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Benitec Adds Rare Form of Muscular Dystrophy to Pipeline, Seeks Collaboration for Pain Program


By Doug Macron

Australia's Benitec this week announced that it has expanded its pipeline to include a treatment for oculopharyngeal muscular dystrophy, or OPMD, which will be developed in collaboration with the Royal Holloway University London.

The company separately said that it is also exploring a potential partnership with Chinese investigators who have independently conducted research on expressed RNAi-based treatments for pain, an indication at the forefront of Benitec's drug-development efforts.

OPMD is a rare form of muscular dystrophy initially characterized by weakness in the muscles of the eyelids and throat, resulting in difficulty swallowing and keeping the eyes open, according to the Muscular Dystrophy Association. As the disease progresses, weakness in facial and limb muscles often occurs. There is no treatment.

Aiming to develop an expressed RNAi-based therapy for OPMD, an orphan disease, Benitec said it has partnered with RHUL researcher George Dickson, who will lead the effort along with Capucine Trollet, an investigator at France's Pierre and Marie Curie University. Benitec will hold the commercial rights to technologies developed through the arrangement.

Earlier this year, the investigators — along with colleagues at Leiden University, Radboud University, the University of Copenhagen, and the French National Center for Scientific Research — published a paper in Skeletal Muscle describing their work identifying the molecular pathways implicated in the disease.

OPMD is caused by a poly-alanine expansion mutation in the poly(A)-binding protein nuclear 1, but the mechanisms that regulate its onset and progression are “largely unknown,” they wrote in that paper.

An integrated high-throughput transcriptome study of affected muscle tissue of both OPMD patients and animal models revealed that the ubiquitin-proteasome system was the “most consistently and significantly OPMD-deregulated pathway across species,” they noted.

The team concluded that protein entrapment in PABPN1 aggregates is “associated with a substantial transcriptional deregulation of the UPS that, in turn, leads to disruption of homeostasis in skeletal muscles. ... We predict that candidate genes can be selected for functional genomic studies which ultimately lead to the identification of OPMD pathogenesis.”

In addition to broadening its pipeline, Benitec also said that it plans to initiate discussions early next month with Chinese researchers at Central South University in Changsha about collaborating on the company's neuropathic pain drug candidate.

Aside from OPMD, Benitec currently has three programs moving through its pipeline: one in lung cancer; another in hepatitis B; and its lead effort in cancer- and chronic disease-associated pain. The company has been working since 2010 with partners at the University of Queensland to identify the best target for the pain program (GSN 11/11/2010), but it has also been keeping its eye on investigators at Central South University, who have published data on the use of lentiviral-expressed shRNAs for pain control.

Earlier this year, the company highlighted the work of the Chinese team, which reported in Human Gene Therapy that intrathecal injections of vectors expressing shRNAs against protein kinase C gamma, which is believed to be a messenger in intracellular signal transduction, could alleviate chronic neuropathic pain in rodent models.

This week, Benitec pointed to data from the same group and published last year in the Journal of Gene Medicine that indicated shRNAs against PKC gamma could also reverse morphine tolerance in rats.

In that work, the Central South University investigators induced morphine tolerance in the animals through intrathecal administration of the opioid painkiller for six consecutive days. The shRNAs were then delivered into the rats' spinal cords

They found that a single injection of the RNAi treatment “significantly reversed morphine antinociceptive tolerance,” and observed a dramatic down-regulation of PKC gamma mRNA and protein levels in treated animals compared with controls.

Benitec said these findings have “the potential to significantly extend the market" for the same construct the company is using in its pain program, which is largely focused on PKC gamma. “At the same time, the potential of this multi-benefit approach could open up a faster regulatory pathway and a broadened base for the commercialization of Benitec's pain technology.”

In September, Benitec said that it had hired a contract research organization to help it prepare the pain drug for phase I testing under US Food and Drug Administration protocols (GSN 9/22/2011). Benitec also said it has contracted a preclinical drug-development organization based at the University of Queensland to generate the data needed to begin human trials.

At the time, the company indicated that the program could move into human testing within 12 months, initially as a treatment for pain in terminal cancer patients.

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