Taking siRNA Treatments Beyond the Liver

Arthur T Suckow

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5 min read

It was during my PhD in Pharmacology at UC San Diego that I found my desire to launch a biotech company. Amazed by the innovation in the local scene, I was itching to forge ahead – but I also knew that it would be wiser to learn the ropes of drug discovery and development first. With that in mind, I started my career working on small molecules for diabetes at Johnson & Johnson, and then continued that thread in a subsequent job with AstraZeneca way out east in Maryland. A return to San Diego brought me to Regulus Therapeutics, where my work on RNA therapies for serious diseases began. All of this experience fed into the next step in my career, the 2017 launch of DTxPharma. And that’s where the story of the FALCON platform began.

Unlocking the promise of RNA-targeting therapeutics to treat serious diseases has been a goal of the industry for decades. RNA therapeutics can engage targets that are otherwise “undruggable” and open up new avenues for treating diseases by enabling the precise knockdown of a target messenger RNA (mRNA) transcript. They are also relatively simple to manufacture. 

There are many different classes of RNA-based therapeutics, including antisense oligonucleotides (ASOs), aptamers, small interfering RNAs (siRNAs), microRNAs (miRNAs), and mRNA. And the field is rapidly expanding thanks to the recent successes of particular RNA therapies that have validated their clinical utility. One such therapy is nusinersen – a splice-switching ASO that was approved by the FDA in 2016. This drug became the first to treat spinal muscular atrophy. Another example is the drug patisiran, which treats hereditary transthyretin amyloidosis (hATTR) – another rare and devastating disease. Approved in 2018, patisiran was the first siRNA drug to reach the market. 

However, translating potential RNA therapies into a clinical reality is no small feat. One of the major challenges is being able to deliver the drug into the right cell in the right tissue. Cells have evolved over billions of years to prevent attack by viruses that contain RNA molecules and thus siRNAs cannot efficiently penetrate cells to allow the RNA therapy to repress gene expression. Another challenge with siRNAs is that they are rapidly cleared from circulation by the kidney before reaching the target tissue. In fact, most of the recently approved siRNA therapies work only in the liver and therefore limit the number of diseases we can treat with this therapeutic modality. Solving these delivery challenges would open the door to treating many more genetic diseases that require the repression of a disease-causing gene in tissues beyond the liver. And that’s exactly what we have been working on at DTx.

We have developed a platform called FALCON, which stands for “fatty acid ligand conjugated oligonucleotide.” FALCON consists of two components: the first is a small interfering RNA (siRNA) that is a powerful therapeutic modality for inhibiting the expression of disease-causing genes, and the second is a fatty acid motif – a combination of fatty acids that are optimized for the type of tissue we are targeting. Linking these fatty acid motifs to the siRNA enhances biodistribution and cellular uptake, and allows the treatment to perform better at repressing disease-causing genes in tissues beyond the liver.

FALCON’s siRNAs are made up of two RNA strands. The passenger strand connects to the fatty acid motif and the guide strand acts as a template for interacting with target messenger RNA. Upon delivery of the FALCON siRNA into the bloodstream, the attached fatty acid motif binds to chaperones – albumin and other circulating blood proteins, allowing the siRNAs to be readily distributed throughout the body, while preventing rapid clearance of the siRNA by the kidneys. Upon reaching the target tissue, the FALCON siRNA dissociates from the albumin and interacts with fatty acid receptors, enabling the uptake of the siRNAs into the target cell. Once within the cell, the siRNA interacts with its target mRNA via the RNA-induced silencing complex (RISC). This interaction subsequently leads to cleavage and triggers degradation of the target mRNA, ultimately reducing the expression of the disease-causing proteins. 

In preclinical studies, FALCON siRNAs have demonstrated potent and durable repression of target genes, with a good safety profile. We’ve proven that they can be delivered through multiple routes of administration (namely IV, SQ, IT, and IVT), and can be manufactured at a relatively low cost. The next step in the FALCON’s mission is target selection. 

At present, our portfolio of FALCON siRNAs is focused on rare diseases, with an initial emphasis on neuromuscular, muscle, and CNS therapies. The company’s lead program is focused on Charcot-Marie-Tooth 1A or CMT1A, a debilitating and progressive neuromuscular disease and the most common inherited neuromuscular disorder. Around 150,000 people in the US and EU live with this condition, and there are currently no approved therapies.

CMT1A is driven by a duplication of the PMP22 gene in Schwann cells, which are responsible for myelinating axons. The over-expression of PMP22 prevents proper myelination of peripheral nerves​, leading to significant disability and a poor quality of life. Our PMP22-targeted FALCON siRNA, called DTx-1252, reverses the disease in the gold standard preclinical model of CMT1A and achieves meaningful tissue exposures, deep target repression, and a wide safety window based on studies in non-human primates (NHPs) and rodents. We are planning to enter the clinic with this program in 2023.

In addition to our lead program, we have several other plates spinning. In rodent and NHP studies, we have achieved potent and durable knock down of genetic targets in muscle tissues, and so we now have a FALCON siRNA targeting a rare, neuromuscular disease in preclinical development. Also, based on encouraging rodent data that show we can achieve potent repression of genetic targets in the CNS, we have initiated a program in a rare CNS disease. Further still, we have early and encouraging preclinical target repression data in skin, heart, and lung tissue, demonstrating a rich opportunity to develop FALCON siRNAs to treat diseases in many therapeutic areas that were previously untreatable.

The evolution of FALCON over the last five years required the support and patience of an army of family, friends, colleagues, and investors. I’m proud of our accomplishments so far and very much look forward to moving FALCON into clinical development over the next 12 months. 

Falcon asset from Pexels

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