CellAge: Targeting Senescent Cells With Synthetic Biology

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Senescent Cells – Taking Out the Trash for a Healthier You

Here at CellAge we believe it is a great thing to be healthy, capable and enjoying life at any age. We also believe that you deserve to have safe and effective medical treatments to make this happen, and this is why we are working hard to create breakthrough therapies that will treat one of the key reasons for age-related disease: senescent cells.

The Problem

Senescent cells are aged, damaged, and non-dividing cells that build up in the body over time, causing inflammation and contributing to diseases such as cancer, heart disease and osteoarthritis. These cells are normally disposed of by the immune system after following a self destruct program called apoptosis, but as the immune system ages it stops clearing away these cells. Imagine a city whose trash no longer gets collected; not something you want!

Thankfully exciting new research has shown the potential for a revolutionary therapy that could help postpone and treat a wide variety of age-related diseases by removing these senescent cells. Recent studies have even shown that removing senescent cells from mice dramatically increased their healthy period of life, which means the therapy helped the body to maintain healthy balance for longer.

Scientists are now considering the next crucial question, can these health benefits be translated to people? It turns out that to answer this question positively, we have to solve a key problem: we need a better way to accurately target senescent cells for removal.

The Solution

The current methods scientists use to identify and remove senescent cells have many limitations such as being too large to use in present gene therapies, being too imprecise in the range of cells affected, or simply being incomplete in cell targeting and removal. CellAge is building a new senescent cell targeting system that overcomes these limitations through the development of synthetic promoters, special DNA sequences that can regulate the activity and expression of genes:

The Details

In short, CellAge is going to develop synthetic promoters which are specific to senescent cells, as promoters that are currently being used to track senescent cells are simply not good enough to be used in therapies. The most prominently used p16 gene promoter has a number of limitations, for example. First, it is involved in cell cycle regulation, which poses a danger in targeting cells which are not diving but not senescent either, such as quiescent stem cells. Second, organism-wide administration of gene therapy might at present be too dangerous. This means senescent cells only in specific organs might need to be targeted and p16 promoter does not provide this level of specificity. Third, the p16 promoter is not active in all senescent cells. Thus, after therapies utilizing this promoter, a proportion of senescent cells would still remain. Moreover, the p16 promoter is relatively large (2.1kb), making it difficult to incorporate in present gene therapy vehicles. Lastly, to achieve the intended therapeutic effect the strength of p16 promoter to drive therapeutic effect might not be high enough.

CellAge will be constructing a synthetic promoter which has a potential to overcome all of the mentioned limitations. A number of gene therapy companies, including uniQure, AGTC and Avalanche Biotech have successfully targeted other types of cells using this technology. With your help, we will be able to use same technology to develop tools and therapies for accurate senescent cell targeting.

We have teamed up with leading synthetic biology company, Synpromics, to create two new exciting systems for detecting and removing senescent cells. The great news is, a number of gene therapy companies, including uniQure, AGTC and Avalanche have already successfully used similar technology to target other kinds of cells; we are confident we can do the same for senescent cells.

Our primary goal with this project is the creation of SeneSENSE, a new system that can overcome the limitations of other approaches and provide researchers with an accurate way to detect senescent cells. We predict this system could also be used as a quality control step in the stem-cell therapy manufacturing process to make cell therapies safer! As we want to foster the development of senolytic therapies, we plan to give SeneSENSE to other scientists for free, to help them improve their results. We aim to have our cell detection system ready by Q4 2017 enabling researchers to benefit in the near future and helping to speed up progress.

Our secondary goal is to create SeneHEALTH, a system designed for the removal of senescent cells with a high level of accuracy. The first steps will be to treat children with progeria followed by chemotherapy patients, who could benefit from these therapies due to a higher accumulation of senescent cells.

With your help, we can develop tools and therapies for accurate senescent cell targeting and removal. Ultimately this means we could postpone and treat a wide range of age-related diseases, helping you to remain healthier as you grow older. Life should be full of joy, not pain from chronic diseases you can help us to make this a reality.

	$20,000: Initial Goal – Candidate promoter design   Our first work project is to design candidate synthetic promoters which would be able to accurately detect senescent cells. To do that, we will analyse transcription profiles of a number of senescent cells. To cover all different senescence states, we will analyse senescent cells from different tissues and at different stage of senescence. We will use this data and proprietary bioinformatics algorithms to design genetic circuits which are specific to these cells.
	$40,000: Stretch goal 1 – Assembly and screen   After we have designed our senescent cell specific genetic circuits, our next goal will be to perform the actual DNA assembly, along with screening for functionality. This stage will require an additional $20,000 in funding for DNA synthesis, cloning and functionally testing our promoters in different cell types through the use of flow cytometry and microscopy. At the end of this stage, we will have our lead promoters identified.
	$80,000: Stretch goal 2 – Lead candidate optimization and validation   By taking our lead candidates through an additional round of “Design-Build-Test” cycle, we will be able to optimise the DNA sequence, add any additional specificity and exclude unwanted effects. This stage will end when we conduct a final in vitro screen which will allow us to validate specificity of our candidate promoter in different cellular contexts.

This project will be run by CellAge, working in close collaboration with Synpromics. The complimentary skills and experience of these two teams is the key driving force behind this project. The CellAge team has a diverse number of skills and experience on board. Our core team consists of Mantas Matjusaitis, Azuolas Ciukas and Eryk Jan Grzeszkowiak. Mantas (BSc Biomedical Science) is currently finishing his PhD in synthetic biology (University of Edinburgh) and has been involved in the SENS Education programme, resulting in a publication. Azuolas is finishing his degree in Economics and brings financial experience and business acumen to the team. He has worked in an M&A advisory boutique, Porta Finance (Rothschild’s exclusive partner in the Baltics), and KPMG’s Deal Advisory division. Last but not least, Eryk holds a BA degree in Philosophy, Politics and Economics (University of York) and is currently studying for a MSc in Human Complex Trait Genetics (University of Edinburgh). He is the author of the first Polish blog dedicated to genetic genealogy and speaks regularly on the genealogical applications of genotyping and DNA sequencing at regional and national conferences. In addition to the core team, CellAge is supported by an experienced board of advisors. Dr. Alexandra Stolzing and Dr. Juan Carlos Acosta are providing scientific guidance to the CellAge R&D program. They have both published a large number of high impact peer-reviewed articles, ranging from topics on paracrine senescence to stem cell aging. Their expertise grants CellAge access to world class scientific guidance to ensure a well-evaluated research program. Dr. Mike Capaldi, our business advisor, brings valuable insight into the business side of the project . For the last 18 years, Mike has worked in the biotech/technology sector serving as executive director on the Boards of both publically listed and private companies including Core Group plc, Oxford Asymmetry plc, Mindweavers plc, Synaptica Ltd, Scancell plc, Hunter-Fleming Ltd and CMP Therapeutics Ltd (in the latter four companies as CEO). We believe that a collaboration of many people sharing the same vision can bring a project to a whole new level and transform into a real movement. We would like to extend our deepest gratitude to our key partners who support us on this journey as well as to all the donors and supporters who are helping to make this project possible.

In order to reach as many people as possible and to make this project even more engaging we have partnered with a number of creative technology companies. By supporting our campaign you can become a robot engineer, bioengineer or even crack DNA coding secrets to immortalize your name!

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We hope you are as excited about these rewards as we are, but in the end, the greatest reward that we hope to offer is making people live healthier lives. The possibility of this reward depends on all of us, so please consider donating and spread the word by sharing our project with your friends and family. Thank you!

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