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.

Drug Approval

Interestingly, Genflow is going all out with an explicitly stated anti-ageing intent. Unlike many other longevity companies that pick a suitable disease from the ICD-10 list, knowing that they will then try to broaden its market later, Genflow is banking on regulatory authorities accepting ageing as a risk factor. And risk factors are a permissible target of drugs, for example small molecule pharmaceuticals to lower blood pressure which ultimately reduce the risk of heart attacks and strokes; so there is a good argument to be made.

To be a disruptive longevity company, and to fly the anti-ageing banner, it will need to demonstrate an increase in lifespan or, at the very least, healthspan. It is a well-known problem that studies of interventions to slow ageing are limited by the long lifespan of humans making it impractical to wait for final results (i.e. death of participants) before determining their success.

Genflow will use biomarkers of ageing to determine what impact its treatments have had, without waiting for years, again relying on regulatory precedence. Authorities have prior history of accepting surrogate markers in clinical trials, for example, forced expiratory volume for asthma and progression free survival for cancer treatments. So, the principle is there, though I don’t underestimate the paradigm shift needed to add ageing biomarkers to the list, particularly as individual biological clocks can vary significantly between people of the same chronological age and demographic. Hopefully, the growing volume of literature in this area and the increasing precision of biological clocks (such as epigenetics and IgG glycosylation patterns) will help in this regard.

Conclusion

First off, it is reassuring to see that a company is willing to brand itself as anti-ageing, something unthinkable of anyone seeking serious investment even a few years ago. If successful in getting regulatory approval for an anti-ageing therapy then Genflow is likely to enjoy a significant competitive advantage, and worst case they just have to change their approach and target a SIRT6 linked (and age-related) disease.

Our knowledge of the mechanisms is changing every day, and sirtuins are relatively new to our understanding, so it’s exciting to see proposed therapies using them already. It's also good to see that Genflow isn’t a one-drug wonder. Beyond GF-1002, Genflow will use knowledge gained in that trial to develop other minicircle therapies using SIRT6 but also SIRT7 products to target mitochondria deficiencies.

So, if you’re an investor looking for an exciting opportunity in the innovative longevity industry, then it may well be worth giving Eric Leire a call – his contact details are available here: http://genflowbio.com/contact/

References

SIRT6 is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species – Gorbunova et al – Cell 2019

Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds – David Sinclair - Nature Reviews Molecular Cell Biology 2016

Minicircle DNA breathes life into airway-delivered gene therapy development – System Biosciences

Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure - FDA