The emerging field of epigenetics has caught the interest of many biotechnology industries. Epigenetics is the study of heritable changes in gene expression through modification of genes, rather than changes in the underlying DNA sequence. These epigenetic changes can occur through DNA methylation, histone modification, non-coding RNA. These changes affect the activity of encoded genes and scientists are exploring the effects of epigenetic modifications and errors on gene function, protein production, and human health.
Epigenetic modification opens many doors to new classes of therapeutics. Autoimmune disorders are many times caused by genetic mutations which behave similarly to the epigenome. Developing drugs that can manipulate epigenomic errors will offer a promising cure for cancer and other autoimmune diseases.
Chroma Medicine (Cambridge, MA) is pioneering a new class of genomic medicines that harness epigenetics to revolutionize the treatment of genetically driven diseases. In November 2021, Chroma Medicine announced $125 M in financing to deliver epigenetic editing. CEO, Catherine Stehman-Breen says “Epigenetic editing is the next frontier in genomic medicine with the potential to transform the treatment of genetically driven diseases. By harnessing nature’s innate mechanism to modulate gene expression, we can durably and precisely control gene expression without fundamentally changing or cutting the underlying DNA sequence.” With this source of financing and with a highly experienced team of innovators, Chroma is committed to achieving this vision.
Vertex Pharmaceutics (Boston, MA) led by Reshma Kewalramani has recently partnered with Mammoth Biosciences (Brisbane, CA) to develop in vivo gene editing therapies for life-threatening diseases. Mammoth Biosciences will be providing their CRISPR platform consisting of novel Cas enzymes. Vertex has also collaborated with CRISPR Therapeutics and Obsidian Therapeutics in the past to create drug therapies for sickle cell land beta-thalassemia using CRISPR technology. Vertex has a large growing pipeline for many genetic diseases where epigenetic therapy can play a role in.
Twentyeight-seven (Watertown, MA) is another company taking steps towards RNA drug discovery. Twentyeight-seven carefully selects proteins that bind regulatory RNAs to achieve simultaneous suppression of multiple oncogenic pathways and to offer a wide safety margin. Their lead target is LIN28 which controls many oncogenic pathways and the ability to inhibit multiple cancer pathways simultaneously. Twentyeight-seven is currently developing compounds to other RNA-binding proteins. Twentyeight-seven is led by an experienced team of scientists. President and CEO, Kazumi Shiosaki, was previously start-up CEO and co-founder of Epizyme, a leader in novel therapeutics.
Small-Molecule and CRISPR Technology
These innovative companies are using small molecule drugs, CRISPR technology, and novel approaches to develop therapies for cancer, sickle cell, and other diseases. When Twentyeight-seven was founded in 2016, the researchers did so to develop small molecules that would decrease Lin-28 found in cancer cells, which would increase let-7, a microRNA and cancer suppressor. Small molecule drugs have a low molecular weight that can easily enter the cell making an impact on proteins or cancer cells for example. They make great tools for targeted therapies in epigenetics. The scientists at Twentyeight-seven chose to harness the power of small molecule drugs to treat cancer, but the company has recently opened its doors to collaborate with organizations to research therapies for other diseases that stem from a dysregulated Lin-28/ let-7 pathway. Lin-28 is a “highly evolutionarily conserved RNA-binding protein involved in determining cell fate during embryogenesis of many organisms, including humans”. Most healthy people don’t have Lin-28, however it is re-expressed in some cancers and even re-activates oncogenes by decreasing the amount of let-7 present.
Vertex is using small molecule drugs and CRISPR technology in their approach as they work toward treating sickle cell disease. As previously mentioned, small molecules can be used to target areas within the cell, and CRISPR can also be used in epigenetic therapies. CRISPR-Cas9, a gene editing tool, is being used to investigate a possible one-time treatment for individuals with sickle cell disease. Sickle Cell Disease is caused by “a mutation in the beta-globin (HBB) gene”. Hemoglobin, the molecule that carries oxygen in our red blood cells, is encoded by the HBB gene. Sickle hemoglobin (HbS) is the result of mutated hemoglobin. They lead to rigid and obstructed blood vessels which in turn diminish oxygen delivery to tissues in the body. This is where CRISPR technology comes in as a potential life changing option. CTX001™ is a potential “gene-edited therapy” from CRISPR/Cas9 used to edit an individual’s stem cells in order to create fetal hemoglobin in their red blood cells. Fetal hemoglobin is an innate form of hemoglobin that has the ability to carry oxygen, but switches later in life to the adult form. The purpose of utilizing the individual’s own body to switch from adult to fetal hemoglobin is to reduce the symptoms of sickle cell disease.
Lastly, Chroma has developed an adaptable epigenetic editor that can be used to treat a wide array of diseases. This new platform uses the cell’s natural gene regulating power, according to their website, to make their approach “the modality of choice” among other gene editing competitors. While the competitors, for example, may cut DNA to indirectly regulate the gene of interest, leading to truncated or even mutant proteins, Chroma’s approach annihilates the targeted gene’s expression. These three companies have made great strides in epigenetic therapies for several diseases with more breakthroughs on the way.