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Gene therapy rescues mice with SMA

Reversing a protein deficiency through gene therapy can correct motor function, restore nerve signals and improve survival in mice that serve as a model for spinal muscular atrophy, new research shows. The research is published online in the journal Nature Biotechnology (february 28, 2010).
The researchers used an altered virus to deliver a portion of DNA that makes the SMN protein into the veins of newborn mice ranging in age from 1 to 10 days old. Newborn mice that received the treatment demonstrated near-normal motor function (movement) and brain-to-muscle signaling, as well as a dramatic increase in length of survival, with most living upwards of 250 days as compared to untreated mice, which had an average life span of 15 days. The earlier the therapy was administered, the better the result. No effect was seen from gene therapy treatment given to SMA-affected mice at 10 days of age.

"We're replacing what we know is lost. And we have shown that when you put the protein in postnatally, it will rescue the genetic defect," said Arthur Burghes, professor of molecular and cellular biochemistry at Ohio State University and a senior co-author of the study. "This technique corrects the mice considerably more than any drug cocktails being studied as a potential treatment in humans."

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Isis Pharmaceuticals towards an antisense drug

Isis Pharmaceuticals has exclusively licensed certain intellectual property from the University of Massachusetts to develop a potential new therapy for Spinal Muscular Atrophy (SMA). Funding support for the University of Massachusetts' research program responsible for creating this intellectual property was provided in part by Families of SMA.
ISIS recently announced that it had added a SMA drug candidate to its development pipeline, called ISIS-SMNRx. ISIS is developing ISIS-SMNRx as part of its strategy to discover and develop antisense drugs against neurodegenerative diseases.
ISIS' SMA program is part of its collaboration in neurodegenerative disease with Dr. Adrian Krainer at Cold Spring Harbor Laboratory and Genzyme, pursuant to which Genzyme has an exclusive option to license ISIS-SMNRx from ISIS.

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New finding clarifies the cause of SMA

Howard Hughes Medical Institute researchers have made a surprising discovery about the molecular basis underlying spinal muscular atrophy. The findings suggest that there may be a new way to promote survival of neurons.
The disease is nearly always linked to the absence or disruption of a gene known as SMN1. A nearby gene, SMN2, is virtually identical to SMN1, and in principle could produce enough SMN protein to keep neurons healthy but yet somehow fails to do so.
In the March 2010 issue of the journal Genes & Development, investigators Gideon Dreyfuss and Sungchan Cho report on their work solving this mystery. Dreyfuss and Cho found that most of the SMN protein produced from SMN2 is flagged for rapid degradation by a cellular waste-disposal system. Thus, the protein is cleared before it accumulates sufficiently to sustain the health of motor neurons. Blocking this degradation signal could therefore, in theory, be a way to treat SMA, Dreyfuss says.

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Trans-splicing and gene therapy

A process called trans-splicing has been shown to increase levels of a needed protein in mice with a disease resembling severe human spinal muscular atrophy, says a research team at the University of Missouri-Columbia, whose findings were published Jan. 6, 2010, in the Journal of Neuroscience.
The process, which increased lifespan in the mice, may prove to be a promising alternative to a variety of therapeutic strategies currently under investigation for SMA.
The researchers used a technique called trans-splicing, which facilitates the joining of two separate molecules, in this case the SMN2 instructions for the removal of exon 7 and new instructions that cause inclusion of exon 7.
Mice bred to have a disease resembling a severe form of SMA each received a single intracerebral (into the brain) injection of carriers called viral vectors, containing short strands of corrective genetic instructions. Analysis revealed increased levels of full-length SMN in the mice, with trans-splicing detectable in the central nervous system, the kidney and liver and, to a lesser degree, in skeletal muscle.

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