Developing Nanopieces, a Platform RNAi Delivery Technology for Treatment of Multiple Diseases - STTR_Developing Nanopieces
7. Project Summary/Abstract
The bottleneck of developing new RNAi (RNA Interference) drugs is the lack of highly efficient and non-toxic
RNA delivery to non-liver tissues in vivo. It is especially challenging to deliver negatively-charged nucleic acid
into avascular, dense, and negatively-charged matrix in hard-to-reach tissues including joint cartilage. NanoDe
Therapeutics, Inc. (NanoDe) is a development stage company dedicated to developing delivery of RNAi
therapeutics, thereby creating more effective drugs. NanoDe is founded on a novel platform RNA delivery
technology termed NanopiecesTM, a novel biomimetic nanomaterial derived from a small molecule JBAK,
Janus-Base with Amine or lysine (K). Through self-interaction of its biocompatible Janus-Base units mimicking
DNA base pairs, JBAK forms non-covalent nanotubes (NT) with positively charged amine or lysine on the
surface. JBAK NT further assembles with siRNA to form JBAK NP, thereby encapsulating negatively charged
siRNA into positively charged NP. Our preliminary data has shown that 1) NPs can penetrate matrix-rich
tissues that conventional vehicles cannot, and release siRNA therapeutics intracelluarly in high efficiency to
modify otherwise untreatable diseases; 2) NP delivered RNAi therapeutics has achieved successful outcomes
in the treatment of multiple diseases including rheumatoid arthritis, a rare solid tumor called chondrosarcoma,
and post-traumatic osteoarthritis (PTOA) in animal models respectively; and 3) NP has excellent
biocompatibility and biodegradability, which are critical for maintaining minimal toxicity in vivo. The goal of this
Phase I application is to further develop NP delivery technology by using PTOA as a “use case” disease. The
central hypothesis is that the optimal positive charge of NP is one of the critical parameters to enable its
penetration into negatively charged cartilage matrix, endocytosis into chondrocytes, and release siRNA to
inhibit disease gene expression, thereby achieving significant therapeutic effects on PTOA. This hypothesis will
be tested with the two aims: 1) Determining the optimal charge of NP to enable its penetration and retention
within cartilage tissue, transfection into chondrocytes, and inhibiting matrix proteinase ADAMTS-5 gene
expression in chondrocytes, respectively; and 2) Determining the optimal charge of NP to enable its intra-
articular delivery and long half-life within joint, and achieve significant therapeutic outcomes in a PTOA animal
model. The proposed research is innovative because: 1) Essentially different from conventional delivery
vehicles, Nanopiece is a non-covalent vehicle presenting unique advantages, such as versatility in dimensions
and surface charge, affinity to extracellular matrix, excellent biodegradability and biocompatibility. 2) For the
first time, we identify important technology parameters of NP required for successful siRNA delivery including
the optimal vehicle surface charge for matrix penetration, cell transfection, and gene knockdown. 3) The
technology breakthrough enlightens a therapeutic approach to deliver RNAi for treatment of multiple diseases
including PTOA.
