapy

http://en.wikipedia.org/wiki/Jesse_Gelsinger

It is hard to use a viral vector without triggering an immune response. Its also hard to control where the gene will insert itself, if it inserts in the wrong place, cancer will result.

 

[anfleisch]

In our lifetime? It already has been done. Those problems are disease-specific, and in most cases I believe the most difficult is delivery. If you are interested, I did a summer research fellowship at Penn that is run by Dr. Wilson (the lab with the young boy who died many years ago). The focus of the program is gene therapy and it is sponsored by CF foundation. Each Wednesday there is also a talk given tot he small group of under 10 students.

http://www.med.upenn.edu/gtp/education_summer.shtml

 

[anfleisch]

BTW, I thought SCID was caused by a mutation in the specific IL receptors that lead to differentiation and development of mature B and T cells (specifically IL-2)

 

[tungsten87]

BTW, I thought SCID was caused by a mutation in the specific IL receptors that lead to differentiation and development of mature B and T cells (specifically IL-2)

there are many different causes of SCID... see wikipedia. i think you're talking about mutations in the gamma subunit of the IL-2 receptor.

 

[echolalia16]

People have also died from gene therapy

http://en.wikipedia.org/wiki/Jesse_Gelsinger

It is hard to use a viral vector without triggering an immune response. Its also hard to control where the gene will insert itself, if it inserts in the wrong place, cancer will result.

Its funny you should mention this kid, because his death almost killed the projects that I'm working on today. While we should definitely use caution when administering viral vectors to patients, the reason why Gelsinger died was because the head scientist on the project broke a number of rules that were imposed by himself and the FDA (ie ignoring the inclusion criteria for patient acceptance into the trial, not reporting severe advese events previously observed in patients, as well as not reporting animal deaths in preclinical models). Gelsinger was not in the physical state to be accepted into the trial to begin with, and on the day of his treatment he had elevated serum ammonia, which can be fatal in itself. The PI went along with the procedure anyway, and consequentially, Gelsinger's immune system reacted adversely to the introduction of another virus and his body couldn't handle it. The private investigator has since been banned from taking part in any gene therapy research.

 

[muhali3]

Its funny you should mention this kid, because his death almost killed the projects that I'm working on today. While we should definitely use caution when administering viral vectors to patients, the reason why Gelsinger died was because the head scientist on the project broke a number of rules that were imposed by himself and the FDA (ie ignoring the inclusion criteria for patient acceptance into the trial, not reporting severe advese events previously observed in patients, as well as not reporting animal deaths in preclinical models). Gelsinger was not in the physical state to be accepted into the trial to begin with, and on the day of his treatment he had elevated serum ammonia, which can be fatal in itself. The PI went along with the procedure anyway, and consequentially, Gelsinger's immune system reacted adversely to the introduction of another virus and his body couldn't handle it. The private investigator has since been banned from taking part in any gene therapy research.

Regardless, immunogenicity and insertional mutagenesis are still major problems when using viral vectors for gene therapy. I admit that Gelsinger is not the best case to quote since his death could have been easily prevented, but there are still a lot of potential problems that need to be dealt with before gene therapy can become a viable treatment option.

 

[echolalia16]

Regardless, immunogenicity and insertional mutagenesis are still major problems when using viral vectors for gene therapy. I admit that Gelsinger is not the best case to quote since his death could have been easily prevented, but there are still a lot of potential problems that need to be dealt with before gene therapy can become a viable treatment option.

I agree, but half the fun of research is working around these types of problems