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With Primate Testing on Deck, nLife Aims at Partnerships for Neuron Delivery Technology

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Roughly one year after securing €5 million ($6.5 million) in venture capital funding, Spanish oligonucleotide drug developer nLife Therapeutics has set its sights on initiating non-human primate testing of its core intranasal delivery technology, which it hopes will spur licensing deals with bigger industry players, according to the firm's top executive.

To date, the company has inked two technology-evaluation deals with undisclosed pharmaceutical firms, including one that nLife CEO and CSO Andreas Montefeltro said is specifically interested in using his company's neuron-specific delivery approach with RNAi compounds.

Neither has been formalized as a full-fledged licensing arrangement, he told Gene Silencing News this week. However, he said that positive data from macaque studies, planned to begin around the end of the summer, would hopefully lead the way to such a deal.

In the meantime, nLife is proceeding with its in-house work developing an antisense-based treatment for Parkinson's disease, which could be ready to begin clinical testing by mid-2014, Montefeltro added.

The company's key asset is its delivery technology, which involves conjugating a therapeutic nucleic acid, such as an siRNA or an antisense oligo, to an agent that selectively binds to a neurotransmitter transporter within a target neuron. In animal models, the company has established that the approach can be used to deliver oligonucleotides into three types of aminergic neurons: serotonergic, norephinephrinergic, and dopaminergic.

Recently, the US Patent and Trademark Office published an nLife patent application describing the technology.

Originally focused on depression, nLife collaborators reported in 2011 that the approach could be used to deliver siRNA that suppress a negative feedback mechanism that hinders the efficacy of selective serotonin reuptake inhibitors, or SSRIs such as Prozac.

According to that paper, which appeared in Molecular Psychiatry, SSRIs increase extracellular serotonin levels by blocking their physical reuptake in serotonergic axons. “However, this process is severely compromised by the simultaneous activation of somatodendritic [serotonin] … autoreceptors in the mid-brain.”

This activation, the study's authors wrote, reduces serotonergic activity and forebrain serotonin release, “an effect contrary to that required for therapeutic response.”

To address this issue, the investigators developed siRNAs designed to inhibit serotonin receptors and administered them to SSRI-treated rodents via intracerebroventricular infusion, which resulted in an accumulation of the neurotransmitter in target neurons and “marked anti-depressant-like effects.”

To test a more clinically viable route of administration, the researchers also delivered the RNAi agent intranasally and achieved the same results.

In a second study, which is expected to be published this year, the intranasally delivered siRNAs were able to boost hippocampal neurogenesis, a key aspect of depression treatment, after seven days on a level comparable to Prozac treatment, Montefeltro noted.

Buoyed by these data, nLife had planned to further advance an intranasal RNAi therapy for depression through its pipeline, but later decided that the market for such a drug was too crowded. Additionally, market approval would require multiple pivotal trials, which would take more resources than the company has, Montefeltro said.

The company also found playing in the RNAi space to be too expensive, he said, with fees for access to siRNA intellectual property from Alnylam Pharmaceuticals, for instance, costing “several million” dollars.

Instead, nLife has opted to develop antisense drugs based on Isis Pharmaceuticals' off-patent designs, although the company may later begin using Isis' next-generation 2‘-O-methoxyethyl phosphorothioate-modified antisense oligos once those lose patent protection in 2016, Montefeltro noted.

At the same time, it has shifted its focus onto Parkinson's disease, where the path to regulatory approval is likely to be shorter given that no treatments exist for the condition. The company is also considering pursuing orphan drug status for the program by focusing on a rare form of the disease characterized by mutations in the encoding alpha-synuclein, the protein that aggregates within the cells of Parkinson's disease patients.

The depression program remains in early-stage development while nLife directs the bulk of its resources toward Parkinson's disease, Montefeltro said. An effort examining the use of the delivery technology to administer undisclosed anti-obesity agents is ongoing under a pilot study with an unnamed “top 10” pharmaceutical firm.

The firm has also recently inked a deal under which another undisclosed pharmaceutical firm with an established presence in the RNAi field is evaluating nLife's delivery technology, he noted.

Though it is not clear if either arrangement will grow into a broader partnership or licensing arrangement, Montefeltro said that upcoming non-human primate testing of the delivery approach may help with nLife's efforts to close bigger deals.

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