AVI-4658 Success for Duchenne Muscular Dystrophy

By darioringach on Aug 4, 2011
As originally reported by Speaking of Research:

Last Monday the Muscular Dystrophy Campaign announced the fact that antisense oligonucleotide medicine AVI-4658 had performed well in its 2nd clinical trial in 19 boys with Duchenne Muscular Dystrophy (DMD). DMD is one of the most common hereditary disorders affecting the skeletomuscular system, and which results in progressive muscle degeneration, problems in walking and breathing, and ultimately death. because DMD is actually a recessive condition linked to range of mutations in thedystrophin gene found for the X-chromosome, almost all its victims are boys. AVI-4658 is one of the first antisense oligomers – also known as morpholinos – to get evaluated in clinical trials, and may be the outcome of additional than a decade of research utilizing animal types of DMD.

While the mutations responsible for causing DMD are scattered via many regions of the DMD gene – a cluster of mutations in exons 45-52 of the dystrophin gene has become found to get responsible for about 13% of cases. Exons would be the portion of the gene which code for a protein, and a solitary gene can consist of many exons separated by stretches of DNA known as introns; the dystrophin gene has a total of 79 exons. The first step during the process of gene expression – getting from a gene to some protein – istranscription of the DNA sequence – both exons and introns – in to a pre-messenger RNA sequence. The pre-messenger RNA sequence is then spliced to eliminate the introns, and the resulting spliced messenger RNA is translated into an amino acid sequence, which then normally undergoes post-translational digesting to yield the mature protein. The mutations in exons 45-52 of the dystrophin gene outcome in either the translation of the dystrophin mRNA becoming terminated prematurely, or during the manufacturing of the defective dystrophin protein that is rapidly broken down, rather than undergoing digesting to yield a mature functional dystrophin protein. It is this absence of the functioning dystrophin protein that results during the signs and symptoms of DMD. The antisense oligomer AVI-4658 works by binding to and blocking a specific sequence inside exon 51 of the pre-messanger RNA, causing the splicing machinery to skip the impacted exons and yield a shortened dystrophin protein, missing a segment inside it, which nevertheless includes the crucial functional portions at either end of the protein and thus restores most of the dystrophin functionality.

The trial reported final month – funded through the uk healthcare research Council and AVI BioPharma – found that when AVI-4658 was offered intravenously to DMD patients resulted during the expression of dystrophin protein , and the fact that dystrophin was interacting with other proteins as it should. in the greatest doses examined there was an apparent reduction in muscle harm in some patients. The primary purpose of the trial was to assess the safety and tolerability of the therapy – it performed well on both counts – using a secondary purpose of assessing the ability of intravenous AVI-4658 to induce dystrophin expression. The trial was of an insufficient duration to evaluate when the therapy improved muscle strength, this crucial final result will need to be evaluated in long term trials.

In this video Prof. Francesco Muntoni of college college London, who led the project, stresses the interdisciplinary nature of the research that resulted during the development of AVI-4658, and the important contribution created by animal research. In its press release on Monday the Muscular Dystrophy Campaign agrees, stating:

So far researchers have shown this technique to get efficient in a dog and a computer mouse design of Duchenne muscular dystrophy. These animal modelshave been essential with the development of the treatment prior to screening in humans.”

This is quite true, in mdx mice a mutation in exon 23 of the dystrophin gene halts manufacturing of the protein, and the first in-vitro demonstration that exon-skipping could restore dystrophin expression was performed in mdx mice (Dunckley MG, 1998). more than the next few many years a range of antisense oligonucleotides were used to restore dystrophin expression and purpose during the mdx computer mouse design (Aartsma-Rus A., 2007)and additional support for this approach was obtained when antisense oligonucleotides were used to successfully restore dystrophin expression in a canine design that additional closely mimics human DMD compared to mdx computer mouse (McClorey G, 2006).

A Lancet Neurology paper released in 2009 by Prof. Muntoni’s party for the 1stclinical trial of AVI-4658 highlights the crucial role performed by scientific studies during the mdx computer mouse in determining the design and style of the morpholino.

Other chemically modified oligonucleotides have been used in preclinical types and clinical trials. Phosphorodiamidate morpholino oligomers (PMOs; figure 1) are non-toxic, and during the mdx computer mouse design of DMD they were probably the most efficient oligomer chemistry for inducing exon skipping and restoring long-lasting (weeks) dystrophin expression soon after intravenous or intramuscular injection.21–24 PMOs, unlike other antisense oligonucleotides, are uncharged, not metabolised, and in preclinical or clinical scientific studies were not associated with activation of the immune system, anaphylaxis, hypotension, or anti-arrhythmias.25 for the foundation of those data, we have studied the safety and biochemical efficacy of AVI-4658, a PMO designed to target exon 51 that is shipped by intramuscular injection. Here, we statement the results of the single-blind, placebo-controlled, dose-escalation safety and efficacy study of PMOs in patients with DMD.”

But the role of animal types of muscular dystrophy in developing therapy with AVI-4658 has not ended using the begin of clinical trials, the Muscular Dystrophy Campaign point to current research utilizing the mdx computer mouse to optimize the AVI-4658 dosing regime. and the operate on developing exon skipping systems with the therapy of DMD goes on; in 2009 we discussed additional state-of-the-art morpholino systems , in particular morpholino cocktails that could target numerous mutations during the dystrophin gene, and novel peptide-linked morpholino styles that could restore dystrophin expression during the heart – anything AVI-4658 cannot do. The development of peptide-linked morpholinos that can target dystrophin expression during the heart can also be between the additional state-of-the-art strategies below active investigation through the muscular dystrophy campaign, and as you would expect animal research is crucial to this work.

All in all this is actually a quite exciting time for DMD research, with at least two promising exon-skipping therapies in state-of-the-art clinical trials and improved therapies pursuing hot on their heels, it is increasingly possibly that those diagnosed with DMD today face a far brighter long term than earlier generations.

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