Hi, I’m Dr Dan McCulloch, a Lecturer in Medical Biology at Deakin University’s Medical School, Waurn Ponds, VIC Australia.

My research team focuses on finding out how child-hood diseases occur and what we can do to help give children affected by these diseases a better quality of life.

We’d like to go fishing for a cure for Duchenne muscular dystrophy but we need your help! Please view our video online and make a pledge at:  

www.pozible.com/fish4dmd.

There are also great rewards available! Thanks for your support.

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How is this different than the work that's been happening in the US for years?

Hi Keith,

Thanks for your interest and a great question.

We're targeting pathways that regulate inflammation and muscle regeneration in the extracellular matrix, which is the connective tissue surrounding the muscle cells. To date, almost all drug screens and drug discovery Projects for DMD target intracellular pathways, such as gene therapy, exon skipping and corticosteroids/glucocorticoids.

We have recently identified a novel enzyme-substrate axis in the extracellular matrix that, on one hand is required for muscle fibre formation (www.ncbi.nlm.nih.gov/pubmed/23233679) but, on the other hand exacerbates inflammation in a mouse model of DMD (unpublished data). The same enzyme (ADAMTS5) that regulates this process is also a major drug target for arthritis (http://www.ncbi.nlm.nih.gov/pubmed/15800625‎) and is regulated by inflammatory cytokines such as TNF-alpha and interlukin-6, all targeted therapies for rheumatoid arthritis in particular but also some forms of cancer. In addition, we also have evidence suggesting Statins inhibit the activation of this enzyme (unpublished data). No study to date has identified this enzyme (and its substrates) as a target for treating DMD, however there is evidence of its association with progression of the disease in a mouse DMD model (http://www.ncbi.nlm.nih.gov/pubmed/19223608) and in human DMD (http://www.ncbi.nlm.nih.gov/pubmed/11121445). Since we know it is a key player in both muscle biology and DMD pathology, and there are existing therapies that regulate its expression in other disease contexts, we believe we can use those existing therapies for a novel indication of their use in DMD.

Zebrafish carrying the DMD mutation are an ideal model for this approach because they are cheaper than rodents, grow more rapidly and are easier to manipulate. My team also work on rodent models of DMD and have gained valuable information from them to inform us of this current line of investigation.

I'm more than happy to discuss it with you in more depth! Please email me at daniel.mcculloch@deakin.edu.au for further correspondence.

Best wishes,
Dan

Hi Keith,

Further to my previous reply, if you're interested to support our Project but would like independent validation, my colleague Dr Nicole Stupka recently visited Prof. Eric Hoffman, a world leader in DMD research in the USA, to discuss our recent discoveries and ideas about regulating this enzyme-substrate axis in DMD as a potential therapeutic target. Prof. Hoffman's profile and contact details can be found at: http://www.childrensnational.org/research/faculty/bios/cgmr/Hoffman

Best wishes,

Dan

Daniel McCulloch said:

Hi Keith,

Thanks for your interest and a great question.

We're targeting pathways that regulate inflammation and muscle regeneration in the extracellular matrix, which is the connective tissue surrounding the muscle cells. To date, almost all drug screens and drug discovery Projects for DMD target intracellular pathways, such as gene therapy, exon skipping and corticosteroids/glucocorticoids.

We have recently identified a novel enzyme-substrate axis in the extracellular matrix that, on one hand is required for muscle fibre formation (www.ncbi.nlm.nih.gov/pubmed/23233679) but, on the other hand exacerbates inflammation in a mouse model of DMD (unpublished data). The same enzyme (ADAMTS5) that regulates this process is also a major drug target for arthritis (http://www.ncbi.nlm.nih.gov/pubmed/15800625‎) and is regulated by inflammatory cytokines such as TNF-alpha and interlukin-6, all targeted therapies for rheumatoid arthritis in particular but also some forms of cancer. In addition, we also have evidence suggesting Statins inhibit the activation of this enzyme (unpublished data). No study to date has identified this enzyme (and its substrates) as a target for treating DMD, however there is evidence of its association with progression of the disease in a mouse DMD model (http://www.ncbi.nlm.nih.gov/pubmed/19223608) and in human DMD (http://www.ncbi.nlm.nih.gov/pubmed/11121445). Since we know it is a key player in both muscle biology and DMD pathology, and there are existing therapies that regulate its expression in other disease contexts, we believe we can use those existing therapies for a novel indication of their use in DMD.

Zebrafish carrying the DMD mutation are an ideal model for this approach because they are cheaper than rodents, grow more rapidly and are easier to manipulate. My team also work on rodent models of DMD and have gained valuable information from them to inform us of this current line of investigation.

I'm more than happy to discuss it with you in more depth! Please email me at daniel.mcculloch@deakin.edu.au for further correspondence.

Best wishes,
Dan

I'll email you.

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