Writing a Potential Cure for Cystic Fibrosis

Pioneering Medicines, in partnership with the Cystic Fibrosis Foundation, is working toward a cure for cystic fibrosis by leveraging technologies from Flagship-founded companies, including Tessera Therapeutics and its pioneering GENE WRITING platform.

Cystic fibrosis (CF) is a progressive genetic disease that affects the lungs and other organs, limiting a person鈥檚 ability to breathe, making them more prone to infections, impairing their ability to absorb nutrients, and causing other complications. Most people living with CF have a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that results in a dysfunctional CFTR protein. The functional protein acts as an ion channel, helping to maintain the balance of salt and water on surfaces throughout the body, and dysfunction of this channel leads to buildup of thick mucus.

As recently as the late 鈥�90s, the median life expectancy for a CF patient was tragically only 32 years of age. CFTR modulator therapies launched since then (e.g., Trikafta) have dramatically improved survival and quality of life for CF patients, but they do not represent a true cure for the disease. Furthermore, about 10% of people living with CF are not eligible for these medications and have no effective treatment options.

Genetic medicine has the potential to deliver a curative therapy for CF patients regardless of their genetic mutation. However, while early gene therapy and gene editing technologies have shown great promise, they have limitations that hinder their application in CF.

Gene editing or nucleotide base pair editing approaches, for example, are able to knock genes out, or make a subset of single-base pair substitutions in which one nucleotide is replaced with a different nucleotide. They are not able to precisely and scarlessly insert the three base pairs that are missing to fix the most common CFTR mutation (i.e., delta F508).

Gene therapies, such as adeno-associated virus (AAV) therapy, can deliver an entire gene sequence to a cell, but are diluted over time through cell division and often trigger an immune response leading to side effects and preventing redosing.

To overcome these limitations, 蘑菇视频APP-founded is pioneering a new area of genetic medicine that harnesses nature鈥檚 greatest genomic architects: mobile genetic elements (MGEs). In contrast to CRISPR, which evolved to destroy DNA, MGEs evolved to write DNA, using RNA and DNA intermediates to move or copy their own DNA into a new location.

Tessera is building upon this foundation of MGE biology to develop Gene Writers and Gene Rewriters 鈥� new genome engineering technologies that efficiently write large or small therapeutic messages into the genome to treat diseases at their source.

The technologies can make almost any type of genomic alteration without breaking the genome or relying on DNA repair pathways. Gene writing has the potential to be a breakthrough for diseases like CF that require functionality of a critical gene to be restored, whereas today鈥檚 gene editing tools typically turn target genes off by selectively cutting DNA.

Tessera is one of the Flagship-founded companies that Pioneering Medicines is drawing on in a collaboration with the , which is exploring novel treatment options for CF from across the Flagship ecosystem. The goal of the collaboration is to develop therapeutics that address the unmet needs of people living with CF, particularly those who do not have effective treatment options today. As part of the initiative, Tessera is exploring the application of the company鈥檚 RNA Gene Writers to write a whole new functional copy of the CFTR gene at the endogenous locus, a therapy that would be agnostic to an individual鈥檚 CFTR mutation. We are also applying RNA Gene Rewriters to correct the most common CFTR mutation by writing the three missing base pairs into the delta F508 deletion.

Tessera鈥檚 lead candidates for CF are based on a class of MGEs called retrotransposons that convert RNA to DNA via a process called target-primed reverse transcription. These Gene Writers can be delivered as two RNA molecules, the mRNA encoding Tessera鈥檚 Gene Writer and an RNA template encoding the desired genetic change, within a lipid nanoparticle, which overcomes the limitations of AAV delivery to create a scalable, re-dosable genetic medicine. Once the Gene Writer mRNA and RNA template are delivered to target cells, the cell鈥檚 machinery translates the Gene Writer mRNA into Gene Writer protein. These proteins then bind to specific motifs on the RNA template. This Gene Writer-template complex then seeks out the location of the CFTR gene in the genome and, upon recognition, reverse transcribes the template RNA into a DNA sequence that resides in the genome thereafter. This process results in either a small change 鈥� for example correction of the delta F508 deletion 鈥� or a large change 鈥� writing the entire CFTR gene into place. Once the alteration is made, the cell degrades the Gene Writer, while the DNA alteration remains, potentially leading to a permanent cure.

In addition, the collaboration between Flagship鈥檚 Pioneering Medicines and the Cystic Fibrosis Foundation is also pursuing other approaches to addressing the unmet needs of people with CF, levering multiple Flagship technologies and even combinations of technologies to explore several different ways to address this disease.

Tessera鈥檚 platform has the potential to give all people living with CF normal, healthy lung function. This could be a critical step toward developing a cure for the more than 70,000 people globally with this rare disease. We still have a long road ahead for Gene Writing to deliver these benefits to patients with CF, but the progress we鈥檝e made toward our mission of curing disease by writing in the code of life gives us hope that an extraordinary new category of genetic medicines is ahead.

Story By

Geoffrey von Maltzahn

Geoffrey von Maltzahn joined 蘑菇视频APP in 2009 and serves as general partner. He is an inventor, entrepreneur, CEO, and the co-founder of multiple groundbreaking companies in healthcare and agriculture. Geoffrey has co-founded companies鈥�