Thread by @davehava

It’s been said that we can design and program bacteria like we can program a computer with code – however programming is only the beginning of what it takes to advance live bacterial therapeutics to patients – a 🧵 on how it is done (1/)

Today we @synlogic_tx show what it means to bring the power of synthetic biology to medicine, announcing clinical POC for our PKU program and showing the ability iterate and maximize activity in Synthetic Biotics #synbio (2/)

investor.synlogictx.com/news-releases/…

Using synthetic biology, we are able to apply engineering principles to design bacteria to perform specific biological functions – such as the metabolism of phenylalanine to potentially treat #PKU (3/)

Our efforts in PKU started with the development of SYNB1618 – a strain of E. coli Nissle engineered to include two different mechanisms to metabolize Phe in the gut along with the required features for biocontainment (4/)

nature.com/articles/nbt.4…

In healthy volunteers, SYNB1618 dose dependently lowered Phe and produced strain specific biomarkers of activity in a Phase 1/2a study, providing proof-of-mechanism in humans (5/)

nature.com/articles/s4225…

With human proof-of-mechanism data in hand, the question for SYNB1618 became: Does strain activity result in clinically meaningful effects in #PKU patients? (6/)

To translate strain activity to humans and to give confidence in our ability to lower Phe, our team built translational and mathematical models to allow us to predict strain activity and efficacy in humans (7/)
nature.com/articles/s4200…

We use in vitro gut simulation models, together with ex vivo gut-on-chip and preclinical models of disease to extensively characterize strain activity (8/)
investor.synlogictx.com/static-files/4…

Using data from these models and an understanding of disease biology we are able to simulate the clinical efficacy of our strain in patients, which for SYNB1618 suggested lowering of plasma Phe by >20% (9/)

In Phase 2 interim data released today, SYNB1618 lowered fasting Phe in PKU patients, in line with the predictions of our models; in short, it works as designed and predicted! (10/)

For the first time, these data show that a therapy acting from the gut lumen to absorb Phe also impacts systemic plasma Phe levels showing that this approach could be therapeutically relevant for the treatment of PKU (11/)

As we’ve advanced SYNB1618, the world of synthetic biology has rapidly progressed and provided an expanding toolbox of strategies for our scientists to build better and better strains (12/)

Using these tools, our team focused on answering the question of whether we could deliver even more efficacy to PKU patients through a more active engineered strain (13/)

Working with our collaborators @Zymergen (enEvolv) our team developed SYNB1934, an evolved strain of SYNB1618 encoding a PAL enzyme with improved whole cell activity (14/)

Preclinical studies demonstrated a greater than 2-fold improvement in the ability of SYNB1934 to metabolize Phe compared to SYNB1618, and our biomarker driven models predicted increased Phe lowering by SYNB1934 (15/)

investor.synlogictx.com/static-files/6…

The data released today from a head-to-head study of SYNB1934 and SYNB1618 extends the preclinical data, showing that SYB1934 has 2X higher strain activity in humans (16/)

The combined data from the SYNB1618 and SYNB1934 clinical trials highlight what is possible when a powerful platform and the talented team @synlogict_tx are committed to delivering meaningful therapies to patients (17/)

Clinical proof-of-concept in our PKU program and the validation of our approach to developing Synthetic Biotic medicines is a significant advance for our platform and the patients we aim to help (18/)

We @synlogic_tx are just getting started and we look forward to continuing to bring the power of synthetic biology to medicine and patients with our growing pipeline of Synthetic Biotic medicines (19/)

Let's use #synbio to bring back mammoths and making my veggie burgers tastier! But I'll put developing medicines for patients with the team @synlogic_tx is at the top of my list for the future of synthetic biology! (20/20)