A highly Stable and Nonintegrated Human Artificial Chromosome (HAC) Containing the 2.4 Mb Entire Human Dystrophin Gene.

I figured I post this since it is some useful news wrt curing Duchenne in the future with gene therapy...


Hoshiya H, Kazuki Y, Abe S, Takiguchi M, Kajitani N, Watanabe Y, Yoshino T, Shirayoshi Y, Higaki K, Messina G, Cossu G, Oshimura M.
1Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Japan.

Episomal vector with the capacity to deliver a large gene containing all the critical regulatory elements is ideal for gene therapy. Human artificial chromosomes (HACs) have the capacity to deliver an extremely large genetic region to host cells without integration into the host genome, thus preventing possible insertional mutagenesis and genomic instability. Duchenne muscular dystrophy (DMD) is caused by mutation in the extremely large dystrophin gene (2.4 Mb). We herein report the development of a HAC vector containing the entire human dystrophin gene (DYS-HAC) that is stably maintained in mice and human immortalized mesenchymal stem cells (hiMSCs). The DYS-HAC was transferred to mouse embryonic stem (ES) cells, and isoforms of the DYS-HAC-derived human dystrophin in the chimeric mice generated from the ES cells were correctly expressed in tissue-specific manner. Thus, this HAC vector containing the entire dystrophin gene with its native regulatory elements is expected to be extremely useful for future gene and cell therapies of DMD.Molecular Therapy (2008); doi:10.1038/mt.2008.253.

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Before I get too excited, please translate in basic language for me!!!! Thanks!!!
In the absence of a reply from Franco, let me jump in. Some scientists in Japan figured out how to cause a mouse cell to make a correct human dystrophin protein. This is certainly progress, and it's a way to solve a problem for an ultimate cure. Before it becomes a cure, they'll need to do it in human cells. They will then need to figure out how to get those human cells into the bodies of your son or mine without triggering an immune response, and then they will have to figure out how to get those cells to migrate into muscle tissue and start reproducing. They will also need to figure out how to get our boys' existing cells which make the bad dystrophin, as well as the scar tissue and other junk that builds up as our boys' muscles die out of the way, out of the way. I believe that really smart men and women are working on each of these problems this very minute; they need more money and we need more time. Hopefully the at least some of the first generation drugs like exon skipping and PTC 124 for those who will benefit, as well as utrophin upregulation and more systemic drugs like idebenonne and losartan will prove to be good enough to buy us that time.
Thanks Paul,

Just some more info on the subject...

Yes this is good news because it gives us yet another vector to deliver such a large gene, but this one could deliver the whole gene and not pieces that pose other challenges because of the different isoforms that the DMD gene encodes. From my understanding of this technology they are using it with stem cells as the delivery mechanism so depending on the stem cells (i.e. if they are obtained directly from the individual) the immune response can be avoided. They have used the HACs in Dr. Cossu's mesangioblasts so they are looking at restoring muscle and fixing the problem, call it muscle transplants, if you will, with cured muscle tissue. Obviously this is future stuff but considering they are having success in mice models with such an elaborate and ingenious scheme is quite impressive. Gives me great hope with such great thinkers at the battle front.
This is actually a pretty sweet approach for a couple of reasons. The goal of this is not just making the protien or the DMD gene, but inserting a new chromosome. This avoids the problems/risks associated with gene therapy that are related to the therapy gene "inserting" itself into the current genetic code and causing problems (for lack of a better description). Also, single genes don't replicate during cell division, but chromosomes do (took them a while to figure out how to get HAC to do this). Another benefit is that with the full chromosome you can get all of the smaller isoforms of dystrophin as well. As previously indicated there are issues related to stem cells that need to be resolved (immune reaction, getting them to go where we want and turn into what we want). The technology is not there yet, and as you can see the process to make the HAC can't be done on a large scale at this time.
I'm sure there will be many challenges and a considerable amount of time before something like this is viable, but IMO this is exactly the kind of thing that could truly be described as a potential "cure". That being said, I'm not a geneticist so this is only my lay opinion.

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