Circulating "Good" Genes Body-Wide

While Muscle Group members are discovering new targets for drug development, progress will continue to be stunted if the drug can’t reach the central nervous system, a primary player in neuromuscular diseases.

Nearly all large-molecule drugs and 98 percent of small-molecule drugs do not cross the blood-brain barrier, limiting the development of drugs for many central nervous system disorders.  The same difficulty applies to gene delivery strategies. Previous gene therapy efforts to treat two of the most common motor neuron diseases, SMA and ALS (Lou Gehrig’s disease), have failed to bypass the blood-brain barrier.

In a 2009 study Muscle Group members showed that a gene delivery strategy using a subtype of the adeno-associated virus crossed the blood brain barrier and efficiently targeted cells of the central nervous system.  “The ability to cross the blood brain barrier and globally infect the central nervous system opens up the possibility for countless new avenues of investigation for both basic science and therapeutic endeavors,” said Dr. Kaspar.

The Muscle Group has since completed studies demonstrating that genes can be delivered through the vascular system and target desired muscle regions while protecting the patient from widespread dissemination of the adeno-associated virus. This possibility has been verified using pressures and volumes applicable for clinical trials in children with DMD.

“Building on the successes from our 2006 gene therapy trial in which we delivered dystrophin to a localized region in the muscle we now plan to implement this gene delivery using the vascular delivery mechanism,” said Dr. Mendell.  A nearly $8 million grant that the Muscle Group has received from the National Institutes of Health will help develop this vascular delivery system. “This is a critical step in the success of gene therapy,” said Dr. Mendell.

The ability to cross the blood-brain barrier and target motor neurons is also being applied to the treatment of SMA. Using this technique, Drs. Burghes and Kaspar have shown that delivery of SMN to motor neurons of mice models of SMA resulted in substantial correction of disease symptoms.  “The next steps are to move this strategy forward to SMA clinical trials,” said Dr. Burghes. “Exciting times are ahead as we began to move these therapies towards the clinic.”

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