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With AAV Technology in the Clinic, NanoCor Aims to Develop shRNA-Based Heart Failure Drug


While its primary focus remains on preparing its gene therapy for chronic heart failure for phase I testing, NanoCor Therapeutics is also aiming to advance an RNAi-based treatment for the condition.

Doing so, however, will require additional financing, and the company remains on the lookout for funding opportunities, NanoCor founder Sheila Mikhail told Gene Silencing News this week.

NanoCor was established in 2005 as a spinoff of Asklepios BioPharmaceuticals — itself a spinout of the University of North Carolina, Chapel Hill — to develop that Asklepios’ proprietary adeno-associated viral vector-based delivery technology for use in cardiovascular disease.

Asklepios is currently testing the AAV approach with a phase I Duchenne muscular dystrophy therapy, while another spinout, Chatham Therapeutics, is using the delivery approach with a phase I/II hemophilia drug.

According to Mikhail, the delivery technology has two basic components. The first involves so-called biological nanoparticles, which are synthetic AAV vectors derived from the components of different naturally occurring AAV serotypes, as well as certain other parvoviruses.

“Each of those serotypes have different tropisms for different tissues,” Mikhail explained. “We can take different amino acids from each of these naturally derived forms of AAV and put them together to create an artificial AAV vector [that] will have the characteristics we want,” namely the ability to selectively target cardiac tissue.

Amino acids that de-target other tissues, such as the liver, are also engineered into the vector, allowing it to avoid hepatocytes in order to sidestep toxicity issues.

“By combining the various pieces of the naturally derived serotypes, we create a man-made serotype that has the attributes that we’re looking for,” she said. Additionally, the vectors are modified to escape neutralizing antibodies, which allows them to be effective in a greater number of patients.

The second part of the delivery platform involves NanoCor’s so-called self-complementary vector technology.

“In order to create the protein within the cell, [AAV] has to undergo [second]-strand synthesis where a single strand of DNA snaps back on itself, pairs up, and starts expressing the protein,” Mikhail said. “That requires a lot of virus and takes time — it usually takes about a week or so.”

NanoCor researchers developed a self-complementary template where second-strand synthesis has already occurred, she added. “So as soon as the virus gets delivered to the cell, it can start expressing protein,” usually within 24 to 48 hours.

As a result, “substantially less” virus is needed to obtain a therapeutic effect.

With the help of partner Medtronic and a $10 million grant from the National Institutes of Health, NanoCor is moving its lead product candidate, Carfostin, into clinical testing for chronic heart failure. That drug uses the AAV technology to deliver protein phosphatase-1 inhibitor-1, or I-1, as a means of modifying calcium channel cycling to boost contractility in failing heart tissue.

However, NanoCor is also exploring the use of AAV-delivered shRNAs against phospholamban — a protein downstream of I-1 involved in cardiac contractility — to treat chronic heart failure.

That program has thus far advanced into rodent testing, with encouraging results. Moving into large animal studies, however, will require a cash infusion, Mikhail said.

NanoCor is currently exploring different options to raise that money, and it hopes that the clinical data generated by Asklepios and Chatham, along with a recently issued patent (GSN 3/28/2013), will help it find a bigger partner interested in the RNAi effort, she said.