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Review: Exon Skipping as a Therapeutic Approach to Duchenne

Genetics as it applies to evolution, molecular biology, and medical aspects.

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Review: Exon Skipping as a Therapeutic Approach to Duchenne

Postby jonmoulton » Thu Oct 28, 2010 9:36 pm

The Status of Exon Skipping as a Therapeutic Approach to Duchenne Muscular Dystrophy

A nice new review of Morpholinos (PMO) and 2'-O-Me phosphorothioate exon-skipping oligos in animal models and clinical trials has been published in Molecular Therapy. This review also includes discussion of peptide-conjugated Morpholinos (PPMO) and Vi...vo-Morpholinos.

Lu QL, Yokota T, Takeda S, Garcia L, Muntoni F, Partridge T. The Status of Exon Skipping as a Therapeutic Approach to Duchenne Muscular Dystrophy. Mol Ther. 2010 Oct 26. [Epub ahead of print]
http://www.nature.com/mt/journal/vaop/ncurrent/abs/mt2010219a.html

They discuss multiple exon skipping, cardiac uptake, evenness of delivery, various animal models, various delivery enhancements including viral, arginine-rich peptide and octaguanidinium dendrimer. Clinical outcomes are compared.

The paper concludes with a discussion of the regulatory challenges posed by this sort of personalized genetic medicine, finishing with "Thus, imposition of the normal regulatory processes would constitute a major impediment to the application of exon-skipping therapy across the range of patients who might benefit from it. A positive exploration of these issues would act as a trailblazer to the benefit of the progress of personalized medicine in general."

I agree with their assessment of the challenge posed to regulators by this new kind of medicine. If the regulations for oligo-mediated exon-skipping drugs become more permissive as a result of the development of DMD-targeted oligo therapeutics, many more genetic diseases could be treated with exon-skipping oligo. However, the costs to pass the current regulatory barriers will prevent development of most personalized exon-skipping medications; there are just too few people with a given mutation to make the drug approval process financially possible.
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Postby Julie5 » Fri Oct 29, 2010 2:05 pm

3 possible (???) lines of attack -

(1) if there is some kind of underlying commonality in the therapeutic approach that would apply to several genetic diseases (even though the individual disease therapies would be a variation), could one at least get approval for the 'generic' therapy, as a first step, and the cost of getting approval would be shared out amongst a larger group of patients?

(2) get approval in a more 'lax' regime, ie, another country, and have patients treated there?

(3)avoid going for full FDA approval by keeping all patients on endless trials (that way they get the therapy, but with less cost and rigour of approval-qualifying)?? (I appreciate trials themselves can be costly!)

(4) campaign with other patient groups who would also benefit from this approach/generic approach, to get a 'FDA-lite' category of approval that takes into account the issue of a small patient population?

I agree it's a frustrating dilemma, especially when new technology is increasingly driving down the cost of novel therapies - to then be balked by the cost of getting approval to prescribe them!

You raise, I personally think, a very profound issue of what society does about 'rare diseases'. So often, it is basically left up to patients and their families to research, develop and deploy therapies, as it simply isn't 'worth it' for society as a whole to do so...

(Ironically, I personally believe the same is true for cancer - my own area of interest - society tolerates the mortality rates from cancer simply because, in the end, not enough people die from cancer to seriously adversely affect the overall population. Society can 'afford' to lose the half a million people a year (US deaths from cancer)......)

All the very best to you in your dilemma - Julie.
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