Operating Plan

Cell reprogramming

NewLimit is a biotech developing epigenetic reprogramming therapies to extend human healthspan.

Overview

NewLimit was founded to significantly extend healthy human healthspan.

We are developing epigenetic reprogramming medicines to treat age-related diseases on our way to a more general use medicine to control aging itself. The core of our approach is rooted in epigenetic control of gene expression. All of our cells experience functional decline as we age, yet we appear to be able to reverse this functional decline through induced pluripotent cell reprogramming and then re-differentiation to the original cell type. Pluripotent reprogramming reverses cellular “age” while also reversing cell type. NewLimit’s aim is to reprogram cellular “age” without altering cell type.

In some ways this is a narrower task that full pluripotent reprogramming, but the result is more nuanced. The cell type remains the same, while the cell’s epigenetic state and functional abilities are changed. We think these kinds of reprogramming factors could make powerful medicines in a subset of diseases where the root cause is due to functional decline in a specific cell type. We are starting our work in T cells and hepatocytes with specific indications in mind as we iterate towards more general purpose medicines to treat broader aspects of aging.

Scientific Background

Epigenetic Control of Aging

More than a decade ago, scientists discovered that we can rewind the clock of animal development in adult cells by activating just a handful of regulatory genes, “reprogramming” adult cells to their embryonic state. Reprogramming works by rewriting the epigenome, changing the rules that dictate which genes can be turned on and off. Remarkably, reprogramming to an embryonic state reverses many features of aging – reprogrammed cells from young and old animals become nearly indistinguishable.

Early experiments have shown that even partial activation of these embryonic programs can restore function in old cells without erasing their unique identities, improving outcomes in disease and injury models [1]. These results are early and more work is required to validate the magnitude of effect, but they do serve as a hint that robust partial reprogramming is possible. Taken in totality with pluripotent reprogramming, the work suggest that many aspects of aging may be the result of plastic, reversible, changes in the epigenome. If we can construct the right epigenetic program, we could conceivably reverse these changes and restore youthful function to old cells. This rejuvenation could have beneficial impacts across a number of diseases with large, unmet clinical needs.

What’s holding us back? There are both unanswered biological questions and unsolved engineering challenges between us and the first reprogramming therapies. We don’t yet know exactly where partial reprogramming will be most impactful, what programs to execute, or what safety risks reprogramming might present. After those questions are answered, we require a delivery system that can execute our programs in the right cells, at the right time, with the right dose. We outline a few of these open problems below.

None of these challenges are trivial, but all are surmountable.

Scientific Approach

New Limit’s product discovery and development starts with modeling how specific cell types age, proceeds with discovery of novel reprogramming factors that can restore necessary function, and ends with fitting these factors into a drug product for patients. NewLimit’s scientific team will employ single cell multi-omic tools and machine learning methods to address these outstanding challenges and enable therapeutic development. We plan to initially start with two to three cell types, that address specific indication, with distinct risk/reward profiles. For each indication, we will identify target cell populations where we believe epigenetic reprogramming will be disease-modifying and initiate a reprogramming factor discovery campaign to design a therapeutic program.

Payload discovery

Reprogramming factor campaigns will employ a tiered screening strategy, beginning with pooled single cell genomics screens to find factors that restore functional molecular states [2]. Partial reprogramming strategies as described above may serve as a positive control and offer a useful initial search heuristic, but alternative payloads are desirable to reduce the risk of adverse events. Most reprogramming strategies that achieve a stable cell state change require a combination of factors. Even a small hypothesis space contains an intractable number of combinations, so an exhaustive search is infeasible (e.g. ~10^5 combinations of 4 in 40 factors). This has traditionally been a roadblock for the field, but guided search methods from machine learning may allow us to efficiently search the combinatorial hypothesis space and find effective combinations using a tractable number of experiments.

Functional validation

Given hits from these initial screens, we will perform validation using medium-throughput ex vivo assays and finally pre-clinical in vivo disease models. These assays will inherently be unique to each indication program. As we acquire more data spanning each of these assay tiers, we will develop machine learning models to infer later stage assay results from molecular profiles, improving both interpretability and utility of our first-tier screens.

Biological model systems

We believe that performing payload discovery in human cells will improve our chances of reducing human disease burden later on in development. Wherever possible, we will use primary human cells for our payload discovery screens and functional assays, transitioning to animal models for physiological endpoints. We have multiple collaborators interested in providing us with human primary cells in exchange for data.

Focus on disease-modifying endpoints

Each indication program will be evaluated based on pre-defined efficacy milestones and halting criteria. We believe that it’s important to focus our resources on the most promising applications, requiring us to continually re-evaluate our priorities and avoid the sunk costs fallacy. To that end, we will treat our functional assays as the ultimate Key Performance Indicators for each program.

Team Structure

We envision the Scientific Team clustering around four key functions.

Read Genomics experts developing methods to read epigenetic states in single cells

Write – Molecular biologists developing tools to rewrite the epigenome and engineer cell state

Predict – Computational scientists developing models to enable reprogramming factor discovery

Product – Cell biologists and physiologists developing functional assays for indication programs

Indications

We plan to explore two cells types for specific indications in parallel. We believe that developing differentiated medicines addressing unmet clinical needs with few available treatment options is the best path for NewLimit to deliver value to patients in the short run, while building a product fist organization that can deliver on our ambitious mission over the long run. We’re more interested in being the first option available for patients than the N-th. This philosophy guides our indication selection, alongside technical considerations of delivery, safety, and efficacy. We’ve outlined a few indications of interest below, but no decisions are final.

Immunosenescence

Immune system age-related functional decline gives rise to diverse pathologies. Among them, poor vaccine responses, chronic inflammation, and impaired cancer surveillance all present large, unmet clinical needs. By delivering reprogramming factors ex vivo, we may be able to develop reprogramming therapies for some of these indications while minimizing delivery and safety risks. In vivo delivery tools for T cells are also under development by many firms, potentially enabling targeted systemic delivery in the future. High-throughput in vitro functional assays are established and in vivo assays can be performed in humanized animals.

Our preliminary programs of interest are (1) ex vivo epigenetic reprogramming of tumor infiltrating lymphocytes (TILs) for treatment of solid tumors and (2) in vivo reprogramming of T cells in for infectious disease applications.

Fibrosis

Fibrosis emerges with age across a range of tissues, including the heart, kidney, liver, and lung, each representing a massive disease burden to patients. Epigenetic reprogramming has been shown to counteract fibrosis in multiple tissues, and cell type-specific delivery tools are under development by specialized firms. Epigenetic reprogramming is attractive in these indications because it can both suppress aberrant fibrotic cells and restore the regenerative potential of the tissue, unlike most other approaches which only achieve the former outcome. Importantly, these diseases are amenable to both in vitro and in vivo screening.

Both liver fibrosis and idiopathic pulmonary fibrosis (IPF) represent high risk/high reward indications in this space, each with a distinct risk profile. Liver fibrosis has lower delivery risk, but may benefit less from improvements in regenerative potential, while IPF is likely to benefit both from fibrotic cell reprogramming and restoration of regenerative potential in alveolar cells.

Company strategy

Relying solely on a multi-decade mission is not the right way to build a company. We will initially produce products that can be delivered to patients in the short and medium term that have significant impact for these patients, build company value and hone our culture of shipping products. One of our initial projects is the reprogramming of T cells for indications that may include treatment of neoplasms and improved immune activity in the elderly.

We believe focus is imperative not only for our technical approach, but also for indication selection. We will be targeted and specific about the patient populations we initially treat. We will pivot and shift our indications over time, but it is critical to always be designing for a specific group of patients.

In the process of pursuing these goals, we will share the results of our ongoing work openly with the scientific community. We will generate more knowledge than we can act upon alone, and we believe that we can multiply our impact by allowing others to build upon our advances.

Financing

Years 1-5$110M, funded by the founders.

Years 5-6+ – The company will raise outside capital. We believe this is a healthy forcing function that incentivizes the company to build real value that is externally legible. This also offers an opportunity for employees to benefit economically from the increase in company value over time.

Team

We will recruit 20-30 full-time employees by the end of our first year of operations.

In addition to our existing leadership team, we are recruiting for two key open roles.

Head of Research & Development – Most experienced member of the scientific team. This role may be full- or part-time. NewLimit believes the magnitude of our progress vector comes from the people doing the line work, not the senior leadership team. The key contribution of the R&D leader is feedback to the scientific team on the direction of their work, technical approaches to consider, application areas and indications. This leader is more geared to making sure the team is vectoring in the right direction, rather than micromanaging at the individual experiment level. The scientific team will determine the next steps.

Head of Operations – Operational leader who can manage all non-research functions at the company including finance and legal. Key line work is supporting the build and execution of the scientific team and strategy. Objective is to improve research efficiency per unit time, per unit dollar, and per unit of equity.

Scientific Team

Total of ~20 people in Year 1. Total of ~30 people in Year 2.

Computational Biology & Predictive Modeling – 6-10 people
Molecular Technology & Product Development – 15-25 people.

A different approach for a different outcome.

NewLimit is committed to increasing the number of healthy years in each human life. We'll do that by advancing the most imperative areas of the science of aging and formulating practical medicines along the way.

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