After brokering the sale of Cambridge, Mass.-based Idenix Pharmaceuticals Inc. to Merck & Co. Inc., of Whitehouse Station, N.J., earlier this year, the biotech's former president and CEO, Ronald Renaud, is taking on a new project as CEO of Rana Therapeutics Inc., helping the biotech develop its long noncoding RNA (lncRNA) technology. (See BioWorld Today, June 9, 2014.)

He won't be going far. Rana, like Idenix, is based in Cambridge, Mass. "In the Boston area, there's no shortage of young biotech companies," Renaud told BioWorld Insight.

Renaud was looking for something different. "Being part of a start-up is something in my career that I hadn't done before," Renaud said, although he points out that he had experience working with early stage companies while at Thousand Oaks, Calif.-based Amgen Inc. and talked to venture capitalists as part of his job as a biotechnology equity research analyst at JP Morgan, Schwab Soundview and Bear Stearns.

Rana isn't exactly a new start-up, either. The biotech, which was formed in July 2011, landed a $20.7 million series A round in 2012 funded by Atlas Venture, SR One, Monsanto Co. and Partners Innovation Fund. (See BioWorld Today, Jan. 19, 2012.)

INCREASING EXPRESSION

RNAi and antisense drugs reduce expression of a protein by triggering the degradation of the mRNA that codes for the protein. Targeting lncRNAs, in contrast, can increase the expression of a protein.

The lncRNAs, which typically reside on the chromosome near genes they regulate, are transcribed and, while they're still tethered to the DNA, serve to recruit polycomb repressive complex 2 (PRC2). The complex is responsible for methylating histones, which compacts chromatin and silences transcription in the region near the lncRNA.

Rana's single-stranded oligonucleotide drugs bind to the lncRNAs, inhibiting the binding of PRC2, which prevents epigenetic silencing, thereby increasing expression of the nearby gene.

To prevent degradation of the oligonucleotide, Rana uses Locked Nucleic Acid (LNA) drug technology licensed from Santaris Pharma A/S in July 2013. Rana made an undisclosed up-front payment to license the technology for up to 10 RNA targets and is on the hook for target nomination payments, development milestones and royalties on each product developed. Roche AG, of Basel, Switzerland, purchased Santaris earlier this year. (See BioWorld Today, Aug. 5, 2014.)

Santaris' LNA technology uses a methylene bridge that can increase the half-life of the oligonucleotide as high as "weeks to months," according to Rana's chief scientific officer, Jim Barsoum, while retaining a high affinity for the target RNA.

FROM TECHNOLOGY TO TARGET

Rana created a database of lncRNAs and unique PRC2 binding sites identified through a process called RIP-Seq, where RNA-protein complexes are isolated with antibodies to the PRC2 complex and the isolated RNA is converted into DNA through RT-PCR, which is sequenced.

Mapping the lncRNAs to the genome can identify genes they likely regulate since the lncRNAs need to be in close proximity to the genes they regulate. Then it's just a matter of finding diseases where targeting an lncRNA could help treat a disease.

"We're looking for diseases where we know a single gene drive those diseases," Barsoum said.

But the catch is that the disease can't be caused by a mutation in a gene that makes the protein nonfunctioning because increasing expression of those mutated genes isn't going to help fix the problem.

Rana's first two drug candidates fit the bill: a drug targeting an lncRNA responsible for silencing frataxin and another targeting an lncRNA that regulates survival of motor neuron 2 (SMN2).

Friedreich's ataxia is caused by expansion of a triplet repeat in the frataxin gene, which leads to reduced expression of the mitochondrial protein responsible for binding iron that can cause damage to cells in the central nervous system. Inhibiting the lncRNA that silences frataxin expression should increase the protein expression dampened by the mutation, resulting in less iron-induced damage.

In spinal muscular atrophy patients with mutations in survival of motor neuron 1 (SMN1), a related gene, SMN2 can partially substitute for SMN1. Patients with extra copies of the SMN2 gene have less severe spinal muscular atrophy, supporting the hypothesis that increasing expression of the SMN2 gene should help patients.

The affected cells in spinal muscular atrophy and Friedreich's ataxia patients are in the central nervous system, which may help increase the concentration of drug near the target cells because the drugs injected into the central nervous system will stay in the spinal cord and brain. Barsoum said he thinks the drugs might be able to be dosed as infrequently as every three to six months.

Both drug candidates are still undergoing investigational new drug application-enabling studies. Rana hopes to have the drugs into the clinic in 12 to 18 months and is also investigating potential lncRNA targets to treat undisclosed musculoskeletal and inflammatory diseases.

In addition to developing drugs internally, Rana also will pursue collaborations for other diseases that lncRNA-targeted drugs could treat. "I don't think that any one company has the bandwidth to look at all of it," Renaud said.