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Solid Tumors – Tumor-Penetrating Nanocomplex (TPN) Platform™ (U.S.)

What is RNA-based Therapeutics?

RNA Therapeutics is a rapidly expanding drug category that have the possibility of enhancing the standard of care for many diseases. Ribonucleic acid (“RNA”) is a single stranded molecule closely related to Deoxyribonucleic acid (“DNA”) – the chemical that contains, or encodes, genetic information – and is equally important to how cells function. One of the main functions of RNA is to act as a template for proteins to be made in the cell. These messenger RNAs (“mRNA”) copy a portion of genetic code from the chromosomal genome in the cell nucleus and transport the information to the ribosomes, which assemble the proteins to order. As well as carrying these instructions for making proteins, RNAs help to turn genes on and off, assist chemical reactions, slice and dice other RNAs, and even build proteins by transporting amino acids and linking them together. By targeting the mRNAs in a cell, it is possible to block harmful proteins from being produced without attempting to change the genome itself.

Types of RNA-based Therapies

Most RNA-based therapies can be sorted into one of three broad categories: those that target nucleic acids (either DNA or RNA), those that target proteins and those that encode proteins. Hybrid approaches that combine several RNA-based mechanisms into a single package are also emerging. There are two distinct types of RNA-based therapies that target nucleic acids: single-stranded antisense oligonucleotides (“ASOs”), and double-stranded molecules that operate through a cellular pathway known as RNA interference (“RNAi”).

ASOs are short stretches of modified DNA made up of about 13–25 building blocks, or nucleotides. These molecules prevent mRNA from being translated into protein by several mechanisms, including blocking the start of translation or tagging the mRNA for degradation. ASOs can also alter splicing, the process that sculpts a precursor mRNA into its mature form.

RNAi makes use of double-stranded molecules, and as a result, these therapies are tougher to get into cells than ASOs. However, fewer molecules are needed for the therapy to be effective. RNAi involves small interfering RNAs (“siRNA”), 21–23 nucleotides long, or similar molecules such as microRNAs, to degrade mRNA and prevent it from being translated into protein.

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Delivery of RNA-based Therapeutics

Targeted delivery is a major hurdle for effective RNA-based therapies, a hurdle that must be overcome to broaden the clinical application of this type of therapeutic. Because mRNA is inherently unstable, it requires delivery vehicles that will protect the cargo from Ribonucleases (“RNases”) degradation. RNA degradation is an essential component of RNA metabolism. RNases are required for the maturation of stable RNAs and the removal of defective RNAs or RNA species that are no longer required by the cell. There is a need for novel delivery vehicles that will deliver the RNA-based drug to the site of therapeutic action facilitating the entry of the RNA drug into the cytoplasm where it may exert its effect.

Our Approach: TPN Platform™ for effective delivery of RNA-based therapeutics for the treatment of solid tumors

In the world of anti-cancer research, targeting tumor cells is one challenge; penetrating the cells to deliver therapeutics is another. Solid tumors are complex organ-like structures; The tumor microenvironment describes the entirety of the tumor components that are not malignant by themselves. The tumor microenvironment consists of the tumor’s vasculature, connective tissue (stromal cells), infiltrating immune cells, and the extracellular matrix (or “ECM”). The ECM is a non-cellular meshwork of crosslinked macromolecules that form a dense desmoplastic stroma around tumor cells. This complex meshwork, together with the formation of new collapsed and leaky blood vessels, creates a tumor microenvironment in favor of tumor growth and invasiveness. Thus, the presence of ECM, poor/tortuous vascularity of the tumor, and high interstitial tumor pressure may cause, in some cases, only a small fraction of an administered anti-cancer drug to cross this dense desmoplastic stroma barrier and reach the tumor. The combination of specific targeting and efficient delivery could lead to highly effective cancer therapy in humans. 

Lisata’s Tumor-Penetrating Nanocomplex (“TPN”) Platform™ targets intracellular delivery of RNA-based drugs to prevent solid tumor growth. To accomplish this, Lisata designed a TPN that could not only bind a protein overexpressed on the surface of human cancer cells, but also pass through the membrane by way of a cell-penetrating peptide. Once inside the cells, the TPN could release the RNA-based drug directed against the tumor. 

Lisata’s TPN Platform™ utilizes the same tumor-targeted tissue penetrating capabilities that LSTA1 (formerly known as CEND-1) has demonstrated in the clinic to enable effective delivery of nucleic acid-based drugs into solid tumors. LSTA1 targets tumor vasculature by its affinity for alpha-v integrins that are selectively expressed in tumors, but not healthy tissue vasculature. Lisata’s portfolio includes other CendR peptide targeting moieties that can target other cell types, such as immune cells – cells that help the body fight infections and other diseases. These CendR peptides, once bound to their targeted cell types, are cleaved (split/severed) by a naturally occurring proteolytic enzyme expressed in tumors, producing a “C-end-Rule.” Once cleaved, the remaining CendR fragment binds to a second receptor, called neuropilin-1, to activate a novel uptake pathway that allows anti-cancer drugs to penetrate solid tumors more selectively. In TPNs, CendR targeting moieties are combined with other elements to form nanocomplexes that self-assemble with RNA-based drugs to encapsulate and protect from undesired serum protein binding and/or degradation.  The TPN Platform™ also includes endosome-release moieties that can be employed for applications where release from such endosomes will enhance activity in other cellular compartments. The ability of TPNs to deliver RNA-based drugs on a targeted basis to tumor cells and certain immune cells has been demonstrated in models of a range of solid tumors. Lisata is advancing preclinical work to optimize the delivery of RNA-based therapies to high-interest, anti-cancer targets and plans to select one or more clinical development candidates in 2023.

Investigational Clinical Trials of TPN Platform™ in Solid Tumors

TPN Development Candidate (U.S.)
Pre ClinicalPhase 1Phase 2Phase 3
Phase 1
Indication: Various Solid Tumors
Partner/Sponsor: Lisata (U.S.)
Next Development Milestone: Development candidate ID target 2023; Phase 1 planned for 2024
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