Irish biopharmaceutical firm Genable Technologies announced this week that it has acquired an exclusive, worldwide license to Benitec Biopharma's expressed RNAi technology for use in a treatment for the rare ocular disease rhodopsin-linked autosomal dominant retinitis pigmentosa.
Specific terms of the arrangement were not disclosed.
According to Genable CEO Jason Loveridge, the company struck the deal with Benitec as it prepares to advance its drug candidate, called GT038, through preclinical testing and toward the clinic.
Since its inception in 2004, Genable has been “predominantly pursuing proof of concept in a small animal model for a gene therapy-based approach to retinitis pigmentosa,” a currently untreatable condition characterized by the death of rod and cone photoreceptor cells.
The therapy, he told Gene Silencing News, combines gene silencing with gene replacement in order to overcome a key roadblock to treating the disease.
“The problem with [rhodopsin-linked autosomal dominant forms of] retinitis pigmentosa is that it's caused by a range of mutations in the rhodopsin gene … [and different] patients have different mutations,” Loveridge explained.
To address this issue, Genable aims to use an AAV vector to deliver an shRNA that silences both the mutant and wild-type rhodopsin gene, independent of whatever mutation is present. A separate AAV vector is used to replace the gene with a functioning version that sidesteps the RNAi-based inhibition through a wobble base pairing approach.
“The critical parts to the therapy [require] a … construct that suppresses the mutant rhodopsin [and] a construct that replaces [the gene but] is not silenced by the suppression part of the therapy,” he said. On top of that, “you need a ratio of those two so that you manage to always express natural rhodopsin no matter how much suppression goes on.”
GT038 represents “a kind of defined ratio of these two different AAV vectors in the one therapeutic,” which would be administered as a single sub-retinal injection into each eye.
As for concerns over possible side effects associated with gene therapy, Loveridge noted that the AAV vectors employed in the treatment have been demonstrated in the clinic to be safe and are not integrated into the host genome in target photoreceptor cells.
And while there can be untoward immunological responses to AAV vectors, “the eye is immune privileged [and] considered part of the central nervous system,” he said.
To date, Genable has generated preclinical data demonstrating the utility of its approach, and last year published details in Molecular Therapy.
In that paper, company co-founders and their collaborators showed how the suppression/replacement approach could improve retinal function and structure in a mouse model of rhodopsin-linked autosomal dominant retinitis pigmentosa.
On the heels of those findings, Genable is advancing to a porcine model that more closely resembles the human eye in order to better define the ratio of suppression to replacement, Loveridge said.
At the same time, the firm is looking for a manufacturer that can produce both preclinical and clinical batches of GT038, a process that is expected to be completed this year. If all goes according to plan, Genable will shortly begin the toxicology and biodistribution studies required to move into the clinic.
A phase I proof-of-concept study, he noted, could begin in 2014. And while it is a small company, Genable closed a roughly €5 million ($6.1 million) Series B financing round that is expected to provide enough funds to carry it through that first clinical trial.
Despite its initial focus on retinitis pigmentosa, Genable is “not just an ocular company,” Loveridge noted.
“The company has some fundamental intellectual property that covers all approaches to autosomal dominant diseases using a suppression/replacement strategy,” he said. “The strategy has been established in mice, and as we move forward and establish it in pigs, we are ... looking for other opportunities where we think the technology will have application.
“That's an ongoing strategic exercise,” he added.