A team of scientists from Cold Spring Harbor Laboratory (CSHL) led by professor Adrian Kraner, Ph. D., in collaboration with scientists from Isis Pharmaceuticals, has developed a new way of making animal models for a broad class of human genetic diseases – those with pathology caused by errors in the splicing of RNA messages copied from genes. To date, about 6,000 such RNA "editing" errors have been found in various human illnesses, ranging from neurodegenerative disorders to cancer.
The new modeling approach can provide unique insights into how certain diseases progress and is likely to boost efforts to develop novel treatments. It was tested successfully by the CSHL team in mouse analogs of human spinal muscular atrophy (SMA), a motor-neuron disease that is the leading genetic cause of childhood mortality.
SMA is caused by lack of or a severe mutation of a gene called SMN1 (survival motor neuron 1). A similar gene called SMN2 exists, but due to an error in the splicing of its pre-mRNA, the SMN2 gene, when expressed, typically produces only a fraction of the SMN protein needed by motor neurons. While the level of the "backup" gene's protein output varies in individuals with spinal muscular atrophy, Krainer -- a leading expert on splicing -- and his collaborators have succeeded in recent years in devising a method of getting SMN2 to produce therapeutic amounts of protein, enough to reverse pathology in both mild and severe mouse analogs of the disorder.
The team synthesized ASOs that by virtue of their chemical sequence target a different site on the pre-mRNA of the human SMN2 gene, one that exacerbates missplicing. When these negative ASOs were injected into the ventricular brain region of mice engineered to have four copies of the SMN2 transgene, and lacking the mouse's own Smn gene, SMA symptoms became more severe than in control animals.
To achieve this they synthesized tiny snippets of RNA called ASOs (antisense oligonucleotides) and injected them into the cerebrospinal fluid of mice carrying a human SMN2 transgene (i.e., a gene not native to mice). This enabled them to get the therapeutic ASOs through the so-called blood-brain barrier, to reach cells throughout the central nervous system. Krainer's team synthesized an ASO that corrected the SMN2 splicing error and gave rise to therapeutic amounts of SMN protein. Importantly, the ASO was shown to be stable in the body as well as persistent, the effects of a single injection lasting at least half a year in mice.
A version of this therapeutic ASO is now being tested in Phase 1 human trials. But even as the tests proceed, Krainer and colleagues have worked on getting the splice-correction method to work in reverse: using a "negative ASO" to cause or exacerbate disease pathology in neonatal mice, with the approach they call TSUNAMI
Read more at: http://medicalxpress.com/news/2012-08-team-method-diseases-splicing-defects.html#jCp
The new modeling approach can provide unique insights into how certain diseases progress and is likely to boost efforts to develop novel treatments. It was tested successfully by the CSHL team in mouse analogs of human spinal muscular atrophy (SMA), a motor-neuron disease that is the leading genetic cause of childhood mortality.
SMA is caused by lack of or a severe mutation of a gene called SMN1 (survival motor neuron 1). A similar gene called SMN2 exists, but due to an error in the splicing of its pre-mRNA, the SMN2 gene, when expressed, typically produces only a fraction of the SMN protein needed by motor neurons. While the level of the "backup" gene's protein output varies in individuals with spinal muscular atrophy, Krainer -- a leading expert on splicing -- and his collaborators have succeeded in recent years in devising a method of getting SMN2 to produce therapeutic amounts of protein, enough to reverse pathology in both mild and severe mouse analogs of the disorder.
The team synthesized ASOs that by virtue of their chemical sequence target a different site on the pre-mRNA of the human SMN2 gene, one that exacerbates missplicing. When these negative ASOs were injected into the ventricular brain region of mice engineered to have four copies of the SMN2 transgene, and lacking the mouse's own Smn gene, SMA symptoms became more severe than in control animals.
To achieve this they synthesized tiny snippets of RNA called ASOs (antisense oligonucleotides) and injected them into the cerebrospinal fluid of mice carrying a human SMN2 transgene (i.e., a gene not native to mice). This enabled them to get the therapeutic ASOs through the so-called blood-brain barrier, to reach cells throughout the central nervous system. Krainer's team synthesized an ASO that corrected the SMN2 splicing error and gave rise to therapeutic amounts of SMN protein. Importantly, the ASO was shown to be stable in the body as well as persistent, the effects of a single injection lasting at least half a year in mice.
A version of this therapeutic ASO is now being tested in Phase 1 human trials. But even as the tests proceed, Krainer and colleagues have worked on getting the splice-correction method to work in reverse: using a "negative ASO" to cause or exacerbate disease pathology in neonatal mice, with the approach they call TSUNAMI
Read more at: http://medicalxpress.com/news/2012-08-team-method-diseases-splicing-defects.html#jCp
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