Prominent Names in RNA Delivery Discuss What’s Around the Corner
Oxford Global kicked off another exciting discussion group all about RNA therapeutics and emerging technologies for their delivery. Those attending were experts from the leading authorities in the field. Leading the conversation was Susan Rosenbaum, Founder, Chairman, and CEO of Lauren Sciences, a company that has been the recipient of twelve foundation grant awards and won first prize for Global Healthcare Innovation, at BIO 2019. Also in the group were key experts and representatives from Johnson & Johnson, BioNTech, AstraZeneca, and Boehringer-Ingelheim, to name a few.
During the discussion, we heard about Lauren Sciences’ innovative technology, V-Smart®: a global solution for RNA targeting the central nervous system. We also heard from Dr Cees van Rijn, Professor of Nanotechnology and Microfluidics at the University of Amsterdam, about his team’s work on Vibrating Mesh Nebulisers and their opportunities for pulmonary delivery.
The central dogma of molecular biology: that DNA gets transcribed into RNA, which then synthesise proteins. There are also forms of RNA (e.g., shRNA, siRNA, miRNA) that affect production/activity of proteins and, thus, have therapeutic potential. RNA, therefore, should be seen as an invaluable tool for pharmaceutical scientists across the board. Although there is so much potential in RNA, a therapeutic is ineffectual if not able to make it to the right cells, that’s why drug delivery is such a necessary pursuit.
V-Smart® and overcoming the BBB challenge
Ms Rosenbaum started the discussion by outlining how her company is solving what is perhaps the most notorious challenge of delivering RNA therapeutics. This is, of course, the challenge posed by the blood–brain barrier (BBB) when delivering to the central nervous system (CNS); many therapies simply refuse to cross the BBB or, when directly injected into the brain, do not diffuse, and reach their target cells.
However, Lauren Sciences’s V-Smart® technology uses nanovesicle encapsulation in order to provide non-invasive, oral and IV delivery to the brain. The V-Smart® platform is able to encapsulate any oligonucleotide therapy and transmit them to the brain crossing the dreaded BBB; whether it is an mRNA, siRNA, or DNA therapeutic, the system works the same. Furthermore, once these encapsulated therapeutics have made it across the barrier, the V-Smart® system is able to target specific brain cells, further specialising the therapeutic approach.
Their technology uses what they have coined a “brain delivery trifecta”: Macro brain-targeted delivery pre-release, micro brain cell-specific targeting, plus internal cell effects, yielding many advantages. Chief among them being the ability to sustain a selected, targeted release. The V-Smart® therapeutic (containing encapsulated drug) spreads throughout the brain first before, then, targeting the specific cells it needs to. Along with this, Lauren Sciences promises no need for agent modification, high stability, and no degradation.
“The many possibilities for this technology are almost overwhelming.”
Ms Rosenbaum says that Lauren Sciences’ “competitive edge” is the fact that it has been shown to be safe and effective in preclinical animal efficacy trials. The many possibilities for this technology are almost overwhelming. Lauren Sciences is developing V-Smart® therapeutics where macro-targeting is used for neuro-AIDS and chronic pain applications; while other V-Smart® therapeutics are, in addition, micro-targeted to deteriorating motor neurons, dying brain cells, and dopaminergic neurons in ALS, Alzheimer’s, and Parkinson’s applications, respectively. With V-Smart® drugs for ALS and Parkinson’s already proven themselves in animal efficacy models, who knows what new modalities could be around the corner?
Tackling degradation in pulmonary RNA delivery
Dr Cees van Rijn then chimed in to discuss his team’s work on reducing the particle degradation of vibrating mesh nebulisers to achieve pulmonary RNA delivery. Inhalation of RNA is a very worthwhile field to develop. One reason for this is the fact that when vaccines are delivered directly to the lungs, a smaller dose is required to trigger the same immune response as injection, around 20%. Furthermore, it has been suggested that up to 20% of people have an aversion to needles and would prefer to have drugs delivered via an inhaled method, this makes inhalation prosperous for uptake in vaccine and other RNA therapeutic compliance.
Vibrating mesh nebulisers for the delivery of RNA therapeutics work by pushing RNA molecules through nanometre-scale holes in a mesh. Positively charged lipids then bind to the negatively charged RNA and form the inner core of the lipid nanoparticle. The problem that Dr van Rijn and his team at the University of Amsterdam are working to tackle is the fact that the force that is required to push the nanoparticles through the mesh can often deform their nanoparticle structure and even the chain length of the mRNA molecules. When the structure of these particles becomes stressed like this, there is a tendency for the nanoparticles to break down into many sub-particles, possibly ruining their cell permeation efficacy.
It was this understanding of nanoparticle degradation that led Dr van Rijn and his team to test the efficacy of a novel syringe-based nebuliser that uses constant pressure instead of aggravating vibrations. They ultimately found that the standard vibrating mesh devices produced particles with a degradation of 20–40%, whereas the novel syringe-based nebuliser produced particles with only a 2–5% level of degradation, a huge improvement. Dr van Rijn concluded that “the more energy you need to make your nebule, the more degradation of nanoparticles you will find.”
“We've been approached by companies about targeting the ear barrier or the eye barrier and these would all be by non-invasive administration.”
More modalities, more advances
The excitement in the delivery of therapeutics lies in the endless new syntheses and approaches to be tried. Dr van Rijn and Ms Rosenbaum both were decided on some of the special difficulties they would face. Flirting with the subject of nasal delivery, Dr van Rijn commented that: “of course, it’s always problematic to get the right dose into the system”. Perhaps more optimistically, he suggested that Lauren Sciences consider how V-Smart® might fare for pulmonary delivery; “provided, of course, that you make a nebulisation with the carriers, and they stay intact.”
Ms Rosenbaum did reply that she “firmly believed” V-Smart® could be used to target organs other than the brain, such as liver or lungs: “We've even been approached by companies about targeting the ear barrier or the eye barrier and these would all be by non-invasive administration.” However, Ms Rosenbaum made clear that this prediction relates to the distant future. For now, they stick to the CNS due to its uniqueness and lack of current delivery modalities.
Final thoughts on the importance of mRNA therapeutics in the COVID era
The COVID era has seen mRNA go from fairly niche scientific jargon to a near household name, thanks to Pfizer-BioNTech and Moderna’s latest vaccine achievements. Ms Rosenbaum emphasises that it is exactly these accomplishments that prove the importance of the field. Pondering an op-ed written in The Wall Street Journal about mRNA, Ms Rosenbaum said it was always curious to read about pharmaceutical science when it breaks out of the realm of pure science and into public discourse, calling it “very positive and very interesting”. Thanks to developments in mRNA, especially in vaccines, Ms Rosenbaum proclaimed, “I think humans on earth might well live into their 100s.”
For more information about the exciting developments in formulation and delivery, you can sign up to Oxford Global’s formulation & delivery newsletter to receive new content every month. Why not also consider seeing the experts in the field speak on important advances in RNA therapeutics at Oxford Global’s next RNA Therapeutics & Delivery conference.
