A Universal DNA-Based Delivery Platform

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April 1, 2015 (Vol. 35, No. 7)

Gail Dutton

Genisphere’s Nanostructures Are Bulk Carriers with a Delicate Touch

Genisphere is developing a drug delivery platform that enables highly specific targeting for therapeutics and diagnostics through a flexible, multivalent approach. Called 3DNA®, the platform is composed of universally useable DNA nanostructures that can be functionalized with a variety of targeting devices and drug cargos, depending on the intended use.

“The targeting devices can be antibodies, peptides, or other small molecules that typically bind to upregulated markers on a diseased cell,” explains Bob Getts, Ph.D., Genisphere’s CSO. “The therapeutic cargo may consist of small drug molecules; small interfering RNA molecules; genes; or bioactive proteins, peptides, or antibodies.”

Dr. Getts adds that drug delivery by means of the 3DNA platform is not only extremely flexible in terms of design and payload, it is also nontoxic.


A customized version of Genisphere’s 3DNA with two unique cargos (which could be two different drugs, or one drug and one label) and two unique antibodies for targeting.

Scaffold Structure

3DNA is a three-dimensional, branched molecule built from interconnected monomeric subunits of DNA. Two DNA strands anneal to form a monomer with a central, double-strained “waist” and four arms. Base-pairing between the arms of complementary monomers builds the 3DNA, layer by layer, to the desired nanoscale.

Once constructed, molecules that determine targeting and labeling specificity are attached to this nanoscaffold. There are no restrictions to the type of targeting moiety or labeling that may be used, and they may be mixed and matched, according to Genisphere literature.

Typical targeted two-layer assemblies consist of about 3,300 DNA bases and are about 90 nm in diameter. Core 3DNA reagents are 99% solvent in most aqueous media.


Benefits

“Using DNA as a biomaterial for manufacturing offers inherent biocompatibility, since our nanocarriers are fully degraded in the physiological environment,” Dr. Getts asserts. Using DNA also allows Genisphere to control the physical size of the nanocarriers and to use a broad range of drug compounds.

3DNA gets through barriers that obstruct other nanocarriers, he continues. For example, 3DNA is negatively charged, whereas other nanoparticles are positively charged or neutral. Consequently, 3DNA molecules can cross tissue barriers, including barriers to the lung, brain, and encapsulated tumors.

“We can target a molecule on one side of the barrier to cause it to cross,” notes Dr. Getts. “And we can target a second molecule on the other side to reach a subpopulation of cells.

“By leveraging the multivalency of 3DNA structures, specificity and payload density can be significant—10- to 50-fold—with the same biological effects because we can attach hundreds of drugs per carrier. Also, combination therapeutics are possible with our system.”

The 3DNA scaffold also aids drug repurposing, thus effectively extending a drug’s off-patent life. “Any drug that binds or intercalates DNA can be delivered with our system,” Dr. Getts says.
“There are a variety of drug conjugate chemistries with reversible linkers that work perfectly with our technology,” he continues. “Because the platform is modular, it is easy to adapt into multiple formulations of the targeting molecule and drug compound.”

According to Dr. Getts, the best way to assess the value of the 3DNA platform is to look at it in the context of antibody drug conjugates (ADCs), which consist of a targeting antibody coupled to three to four drug molecules. In contrast, he says, 3DNA could use the same antibody or multiple antibodies coupled to tens or hundreds of the same drug molecule.

The ability to mix and match targeting moieties and payloads lets scientists critically finetune the targeting mechanism. “3DNA is, essentially, an ADC on steroids,” Dr. Getts insists.


Collaborations

The company’s preclinical work with its collaborators is focused on cancer and ocular disease. GL-221 for cancer reaches the exterior of the targeted cell with a peptide, and further ensures specificity inside the cell with a promoter upregulated only in cancerous cells. Once the carrier is inside the tumor cell, it delivers a diphtheria toxin gene construct to kill the cell from within.

GL-249 for ocular disease “targets a specific population of cells in the lens of the eye with an antibody, and delivers doxorubicin to destroy the cells from the inside,” notes Dr. Getts. “Genisphere plans to enter the clinic “over the next year or two.”

Genisphere outlicenses the 3DNA platform for diagnostic applications and signed a deal last November with BBI Solutions in the U.K. For therapeutic delivery, however, Genisphere is working with partners.

“Now that we’re shifting our focus to drug delivery, partnering opens the most opportunities for the company,” Dr. Getts explains. “We expect some partnerships to mature into outlicenses for specific applications in drug delivery.”

The ideal partners, he adds, include key academic leaders as well as biotech in the early stages of drug development and big pharma. The immediate goal is to expand partnerships and advance one drug—“one of ours, or a partner’s”—into the clinic. 


Genisphere

Location: 2801 Sterling Drive, Hatfield, PA 19440

Phone: (877) 888-3362

Website: www.genisphere.com

Management Team: Jim Kadushin, COO and Bob Getts, Ph.D., CSO

Number of Employees: 14

Focus: Genisphere, a nanotechnology company, provides tools for targeted drug delivery, clinical diagnostics, and life science research The company’s 3DNA platform is designed to improve specificity and therapeutic payload.



























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