Modulating Gene Expression to Stop Diseases in Their Tracks: a Pioneering Journey
The Omega Therapeutics Team/Courtesy Omega Therapeutics
Nestled in the heart of Genetown, Omega Therapeutics is harnessing the power of epigenetics in an unprecedented way and engineering programmable epigenetic mRNA therapeutics to transform medicine in the service of patients.
“If this works out in the clinic as we intend it to, we will literally transform medicine because we can specifically target the biological root cause of disease, irrespective of the etiology,” said Mahesh Karande, Omega’s President and Chief Executive Officer. “We are simply restoring aberrant gene expression to a normal range and resetting cellular programs without altering native nucleic acid sequences, which we believe will ultimately lead to safer therapeutics and potentially cure disease.”
Omega does this through a fundamental understanding of the organization of the genome. Nature, in its infinite wisdom, has organized genes and their regulatory elements in evolutionarily conserved 3D structures of DNA called Insulated Genomic Domains (IGDs). There are approximately 15,000 IGDs distributed across our 23 chromosomes, and these contain essentially all the genes in the human genome. Omega is therapeutically leveraging this universal operating system for genomic control through its Epigenomic Programming™ platform to rationally design and engineer modular, programmable epigenetic mRNA medicines that can modulate specific 3D loops and control individual or multiple genes, called Omega Epigenomic Controllers™ (OECs).
The platform builds upon the work of Flagship Pioneering and of Drs. Richard Young, Ph.D. and Rudolf Jaenisch, M.D., who in 2016 first identified how 3D closed loops of DNA control genomic activity. As far as Karande knows, Omega is the only company pioneering drug development from an IGD biology standpoint.
There are approximately 200 different cell types in the body, and they all share the same genes. “Epigenetics is what controls changes in gene expression and cellular programs, which determine the identity and function of each cell type, without any changes to the DNA sequence,” said Thomas McCauley, Ph.D., Omega’s Chief Scientific Officer. “Because epigenetics acts at a level above the genome, it is really nature's universal operating system for controlling gene expression.”
The DNA and proteins in human chromatin contain epigenetic or chemical marks that control the state of chromatin, either compacting it to reduce gene expression or opening it up to enhance gene expression. Whereas most companies target epigenetic regulators that work across the genome, Omega takes a more precise approach. “Modulating those marks in a specific and controlled way allows us to precisely tune either one gene or multiple genes, up or down, to treat a particular indication” is what McCauley believes will enable the company to develop game-changing therapeutics. “Our pioneering platform approach allows us to explore historically undruggable targets or inaccessible therapeutic indications,” he explained.
As most of our DNA is regulated by epigenetically controlled 3D structures, Karande shared that the platform has broad applicability and should be able to treat “pretty much any disease by controlling gene expression.” He added, “While monogenic diseases are the ‘table stakes’ of most gene therapy approaches, we feel the true transformative potential of the Omega platform lies in our ability to target complex, real-world diseases with tremendous unmet patient need in areas like oncology, multigenic diseases and regenerative medicine. Epigenetic dysregulation is well-known to play a central role in cancer and targeting master oncogenes like MYC pre-transcriptionally is key to our ability to successfully tune their expression. In multigenic diseases, such as inflammatory syndromes, we can control multiple genes with a single therapeutic by targeting a specific IGD where multiple cytokine genes are co-located.”
The platform’s extensive therapeutic potential encompasses regenerative medicine, where he envisions reconstituting the expression of genes necessary to generating physiologic tissue and organ function. This scope, he said, could also extend to age-related diseases.
The ability to target highly complex diseases where multiple genes are in play with a single therapeutic is a unique differentiator of Omega’s platform. Karande offered the example of acute respiratory distress syndrome (ARDS) that can follow COVID-19 infection. In ARDS, a number of cytokines are overexpressed, creating a cytokine storm that leads to damaging immune hyperactivation. Omega’s platform can tackle the overexpression of multiple genes through a single therapeutic.
The breadth of the approach becomes clear when thinking of IGDs as containing “epigenomic zip codes” which the Company refers to as EpiZips. Omega has mapped and validated hundreds of thousands of unique epigenomic targets to go after.
So far, Omega has demonstrated in vivo proof of concept in disease models, including hepatocellular carcinoma, non-small-cell lung cancer, ARDS and chronic liver disease. Karande is proud of how far the company has come after just four and a half years in existence. “This company was created years ahead of known biology, and we've taken that and converted it into a very deterministic programmable drug development platform,” he said. “We have demonstrated that this biology works in four distinct disease areas so far.”
Also inspiring his confidence is the deterministic nature of the platform because its role is to create programmable and engineered medicines that can be rationally designed.
“Once we lay that epigenetic mark, we know that if nature does its work, we are replicating and tuning the gene to the appropriate level of expression,” he said.
As Omega continues to “thoughtfully prosecute” these programs, the company will rely on its unique ethos, which is ambitious yet humble. “When you are on a pioneering journey, developing medicines that have never been created before, you have to have the highest level of ambition,” Karande said. “On the other hand, you have to have a tremendous amount of humility. We are not doing this alone; we are building on the work of a lot of people, and secondly, we have to earn the right to give these medicines to patients.”
The “ambitious yet humble” motto was embodied by one of Karande’s heroes: Nelson Mandela, the former South African president and anti-apartheid revolutionary.
“Imagine being in prison for 27 years for what you believed in, coming out and building a great democracy, a true rainbow coalition, with no malice in your heart towards anybody. That requires tremendous ambition and a lot of humility,” he said. A painting of Mandela hangs above Karande’s desk; a reminder of his time with Novartis as President and Head of Africa, Pharma and Oncology.
The company will also need more ambitious yet humble leaders as it advances in its pioneering journey toward bringing its programmable epigenetic medicines to human trials. Since 2019, when both Karande and McCauley came on board, Omega has expanded from 20 people to a team of nearly 100, all with the burning ambition to succeed, however, still grounded in humility given the enormous responsibility of eventually treating patients with potentially transformative medicines. As it transitions to a development-stage company, Karande expects to add many more.
Omega hires people with “high learning agility,” he said, and with such a therapeutically broad platform, there is considerable potential for employees to try on different roles. “As science goes, we are living in unprecedented times with an extraordinary understanding and control of biology that has enabled life-saving medicines to emerge. If 2021 has taught us anything, it is that innovative science wins.”
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