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Genflow Biosciences (http://genflowbio.com/) is a new company in the longevity market, but brings with it plenty of experience. It is not shy to say that it considers ageing as a disease, and that its mission is to develop medicines that potentially halt, slow or reverse the ageing process.
Using the latest developments in both cell metabolism and gene delivery techniques, Genflow proposes to introduce extra copies of the SIRT6 gene into cells using minicircle plasmid vectors. Sirtuin 6 is a NAD-dependent enzyme involved in cellular stress resistance, genomic stability, ageing and energy homeostasis.
Genflow has recently launched a seed financing round, looking for 1.5M Euro of investment.
Who’s Who at Genflow Biociences
The company is owned by Eric Leire who has a long history in biotech. Most recently he has been, and remains, Executive Chairman of Immunethep which has developed an anti-bacterial immunotherapy targeting a novel virulence mechanism. Prior to that he was CEO of Enochian Biosciences (previously DanDrit Biotech) developing immunotherapies for cancer. Originally, he qualified as a doctor of medicine (1980) and spent time as a research associate at Harvard AIDS Institute.
Leire is joined on the board by leadership guru Jeneva Patterson from the Center for Creative Leadership (CCL), and also Andrew Scott - economics professor at London Business School, consulting scholar at Stanford University’s Center on Longevity and co-founder of The Longevity Forum.
The company has secured an impressive scientific advisory board including Buck Institute President, Eric Verdin, who is involved in several other biotechnology companies. The SAB also contains Matthew Hirschey, an assistant professor at Duke University focussed on mitochondrial metabolism, and Manlio Vinciguerra from the FNUSA International Clinical Research Center who specialises in cellular signalling and epigenetics mechanisms involved in metabolism and ageing.
Then to top it off, Aubrey de Grey is also on the scientific advisory board. Now, I’ve lost count of how many ventures Aubrey is involved in, but in my opinion it always adds credibility where he is.
On the ground doing the work, the initial trial will be carried out by CMO Dr Tongtis Tongyai in Bangkok. Although better known for his infertility work, he has previously been involved in several trials for cell and gene therapies in immune-oncology.
What is SIRT6?
SIRT6 is one of seven sirtuins found in mammals, labelled SIRT1 to SIRT7. These different sirtuins are found in different locations of the cell (nucleus, cytoplasm, mitochondria) and have various functions. As a group, they are known to be involved in cellular signalling of metabolic regulation, working as protein deacetylases – that is, they remove acetyl groups from other proteins. Importantly, sirtuins are dependent on NAD+ for their operation. They are a favourite topic of David Sinclair who believes that they get distracted by stress-induced DNA damage repair activities, meaning they neglect their gene expression regulation duties.
SIRT6, specifically, is found in the cell’s nucleus and performs, among other things, base excision repair of small (typically single base) DNA damage. Even a single incorrect base can cause mutations, or prevent DNA replication, as seen in diseases such as sickle cell anaemia. Recently, SIRT6 has also been identified as a key sensor of more serious DNA double-strand breaks (DSB) which it flags for repair by other proteins.
A study by Dr. Vera Gorbunova looked at SIRT6 in 18 rodent species and determined that those animals with more active sirtuin 6 had more efficient DNA repair and longer lifespans. Other experiments with mice have shown that disabling SIRT6 results in severe progeria (rapid ageing), and that boosting it (AKA overexpression) extended their lives. Strangely, in one trial this increase in lifespan was only observed in male mice so it will be one to monitor in any human studies.
SIRT6 is also acknowledged as a tumour suppressor, with low levels of it observed in colon and pancreatic cancers.
Genflow’s Proposal for SIRT6 Therapy
Genflow is planning to introduce extra copies of the gene SIRT6 gene to human cells using minicircle plasmid vectors.
Plasmids are circles of double-stranded DNA that float outside the main chromosome and are exchanged between bacteria to share selective advantage such as antibiotic resistance. Minicircles are plasmids stripped of unwanted components, such as the origin of replication, and injected with a gene of interest to be transferred to target cells.
The smaller size of minicircles allows for more efficient transfections and offers sustained expression of the transgenes (a couple of weeks in dividing cells, and potentially months in non-dividing cells). And as they don’t contain any bacterial DNA sequences, nor the ability to self-replicate, they are generally considered safer than plasmids.
The company is planning an in vitro study of its lead candidate GF-1002 to assess its impact on DNA damage repair and to check for liver toxicity, as well as an in vivo program using mice models (from Charles River Lab and Genoway) to determine possible dose levels (using the distribution of RFP) and toxicity. Genflow will initially use the regular SIRT6 gene, however, it may in future screen other species for even more robust SIRT6 genes that could have a greater effect.
An initial dose ascending ANGEL trial will be conducted in Thailand, which will hopefully allow a subsequent phase I/II in Europe/UK to save some time by both evaluating safe dosing and obtaining early indications of efficacy.
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