Quethera sera: Gene therapy comes good in Cambridge

Reanimating the brain's biology could stop glaucoma and even Alzheimer's, says Quethera

While Cambridge is a global hotspot for genomics, gene therapy isn’t as actively researched here as it is in other clusters, says Dr Peter Widdowson, CEO and co-founder of Quethera, a gene therapy firm dedicated to improving the future treatment of common blinding eye diseases.

Quethera’s senior team is Dr Widdowson and Professor Keith Martin. Prof Martin is aligned to the University of Cambridge’s Departments of Clinical Neurosciences and Ophthalmology and is a consultant ophthalmologist at Addenbrooke’s Hospital where he leads the glaucoma service. He’s also president-elect of the World Glaucoma Association.

Dr Widdowson has more than 30 years of drug discovery experience with roles at Servier (research group leader), AstraZeneca (senior scientist and project research manager), Pfizer (senior scientist and project research manager), OSI Pharmaceuticals (director of pharmacology) and, most recently, as head of preclinical development at Oxford BioMedica.

“I was first introduced to gene therapy eight years ago while at Oxford BioMedica,” he says over tea at the Gonville Hotel. “I stayed there four years. Quethera was formed in 2013 with the aim of working in the gene therapy field, and I teamed up with Keith in 2014. He had some interest in glaucoma and had done some work in 2000 that hadn’t moved on for three reasons, one being the no one ever talked of injections in the eye then, Secondly, no one knew how well-tolerated treatments would be if injected into the eye, and thirdly, that no one knew how to do a very small clinical trial that doesn’t cost hundreds of millions of pounds.”

Those concerns have since been largely overcome.

“I approached Keith, we’ve got a lot of complementary skills, I’ve worked in the regulatory field and Keith has a clinical background, so in 2014 we agreed to get together, we got the seed money coming through in August 2015 from Cambridge Enterprise and the Rainbow Seed Fund of Midven, from them we raised £400,000 plus £100,000 from the Wellcome Trust. I said that by August 2016 we’d have some provisional data.”

The main focus is currently glaucoma though, remarkably, it may be possible to re-purpose the treatment to treat tinnitus and Alzheimer’s disease.

“Glaucoma is where the ganglion cells in the retina die. The cell bodies are located in the retina, their long axons are connected to the brain, that’s how the wiring works. If those cells die you lose the connection.

“Intraocular pressure is a secondary factor in glaucoma. There are effective drugs to lower the pressure, but even so around 15 per cent of patients will proceed to blindness in one eye. There’s half a million glaucoma sufferers in the UK and 50,000 have gone blind in at least one eye. The prevalence is increasing around the world as people live longer into old age.

“We’ve shown our gene therapy works beautifully in animal models and now we need to raise serious funds. We’re currently two months away from raising the money – from venture funding – and there’s three pharma companies looking to fund us. Our lowest target is £8million, but we’ll probably raise a bit more than that.”

So what’s the excitement all about? Quethera has developed a treatment which stops the ganglions from dying, but to do this it is aiming to improve the normal biology in the amyloid around the ganglions. Amyloid build-up plays a factor in the ganglions’ demise. Quethera’s procedure involves a protein called BDNF – brain-derived neurotrophic factor – which is a member of the neurotrophic family of growth factors found in the brain.

“The gene therapy involves squirting DNA into target cells which then restore normal function. In the class pharmacology for glaucoma, the BDNA is there but can’t get to where it’s meant to be.

“Cells are designed to keep foreign DNA out: however we can utilise the natural ability of viruses to introduce foreign DNA into cells which can then be designed to make therapeutic proteins.”

What Quethera does is build a “stripped-down viral box” called a vector, which is a virus without any damaging content.

“The product is a squirt,” says Dr Widdowson, “intra-vitreally administered, that is injected. It uses the same route as Lucentis uses for macular degeneration.”

Lucentis is a prescription drug developed by Genentech, a subsidiary of the Roche Group, which is administered into the eye by injection.

“The beauty is, the patient only needs one administration, and after that the ganglion cells in the retina make their own therapy: the BDNF binds to the receptors and stops them from dying. We restore their normal protective ability using a vector from a single injection, which is so simple that a nurse can be trained to administer it. So there’s no eye-drops, it’s a neuro-protection that works all the time. We know the viral vector is extremely well tolerated.”

The treatment model, which Dr Widdowson calls “the BDNF TrkB construct”, is potentially multi-faceted. The viral vector injection could be used in other conditions including Alzheimer’s Disease, which has also been linked to amyloid accumulation as well as loss in the ability of nerve cells to connect with each other.

“It also worked out that the BDNF TrkB construct can be used for hearing loss as well, using the route from the cochlea to the brain. If you can prevent the loss in nerve cells in the ear you could potentially prevent tinnitus, which occurs when you lose the signal from the ear to the brain, and the wiring rewires itself as it’s looking for a signal from the ear. Hearing loss is particularly exciting in that sense, so we’ll be able to help with improving the function of cochlear implants.

“There’s also a lot of literature linking our product to Alzheimer’s, which would involve using stereotaxic surgery.”

Stereotaxic surgery is invasive surgery which allows precise positioning of the gene therapy drug to be administered into specific regions of the brain.

“It’s an injection in the brain, again a one-off. The literature would support that it could reverse the symptoms of Alzheimer’s Disease. Our treatment restores connectivity between learning and memory – the data shows that if you restore BDNA signalling in a tiny area of the brain then you could restore normal learning and memory processing. However, our gene therapy is not directly designed to remove the amyloid deposits.”

It works because the signalling is reanimated and becomes strong enough to cut through the crud of amyloid deposits. “If we can show it’s an open-door target – and we’re very hopeful for that – then we’re hoping to have some good data by mid-2018.

“We’re a long way from a solution but that’s what we’re doing. I’d like to think that we’ve got the most exciting gene therapy portfolio out there for health and quality of life.”

It’s hardly surprising that these innovations have attracted attention, but even so the business model is being built around the science rather than the other way round, and there’s a lot of regulatory hurdles to be jumped and efficacy data to be approved before the therapy can be adopted in patients.

“We’ll never take this all the way to the market, we’ll partner with a pharma, and that’s up to the management team and the board, that’ll be eight years away, these things don’t happen overnight, so 2026.

“The timeline to complete proof of concept phase two is four years, depending on the strength of the signal. What we’re aiming to do is to slow, or stop, the rate of progression. The potential is here: the target is to reverse glaucoma, and there is a little bit of potential to do that, but the conservative goal is to stop the patient from going blind in their lifetime, and that saves huge costs associated with social care, so if we can stop people going blind you’re keeping costs down.

“That’s your aim: to slow or stop progression altogether, so they don’t go blind at 85 years old.”

- Quethera was highly commended at the inaugural Cambridge Independent Entrepreneurial Science & Technology Awards on September 21.