April 2023 Progress Update

Overcoming a primary challenge

What were we up to in March?
In lieu of a written update for March 2023, we held a live Progress Update event at NewLimit HQ in South San Francisco. Check out the recording here for a quick summary of progress in our first few quarters: livestream.newlimit.com

NewLimit is developing therapies that reprogram cell age without changing cell type. To achieve this ambitious goal, we’re building screening technologies that enable us to test many reprogramming strategies for their ability to make old cells “look” young.

In April, we performed our first reprogramming screens in primary human T cells, bringing us a step closer to finding an impactful reprogramming strategy.

Alongside experimental progress, we also welcomed two new members to our team:

• John Leonard as a Director, Immunology

• Jenny Ng as a Research Associate II, Immunology

Both John & Jenny will be joining our Immunology team focused on developing high-throughput functional assays and gold-standard pre-clinical models.

A few highlights from our work this month:

Atoms

Partial reprogramming screens in primary human T cells

• In April, we completed our first partial reprogramming screen in human T cells taken from healthy young and old donors. Similar to our screens in a cell line model from February and March, we were able to test hundreds of reprogramming combinations simultaneously.

• We believe this is the largest partial reprogramming screen in primary cells that has been performed. Not only does it demonstrate that the NewLimit Discovery Engine can be applied to primary cells, but these are also the first data where we can being to ask — which partial reprogramming interventions make old cells look younger?

• While it may seem like a small step to move from a cell line to real, human T cells, it was technically challenging. Every step of the process from gene delivery, to reprogramming induction, to cell profiling required optimization to work in primary cells. We’re incredibly proud of our team for pushing through the technical hurdles.

Early results from our first primary T cell screen. Similar to our performance in a cell line model, our assay discriminated negative and positive controls, recovered known reprogramming effects, and revealed factors that induce novel phenotypes.

Bits

Prioritizing transcription factors for partial reprogramming screens

• Now that our reprogramming screens are up and running in primary cells, a natural question arises — what partial reprogramming factors should we test?

• Our Predictive Modeling team set out to answer this question quantitatively this month. They’ve nominated our first expanded set using a diverse collection of sources: existing data on functional effects in primary T cells, our own internal epigenetic aging maps, gene activity covariance during ontogeny, and our predictions from our own internal TF → Function prediction models.

• Along the way, we’ve made some of our first open source contributions back to the community. Thanks to the scvi-tools team for a collaborative development process!

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