Exploring a Decade of RNA Delivery: Beyond the Liver

With the potential to revolutionize the treatment of infectious diseases, cancers and single gene disorders, RNA therapeutics hold immense promise. To make this promise a reality, researchers must develop sophisticated delivery methods to ensure that RNA molecules reach the intended target cells while avoiding exposure to off-target cells. Furthermore, they must expand the scope of application beyond the liver.

Y ogev Debbi is a pioneering entrepreneur who is revolutionizing the biotechnology industry. He is the co-founder and CEO of Mana.bio, an Israel-based company that specializes in developing cutting-edge RNA and DNA delivery technologies. With Debbi at the helm of Mana.bio, the firm is quickly becoming a leader in the field and is aiming to build the “space shuttle” of genetic delivery.

The astronaut, the RNA, needs to reach the space station and fix it, but they can’t do it alone. To make this mission a success, they need the reliable aid of a space shuttle, equipped with oxygen and seatbelts that can make the journey past the atmosphere. We build space shuttles, so that our astronauts can make their way to the stars.

Debbi declared that the last two decades have been all about decoding and encoding nucleic acid, and the next will be about transporting DNA and RNA. With the progress we have made, the future looks very promising and exciting!

Eleven Therapeutics, with locations in Tel Aviv, Cambridge, U.K. and Boston, is revolutionizing the healthcare industry by combining the power of oligonucleotide therapeutics and AI. According to Iris Grossman, Ph.D., Chief Therapeutics Officer, this innovative approach will have a profound impact on the field of medicine.

For RNA therapeutics to be successful, three crucial elements must be perfected: potency, durability, and delivery. Only then can these therapeutics make it to the clinical setting and eventually the market, according to Grossman.

Most Effective Route of Delivery?

Grossman declared that the conjugate class is the most effective and efficient way of delivering RNA.

The CMC and its characterization efforts have a single backbone that is essential to your main moiety. This unity of purpose is essential for success, as it brings together all the elements that make up your main entity.

Conjugates are an incredibly powerful tool in drug delivery, as they are able to target specific receptors with impressive precision. These receptors are often composed of small molecules, antibodies, and/or aptamers, allowing the conjugate to selectively bind to only the desired area. This method of delivery allows for a much more efficient and effective treatment, as it is able to precisely target areas of need.

N-acetylgalactosamine (GalNAc) short interfering RNA (siRNA) conjugates offer a unique opportunity for targeted delivery of siRNAs to the liver. A 2018 review in Nucleic Acid Therapeutics revealed that Tris-GalNAc binds to the asialoglycoprotein receptor, which is highly expressed on hepatocytes, allowing it to rapidly enter the cell through endocytosis. Despite the uncertainty surrounding the exact mechanism of action, these siRNA conjugates have been shown to elicit a robust and target-selective RNAi response in vivo.

Despite many attempts, very few alternatives to GalNAc, a molecule that plays a crucial role in the functioning of healthy cells, have been discovered. According to Dr. Grossman, this holds true for other tissues as well, leaving us without a viable solution for many issues.

She noted that while Lipid Nanoparticles (LNPs) are an appropriate solution in the absence of conjugates, there are potential issues with immunogenicity and cytotoxicity that should be taken into account, particularly when considering frequent and repeated doses for long-term treatment.

In order to broaden the range of delivery options, Dr. Grossman emphasized the use of antibodies and polymers, as well as the addition of targeting moieties to LNPs to direct delivery to specific types of cells. By utilizing these strategies, researchers can explore new possibilities and open up more efficient and effective drug delivery avenues.

Lungs: The Next Frontier?

The lung has recently become a prime target for RNA therapeutics, leading to a surge of interest in its potential to revolutionize treatments. With its unprecedented potential to treat a wide range of diseases, the lung is now at the forefront of medical research and innovation.

Mana.bio has developed an innovative AI/ML-based delivery system based on lipid nanoparticles (LNPs), which are able to precisely target the lungs, completely bypassing the liver. This groundbreaking technology promises to revolutionize drug delivery and treatment.

For the first time ever, AI has been used to create an innovative LNP delivery system for mRNA, which could potentially be a groundbreaking solution to treating single-gene diseases such as cystic fibrosis (CF). This new system has the potential to revolutionise the way mRNA is administered to cells in order to effectively treat these conditions.

Mana.bio is on the hunt for collaborators to tap into its innovative delivery technology for the perfect payloads and indications. The company is also focusing on expanding its RNA delivery capabilities to other organs. With its cutting-edge technology, Mana.bio is setting the stage for a new era of delivery solutions.

Grossman delved into the world of RNA interference modalities, including the use of antisense oligonucleotides (ASOs) and siRNAs. These modalities offer great promise for future advances in the field, and Grossman expounded on their potential applications.

The remarkable precision and potency of CRISPR-based gene therapies have been well-documented, yet the challenge of delivering these treatments to their intended target remains. To date, only the liver has been successfully targeted using this method, highlighting the need for further development in this area.

Come and join Dr. Grossman as he leads a session devoted to addressing the challenge of ex-liver delivery of nucleic acid therapeutics and discovering new horizons to cure rare disorders at the upcoming Biomed Israel conference. This session will explore facts and myths on this topic, and provide a platform to discuss potential solutions. Don’t miss this chance to learn more about this exciting and important area of exploration!

Eleven is revolutionizing the field of chemistry with its AI-based platform, allowing scientists to explore the entire chemical space and uncover the hidden connections between the structure and activity of RNA molecules. By unlocking these secrets, Eleven is ushering in a new era of more precise and effective medicines.

The groundbreaking DELiveri platform from the company allows for the precise insertion of a genetic circuit into the desired cell, revolutionizing gene engineering.

Using mass spectrometry, scientists can achieve a highly efficient screening engine. With this technology, researchers are able to both amplify the intensity of the signal and reduce background noise, making it incredibly selective. This provides a powerful tool for identifying and analyzing molecules and compounds.

Using the latest DNA-encoding technology, the company is able to run a library of cells with hundreds of thousands of entities simultaneously. By utilizing this process, the company is able to screen vast numbers of entities in a single go. It’s a remarkable breakthrough in the world of scientific research.

Eleven is partnering with the Bill & Melinda Gates Foundation to develop groundbreaking prophylactics against COVID-19 and the flu, as well as a third indication targeting a yet-to-be-named chronic respiratory disease, which is closely related to the company’s primary focus. These prophylactics have the potential to revolutionize the way we prevent and treat respiratory illnesses.

SpliSense is revolutionizing the way Cystic Fibrosis is treated! Located just 45 minutes away in Jerusalem, they are utilizing their innovative technology to deliver an effective treatment directly to the lungs via inhalation. This groundbreaking approach is making a real difference in the lives of those suffering from the condition.

SPL84, the company’s lead asset, has the potential to revolutionize care for cystic fibrosis (CF) patients carrying the 3849+10 kilobase (Kb) C->T splicing mutation in the CFTR gene. Developed with the aim of providing a transformative treatment option, SPL84 is poised to make a lasting impact on the lives of those affected by this mutation.

SPL84 is a remarkable RNA molecule, incredibly small, short and single-stranded. Its ability to enter the cell without any need for a carrier or lipid nanoparticles is nothing short of astonishing. According to Gili Hart, Ph.D., CEO, SPL84 is truly a remarkable feat of nature.

Vertex is pioneering a groundbreaking mRNA therapy, VX-522, designed to treat the root cause of CF lung disease. In an innovative collaboration with Moderna, the therapy is delivered via inhalation of a lipid nanoparticle encapsulating CFTR mRNA, offering a revolutionary solution to this debilitating condition.

Targeting the Brain

RNA therapeutics offer exciting potential for treating a wide range of neurological diseases beyond the lung. By targeting specific areas of the body, these therapeutics offer a promising new way to address a variety of neurological disorders, from Parkinson’s Disease to Alzheimer’s Disease and beyond. With the potential to revolutionize treatments for these complex conditions, RNA therapeutics hold the promise of improving the quality of life for many patients.

The formidable blood-brain barrier has long presented a challenge to delivering treatments for neurological diseases. However, advances in the field have made it possible to develop RNA-based therapeutics that can overcome this obstacle. Examples include Sarepta Therapeutics’ Exondys 51 (eteplirsen) for Duchenne muscular dystrophy and Biogen’s Spinraza (nusinersen) for spinal muscular atrophy, both of which have been approved for use. With continued advances, researchers are hopeful that more treatments may soon become available to those suffering from neurological diseases.

A plethora of promising treatments are on the horizon for Huntington’s Disease, ALS and frontotemporal dementia. Amsterdam-based uniQure is developing AMT-130, a microRNA-based therapy that reduces the production of mutant HTT, while Wave Life Sciences is working on oligonucleotide treatments that could offer a breakthrough in these conditions. With so many potential therapies in development, hope is on the horizon for those affected by these devastating diseases.

RNA therapeutics have tremendous potential to revolutionize the treatment of diseases such as Parkinson’s and Alzheimer’s. By targeting specific components of the underlying biology, these therapies offer an exciting new approach to tackling conditions that have long posed an immense challenge to researchers and health care professionals alike. With RNA therapeutics, we may finally be able to gain a better understanding of these diseases and develop effective treatments for them.

Designing an astronaut is the first step to achieving an out-of-this-world experience. With the right vision and creativity, this will lead to a mission of exploration and discovery like no other.

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