Assessment of Nanoparticle Assemblies for Efficient Gene Therapy Vehicles
Abstract
Gene therapy has the potential to offer the most transformative shift in medicine since the invention of antibiotics. From its beginning, the goal of medicine has been to precisely identify the source of a disease, and then eliminate it from its source with surgical precision. Gene therapy promises to do just such a task with strategies such as messenger RNA (mRNA) disruption by RNA interference (RNAi), engineered mRNA replacement, and, most recently, direct edits to the genome through clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated proteins (Cas) ribonucleoprotein complexes (RNPs). In these cases, nucleic acids form a central part of their composition and they are each suffering from a lack of optimal delivery strategies. An optimal delivery vehicle will (1) selectively target tissue and cells, (2) enter into the cell, (3) be non-toxic and non-immunogenic, and (4) precisely deliver the optimal numbers of therapeutic molecules to be most effective while reducing or eliminating off-target effects. Currently, such a delivery platform does not exist on the market. To address this need, our goal is to build a new delivery vehicle from the ground up, precision engineered to atomic detail including size, geometry, chemical composition, cargo stoichiometry and capacity, targeting capabilities, and programmed release. In our beachhead platform, we are developing a non-viral, nucleic acid-based nanoparticle delivery vehicle designed to deliver CRISPR RNPs in precise numbers to targeted cells. The delivery of intact CRISPR-RNPs, rather than viral or plasmid DNA or mRNA encoding for the protein complex, has been shown to achieve high efficiency, low off-target editing while reducing immune response, required for the development of a next generation gene editing therapeutic. Current delivery of nucleic acid therapeutics is through direct injection, viral delivery, or lipid nanoparticles. Direct injection has shown promise, especially through modifications of the nucleic acids for stability, immune evasion, and increased uptake. However, direct injection does not allow for stoichiometric, multiplexed co-delivery of therapeutic moieties and has limited targeting capacity. Viral delivery offers tissue-specific targeting through viral surface proteins, but the genetic size is limited and therefore delivery of multiple components is not feasible. Lipid nanoparticles are widely used and powerful modalities for delivery, but lack stochiometric control of cargo, nor are there refined methods for tissue- and cell-specific targeting. Here, we are developing the market for structured nucleic acid nanoparticles, which can have the benefits of each of the other delivery modalities with direct RNP delivery, tissue- and cell-targeting by surface protein display, and precise control over the cargo stoichiometry and release. Thus, we believe our technology can greatly impact the gene therapy field to help it achieve the promises it has set forth. To achieve these goals, we are investigating the marketability and intrinsic value of the technology that we have developed. To do so, we will be canvasing local biotechnology, pharmaceutical, national biological defense, and delivery industries, both startups and large companies, and hospitals in the Boston area, as well as in the San Francisco, San Diego, Seattle, Texas, and Washington D.C. areas. Through interviews we will gain a better understanding of the market as we work towards a lean business model to prove out our technology. Further, we will obtain some specific preliminary data on in vitro use of our technical platform to show functionality that will be vital for future investment, including studies on improving delivery efficiency and developing the process workflow for scaling up the platform for therapeutic needs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Feb 14, 2019
- Source ID
- W911NF1810436
Entities
People
- Mark Bathe
Organizations
- Army Contracting Command
- Massachusetts Institute of Technology
- Office of the Secretary of Defense