The next frontier of precision medicine — editing the epigenome
Gene editing has taken the biotech world by storm since the initial discovery of CRISPR-Cas9, which holds the promise of a potential one-time treatment. In the past couple of years, we have started to see gene editing approaches driving a benefit in human disease with CRISPR Therapeutics showing clinical efficacy for their ex-vivo editing approach in sickle cell disease/β-thalassemia; Intellia showing positive clinical data for their ATTR amyloidosis program; and Editas showing a benefit for their LCA10 program.
However, despite significant scientific progress, first generation platforms still have limitations in terms of breadth of targets, ability to address multiple targets at once, and genotoxicity concerns. Researchers in academia and industry have since iterated upon these initial gene editing tools to overcome some of these concerns — with epigenome editing being one of the most promising examples.
Epigenetics 101
The somatic cells in our body have the same DNA that together encode ~20–25k genes, but yet there are approximately 200 different cell types in the human body, each with their own specialized function. These cellular differences can be explained by epigenetics. Epigenetic changes are controlled by a diverse set of proteins that can alter the structure of chromatin to turn genes “off” and “on.” These changes include DNA methylation, histone methylation, histone acetylation, and others. The resulting difference in gene expression pattern leads to a different set of genes that are expressed in each cell.
Epigenome editing is a new frontier in genomic medicine
Epigenome editing leverages the cell’s endogenous system to enable the regulation of gene expression without modifying the underlying DNA sequence. At the core, an epigenome editor consists of two parts connected by a linker:
(1) Catalytically inactive (non-cutting) DNA binding domain (DBD): precisely localizes effector domains to target specific region on DNA. Examples include dCas9 (cas9 with endonuclease domain that is mutated so it can bind DNA but does not cut DNA) and zinc fingers.
(2) Effector domains (EDs): One or more protein(s) that elicits a change in the epigenome. Of note, multiple epigenome effectors can be combined to augment a desired effect. Examples include transcriptional repressors (e.g. KRAB), transcriptional activators (e.g. VP64), DNA methyltransferases (e.g. DNMT3A), DNA demethylases (e.g. TET1).
Epigenome editing is a potentially tunable system where the effector domain(s) can be adjusted so that modifications can be transient or permanent and gene expression can be upregulated or downregulated and by different degrees.
Epigenome editing provides several advantages over other genomic medicine approaches including:
1. Improving safety and genotoxicity concerns: with epigenome editing, there is no cutting of the DNA which obviates concerns around DNA mutagenesis/translocation risk, activation of DNA damage responses, and off-target DNA editing.
2. Enabling multiplex regulation of genes: with epigenome editing, a single epigenome editor can be given with multiple gRNAs to downregulate/upregulate multiple genes simultaneously as the genotoxicity concern (particularly around translocations) is reduced.
3. Increasing the breadth of addressable targets: with epigenome editing, it is possible to now target non-coding RNA, novel epigenetic targets, and even increase expression of whole genes. For genes where there are concerns with overexpression, epigenome editing can achieve native levels of gene expression by maintain all of the natural regulation encoded in the endogenous locus, including promoter, distal regulatory elements, UTRs and microRNA regulation, isoforms and splicing, etc.
Pioneering epigenome editing at Chroma Medicine
The first time I met the management team at Chroma Medicine, I knew they were building something special. Chroma Medicine has assembled a world class team, a differentiated platform, and a strong pipeline to really enable the company to be a leader in the epigenome editing field, particularly around single administration (‘hit-and-run’) approaches where transient expression of an epigenome editor can lead to stable and permanent gene expression changes.
Chroma Medicine has gathered some of the leading scientific researchers in epigenome editing and gene editing as part of the founding scientific team including David Liu (Broad), Keith Joung (MGH), Jonathan Weissman (Whitehead), Luigi Naldini (SR-TIGIT), Luke Gilbert (UCSF, Arc), and Angelo Lombardo (SR-TIGIT).
- Jonathan Weissman and Luke Gilbert were involved in the foundational epigenome editing publications in 2013 that showcased the ability to leverage dCas9 for sequence-specific control of gene expression (Qi et al. Cell 2013, Gilbert et al. Cell 2013).
- Angelo Lombardo and Luigi Naldini showcased proof of concept that a transient administration of an epigenetic editor can drive a durable change in gene expression in 2016 (Amabile et al. Cell 2016).
- Jonathan Weissman and Luke Gilbert subsequently demonstrated in 2021 that a single fusion construct could enable durable epigenome editing through >450 cell divisions (Nunez et al. Cell 2021)
- David Liu and Keith Joung are both scientific co-founders in many next generation gene editing therapeutic companies. David Liu is a scientific founder behind Beam Therapeutics, Editas Medicine, and Prime Medicine among others. Keith is a scientific founder behind Beam Therapeutics, Editas Medicine, and Verve Therapeutics among others.
Chroma Medicine has built a prolific product engine with multiple programs in development for both single and multiplex gene regulation in in vivo and ex vivo settings. The company recently presented exciting data at ASGCT 2023:
- Epigenetic editor targeting PCSK9 showed 99% silencing of PCSK9 in vivo after a single dose of the epigenetic editor through 5 months of observation with no detectable off-target changes in gene expression or methylation.
- Epigenetic editor targeting the HBV genome demonstrated robust and durable reduction of Hepatitis B surface antigen (HBsAg) below the lower limit of quantification after a single administration in a transgenic HBV model.
- Epigenetic editor in primary T cells demonstrated simultaneous editing of three genes with no indels, genomic alterations, or chromosomal rearrangements. In contrast, simultaneous triple editing with a cas9 nuclease generated significant chromosomal abnormalities.
Chroma Medicine joins Mubadala Capital’s biotech investment portfolio
We are excited to be part of Chroma Medicine’s $135 million Series B fundraising round alongside GV, ARCH, DCVC Bio, Sixth Street and existing investors. Chroma Medicine joins other visionary companies in Mubadala Capital’s biotechnology portfolio in next generation cell & gene therapy technology such as Pretzel Therapeutics, Orca Bio, Alloy Therapeutics and Lyell Immunopharma.
Chroma Medicine is using this new financing to progress the development of existing pipeline programs while continuing to scale its next generation epigenome editing platform. Our team is excited about the potential of Chroma Medicine and its critical role in building precision epigenome targeted medicines and are thrilled to be partners on this journey.
