Axial: https://linktr.ee/axialxyz
Axial partners with great founders and inventors. We invest in early-stage life sciences companies such as Appia Bio, Seranova Bio, Delix Therapeutics, Simcha Therapeutics, among others often when they are no more than an idea. We are fanatical about helping the rare inventor who is compelled to build their own enduring business. If you or someone you know has a great idea or company in life sciences, Axial would be excited to get to know you and possibly invest in your vision and company . We are excited to be in business with you — email us at info@axialvc.com
Odyssey Therapeutics develops precision immunomodulators and oncology medicines. Founded in 2021, the company assembled a team of experienced drug developers & scientists to efficiently select targets and define therapeutic profiles. Led by Gary Glick who previously founded companies from Scorpion Therapeutics & First Wave Bio to IMF Therapeutics.
Odyssey is premised on 3 pillars: (1) targets with strong (genetic) validation, (2) expanding the druggable genome, and (3) pursuing MoAs to treat larger patient populations. With experience in drug discovery & foundational biology as the leading advantage, the company has built a technology platform to use ML/systems biology to mine pathways for targets, use genomics to validate them, and match a modality for target modulation.
Building a pipeline across oncology and immunology. Drugging transcription factors, Tregs, and more. Mainly with small molecules. Working to make their workflow more efficient: ID'ing relevant targets, determine pharmacological mechanisms of intervention to correct the disease, and optimizing their candidates for clinical development.
Evolution of an adenine base editor into a small, efficient cytosine base editor with low off-target activity
The paper invents a new class of cytosine base editors (TadCBEs) derived from the deoxyadenosine deaminase TadA-8e. TadCBEs are smaller and exhibit lower off-target activity than current CBEs, while maintaining high on-target activity.
TadCBEs were developed using phage-assisted continuous and non-continuous evolution (PACE/PANCE) to change the substrate specificity of TadA-8e from adenosine to cytidine. TadCBEs are highly active and exhibit similar or higher C:G-to-T:A editing efficiencies compared to current BE4max, evoAPOBEC1-BE4max (evoA) and evoFERNY-BE4max (evoFERNY) CBEs across a variety of sites in mammalian cells. Off-target analysis reveals that TadCBEs induce lower Cas-independent off-target DNA and RNA editing than widely used APOBEC-based CBE variants. The addition of a V106W mutation further reduces off-target editing by TadCBEs, refines their editing window and improves C:G-to-T:A selectivity while preserving peak on-target editing efficiency.
TadCBEs were extensively characterized using a library of 10,638 genomically integrated, highly variable target sites in mouse embryonic stem cells (mESCs) to determine the selectivity and sequence context preferences of TadCBEs. TadA-CDs are also compatible with SpCas9 (PAM = NGG), evolved eNme2-C Cas9 (PAM = N4CN) variants and SaCas9 (PAM = NNGRRT), facilitating broad target accessibility. Finally, the authors demonstrated that TadCBEs can be used for efficient multiplexed cytosine base editing in primary human T cells at therapeutically relevant loci and for cytosine base editing at a therapeutically relevant site in primary human hematopoietic stem and progenitor cells (HSPCs).
https://www.nature.com/articles/s41587-022-01533-6
Reprogrammable TnpB polypeptides and use thereof
This patent discloses programmable TnpB polypeptides and their use in targeted gene modification & nucleic acid editing. TnpB proteins are hypercompact RNA-guided DNA endonucleases. The engineered TnpB polypeptides are made up of a RuvC-like domain and an nucleic acid component (coRNA) with a scaffold and a reprogrammable spacer sequence. The coRNA molecule can form a complex with TnpB and target a polynucleotide.
The TnpB polypeptides can cleave the polynucleotide, introducing base edits, and inserting new sequences. The patent also discloses vectors and cells comprising the engineered TnpB polypeptides and coRNA molecules. Offering a new effector for gene editing.
https://patentimages.storage.googleapis.com/6a/29/9f/c218299b16d61c/WO2022159892A1.pdf
How does phage-assisted continuous evolution work?
Phage-assisted continuous evolution (PACE) is a technique for evolving proteins by using bacteriophages to amplify and select for advantageous mutations. In PACE, a gene encoding the protein of interest is inserted into the genome of a bacteriophage. The bacteriophage is then used to infect a culture of bacteria. The bacteria that produce the protein of interest will be more likely to be infected by the bacteriophage and will therefore produce more bacteriophages. This process is repeated over many generations, allowing for the accumulation of mutations in the gene encoding the protein of interest.
PACE is a continuous evolution technique because the selection and amplification of advantageous mutations occurs continuously, without the need for human intervention. This makes PACE a very efficient way to evolve proteins.
PACE has been used to evolve a wide variety of proteins, including enzymes, antibodies, and receptors. It has also been used to evolve proteins with new functions, such as the ability to bind to new molecules or to catalyze new reactions:
1. A gene encoding the protein of interest is inserted into the genome of a bacteriophage
2. The bacteriophage is used to infect a culture of bacteria
3. The bacteria that produce the protein of interest will be more likely to be infected by the bacteriophage and will therefore produce more bacteriophages
4. The bacteriophages are then collected and used to infect a fresh culture of bacteria
5. This process is repeated over many generations, allowing for the accumulation of mutations in the gene encoding the protein of interest
6. After many generations, the bacteriophages are collected and the gene encoding the protein of interest is sequenced
7. The sequenced gene is then used to produce the protein of interest, which has now been evolved to have new or improved properties
Scientist Stories: Terry Orr-Weaver, Cell Division and Chromosome Segregation
Orr-Weaver's research addresses regulation of cell division during development, and her laboratory has discovered crucial control proteins for chromosome segregation and DNA replication as well as providing key insights into how cell size is regulated during development
TopOMetry systematically learns and evaluates the latent dimensions of single-cell atlases led by Davi Sidarta-Oliveira & Licio Velloso https://www.biorxiv.org/content/10.1101/2022.03.14.484134v2
Vault: Regeneron
"The next challenge in biology. Well, there’s so many challenges, and so little time. The challenges of how we are formed. We’re making great progress on how development of a complex organism such as ourselves, with skin and hair and all these other different tissues develop from the 35,000 genes. We’re going to understand that and that’s going to underwrite a lot of development of new drugs and treatment for diseases but then we look at the real challenge and ultimate challenge. There’s nothing that a human biologist would like to study more than the brain, the human brain. It’s a fascinating organ."
- Phillip Sharp, Nobel Prize for discovering splicing and co-founder of Biogen