How Adrestia Therapeutics is pioneering synthetic rescue - an interview with Prof Steve Jackson and CEO Robert Johnson
A new approach to tackling genetic diseases could unlock treatments to some of the most intractable conditions, it is hoped.
Spinning out of the academic research of Prof Steve Jackson at the University of Cambridge in 2018, Adrestia Therapeutics is focused on synthetic rescue as a means of developing therapeutics.
The company, which employs 30 people on Babraham Research Campus, recently appointed Robert Johnson as its first full-time CEO and is focused on taking its pipeline into the clinic – and then to market, as a fully integrated pharmaceutical company.
Its approach could have an impact on a host of rare diseases, and many conditions with a genetic component from heart failure to Parkinson’s and Alzheimer’s.
It is a bold vision, and one that has attracted investor backing with a Series A fundraising in December 2020, co-led by GSK and Ahren Innovation Capital, along with an exciting drug discovery collaboration with GSK featuring five projects – each eligible for post-option milestones of up $230m (£175m) plus royalties.
What then, is Adrestia doing differently that gives rise to such confidence that it could hold the keys to unlocking progress in treating genetic diseases?
“There are a great many genetic diseases now understood and just about every aspect of them – even those we would consider to be sporadic – are influenced by genetic factors and of course, also by the environment,” begins Prof Jackson, who is CSO and co-founder of Adrestia.
“We know there are around 20,000 human genes. We know that mutation in, let’s say, gene A can give rise to a monogenic disease or disorder. But we’ve known for many years that genes don’t work in isolation. The products of genes work together with products of other genes in a network of activities.
“And so there has been a growing body of data over the last 100 years indicating that the influence of one gene or its mutation is also influenced by other genes. Those influences can be pushing things in the direction of making the disease worse, or expressing earlier, or those other gene variants could be pushing things in terms of alleviating, or ‘rescuing’, the disease.”
Adrestia takes the approach in a different direction.
“What we’re focused on at Adrestia is synthetic rescue. Most people would think with genetic diseases that if you have a defect in gene A, you could correct that by correcting the gene – putting the correct copy of the gene back in or, if the gene is no longer making what it should, you can maybe – through some other route, such as intravenously – provide to the person the product that’s missing.
“What we’ve realised in Adrestia is outside of that paradigm for treating genetic diseases are all these modifier genes that influence the activity and expressivity of that mutation that are also potentially targetable.
“If we can identify synthetic rescue genes for a defect in gene A, we can target those genes, but we can also target the products of those genes with drugs.
“What we’re doing in Adrestia is using technologies such as genome engineering and CRISPR-Cas9 approaches and we’re building precision genetic models of devastating human diseases that often hit people in childhood, but also affect people later on in their lives.
“We’re coming up with a phenotype – something that we can measure in the test tube in the lab that distinguishes this mutated cell from a normal version. And then we can carry out screens across the whole human genome to identify these modifier genes.
“It’s been a series of Eureka moments over the last few years, starting at my academic lab at the University of Cambridge and more recently in Adrestia itself.
“These screens are very, very powerful. If you set up the screens right, you invariably identify these modifier genes.”
As Adrestia continues to identify these modifiers, it is also moving those it has already found into the drug discovery process for a range of genetic diseases.
“Initially, we’re looking to have a line of sight to develop drugs that will treat these genetic diseases – some of them quite rare. But we’re also looking for opportunities to expand these into more sporadic or polygenic diseases down the line,” says Prof Jackson.
“We’re now trying to deliver on that as a business and it’s great that Rob’s recently joined us as CEO to lead us in this exciting quest.”
The promise of this science is what attracted Rob to the company.
He previously co-founded Boston-based gene therapy company Affinia Therapeutics and has held posts in biotech and pharmaceutical management consulting.
“I had a moment in my career when I was working for a cancer vaccine company. And like other cancer vaccines, it failed at clinical trials and I thought I really would like to develop a drug and be involved with a successful drug.
“Across the industry, if you are developing a drug in genetic diseases, you have a much higher chance of success than in non-genetically defined diseases. And if you are developing a drug against a target that has got human validation, you are twice as likely to show efficacy.
“There is human evidence of this whole concept of synthetic rescue happening in nature. There are people who have been born and they have a mutation in the cystic fibrosis gene and so they should have cystic fibrosis, but they were lucky enough to be born with another gene, which is a modifier of the CFTR gene, and that second mutation is rescuing them from disease.
“There are very few people identified with this, but they are there.
“Something we learn about at school is that if you have sickle cell anaemia, you are resistant to malaria.
“I worked in a next-generation gene therapy technology company before. But even with these tools, there are so many genetic diseases where we scratch our head and think ‘how can we possibly drug this disease?’
“It is for these really intractable, often very nasty, genetic diseases where Steve’s and Adrestia’s synthetic rescue technology comes to hand.”
But if the approach is to target modifier genes, how can we guard against unwanted toxic effects?
“This is a conundrum across all of medicine. You need to get the dose right,” replies Prof Jackson, who is the University of Cambridge Frederick James Quick and Cancer Research UK professor of biology and the head of Cancer Research UK Laboratories at the Wellcome Trust/Cancer Research UK Gurdon Institute.
“What we’re finding is that many of these synthetic rescue targets that we’ve identified, if you take their products out, there is very little by way of pathology that we’ve been able to see. So it really is about rebalancing something that has become unbalanced in these patients.
“An interesting paradigm is that in a person in which all the products of genes are working in the right way if you mutate gene A, things going into an imbalanced state and, in many cases, it is these imbalanced actions of these other gene products that are actually causing the pathology. Targeting those in a genetic disease patient will take out this toxicity, which is driven by these other pathways.
“We’re finding these effects are pretty clean and translating very well so far. We initially carry out a screen, but we’re also seeing these synthetic rescue relationships operate in different cell types and are working out in in vivo disease models, which obviously gives you more comfort.”
And Adrestia is connecting its findings into our growing understanding of human genetics.
“When you talk to most clinicians in the genetic disease space, they say: ‘We know that this gene mutation causes the disease, but we know that in patients with different genetic backgrounds, some get it worse and some get it more mildly than others.
“So we’re on the cusp with forays into human genetics, through things such as Genomics England and UK Biobank, and there is already evidence that variants of some of these synthetic rescue genes operating across normal populations.
“We’re doing things experimentally but we’re increasingly going to be looking into this human genetics data, hopefully to get signals of safety for our targets, and if there are signals for potential toxicities and you are aware of them, you can potentially get the balance right when you eventually take medicines into the patients.”
The synthetic rescue approach, then, builds on our growing understanding of the complex network of human genetic relationships.
“If we go back a couple of decades to when the human genome was determined, everybody was thinking that this was going to cure diseases, but of course, it won’t – it just gives us the ground rules for our genetics. Then there was the idea that we could identify all the individual genes and what they are doing, but of course they don’t work in isolation.
“They absolutely work together in networks and complexes. We’re on the cusp of starting to understand those inter-relationships and in the end it is those relationships that impact on how cells actually function, connected to the environment – and included in that environment is drugs.”
Adrestia’s pipeline is potentially very broad, but builds on Prof Jackson’s research of DNA damage repair mechanisms.
“A lot of this starts out in my academic lab, where over the last 25 years we’ve become expert in understanding cellular physiology, particularly in relation to DNA repair mechanisms. DNA is being damaged in our cells all the time and there are these sophisticated mechanisms to mediate and repair.
“It is quite a complex arena, but we know that DNA repair defects in genetic diseases show up as cancer, immunological defects, neurological conditions and neurodegeneration as well as having some impacts in other diseases, such as cardiovascular and reproductive arenas.
“So the backdrop to some of the initial programmes in Adrestia is focusing on those areas with these DNA repair connections, including Huntington’s disease.
“Huntington’s disease and a range of others have extra copies of repeat sequences in the gene. We are using our platform now to find ways of alleviating the toxicity of these expanded versions of these genes.
“It turns out that DNA repair mechanisms, which are normally good, are actually involved in the expansion in somatic cells that are probably involved in these disease phenotypes arising in patients at various stages of their lives.
“Synthetic rescue is playing out in that arena as well but as we move forward, we can see this operating in a range of other areas as well and we are building expertise in the company to have a broader play, and this is being enhanced by our collaborations with GSK. We have a multi-project relationship with GSK exploring other areas of interest to them, but outside of our core focus.”
Rob says the company’s pipeline is most advanced in the broad fields of “neurology, neuromuscular diseases and cardiomyopathies”.
“Some diseases we are hoping to treat have no approved drugs and there is virtually nothing in development, so we are truly trying to go after diseases with high unmet need,” he explains.
There are a number of reasons why some genetic diseases have proved so intractable, even with recent advances in developing gene therapies.
“There are different approaches to gene therapy but one of the most popular is to use AAV, which is a type of virus that we use to get DNA into cells. It’s a very small virus, so it’s packaging capacity is very low. If you have a big gene, you can’t fit it into that virus. There are lots of diseases with large genes. Muscular dystrophy is an example – dystrophin is a huge gene,” says Rob.
“It’s really hard. You have to start shortening the gene in order to fit it into the virus but, by shortening it and making those changes, you are compromising on the in vivo function.
“But assuming you can fit the gene into the virus, you then have to get the virus to infect the right cells, and that’s a big challenge. The virus is incredibly inefficient actually.
“Often gene therapy trials are treating children. The amount of virus particles you are giving is a multiple of the number of cells in the body but, even with that high dose, only a small fraction of the cells that you want to be transduced are infected by the virus, so the level of efficiency can be quite low.
“The distribution can also be quite challenging. It’s really hard to get into deep brain structures that you need to get into for some neurological diseases. It’s really hard to get into muscle cells. The liver is generally OK, but even that is not a very efficient process. So the industry really needs a whole step level in the level of transfer.”
And that is where Adrestia comes in.
“The approach we’re taking is different to gene therapy but the therapeutics that we’re aiming to deliver could be used in a complementary sense down the line potentially,” notes Steve.
Rob adds: “We’re looking initially at other modalities that are more proven, such as small molecules.
“One of the challenges for gene therapy is the high upfront cost – perhaps a million-plus dollars for one shot that hopefully is curative.
“With a more conventional modality like a small molecule, you do have the opportunity to spread that cost over a period of time.”
That, he notes, makes development of these rare disease treatments potentially more commercially viable.
And Steve believes Adrestia is ideally placed to achieve its ambitions.
“Our vision is to become a fully integrated pharmaceutical company. That’s where we’d like to be: Identifying and validating targets, taking them forward into the drug discovery process and taking them to market – I think that’s something we can do with the right funding in the area of genetic diseases,” he says.
“We are building the drug discovery aspect of the company, initially through building a team in-house, but using certain CRO [contract research organisation] activities on the outside to move those forward.
“To be a successful biotech company in the UK, being in Cambridge is a great place to be right now. The ecosystem is still growing and the KOLs [key opinion leaders]. We need to think worldwide in terms of the science and clinical arena, but Adrestia is plugging into all of that to make the most of what we’ve got.”
Prof Jackson’s blockbuster background
Armed with growing knowledge about genetic relationships amd DNA repair mechanisms, Prof Jackson founded and scientifically led KuDOS Pharmaceuticals in 1997.
Acquired by AstraZeneca in 2006, it was responsible for the creation of the olaparib – sold as the blockbuster drug Lynparza – variously approved around the world for treating a host of cancers, including breast cancer, pancreatic cancer, prostate cancer and cancers of the ovaries, fallopian tubes and the peritoneum.
It works as a PARP inhibitor – preventing the protein Poly (ADP-ribose) polymerase from repairing the DNA of cancer cells when they become damaged, meaning the cells die. It works in cancer cells with changes in the BRCA gene.
The drug exploits a concept known as “synthetic lethality”.
“That is pushing cancers into death through mutations in certain cancer genes,” explains Prof Jackson.
“It’s called synthetic because it’s putting more than one thing together to generate an output, or something new.”
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