Next-generation medicines

Professor Nagy Habi had a Eureka moment while pedalling an exercise bike during a lunchtime gym session. “I thought to myself ‘If I’m in the gym, I can’t also be in the operating theatre or watching a play in the West End’,” says Habib, Professor of Hepatobiliary Surgery at Imperial. “I wondered whether it might be the same for liver cells. Perhaps they can either use their energy to produce albumin or to power cell division, but not both at the same time.”

Albumin prevents fluid leaking out of blood vessels, and transports hormones, vitamins and other important substances around the body. The protein was on Professor Habib’s mind because his patients with liver damage have low levels of it. After his exercise session, he called a colleague with whom he was investigating the use of a small activating ribonucleic acid (saRNA) to treat liver disease. “I asked him whether our cell cultures producing albumin also had lower cell counts, and he said ‘Yes, Prof’. That’s when we began to wonder whether by increasing the expression of a gene to improve liver function, we could at the same time treat liver cancer.”

Ten years on and MiNA Therapeutics, a company co-founded by Professor Habib, is running the world’s first clinical trials of therapeutic saRNAs. The groundbreaking work has only been possible because Professor Habib was keenly aware of the importance of working with those in other fields and harnessing the talents of colleagues in both academia and industry. In reaching out beyond traditional boundaries, Professor Habib’s approach has much in common with other leading researchers at Imperial’s Centre for Advanced Therapeutics.

The Centre for Advanced Therapeutics

Launched in early 2020, Imperial's Centre for Advanced Therapeutics brings together pioneers in the fields of RNA therapeutics, biomaterials, cardiology, haematology, respiratory medicine, neurology, vaccines and vectorology.

It facilitates the sharing of ideas, expertise, facilities and training to speed the development of new treatments. Gene- and cell-based therapies, and tissue engineering – collectively known as Advanced Therapeutic Medicinal Products (ATMPs) – make up most of the Centre’s focus.

Some ATMPs have been improving the lives of patients for several years, while others being researched have the potential to revolutionise the treatment of a wide range of conditions.

Gene therapy and cystic fibrosis

Eric Alton, Professor of Gene Therapy and Respiratory Medicine at Imperial's National Heart and Lung Institute (NHLI), is another clinician who understands the immense value of collaborating with laboratory-based colleagues in different fields. In the 1980s, Professor Alton carried out pioneering work that revealed in greater detail the causes of abnormalities in the flow of sodium and chloride across mucous membranes in the noses of those with cystic fibrosis. His research led to the worldwide introduction of a diagnostic test based on identifying the greater differences in the voltage of electrical signals across membranes lining nasal cavities in those with the condition.

Cystic fibrosis is an inherited disease caused by abnormalities in the CF transmembrane conductance regulator (CFTR) gene. The identification and cloning of the CFTR gene in 1989 raised hopes that the condition might be treatable with gene therapy. Researchers investigated different ways to get healthy versions of the CFTR gene into the airways of patients. Many of the early gene therapy trials of the 1990s used either adenoviruses or adeno-associated viruses as vectors. While this showed some promise, neutralising immune responses often rendered repeat administration ineffective.

Groups at Imperial and the Universities of Oxford and Edinburgh formed the UK CF Gene Therapy Consortium in 2001 to better coordinate their efforts, with Professor Alton as its lead coordinator. By this time, he had been joined at Imperial by Professor Uta Griesenbach, a geneticist who moved to NHLI from the Canadian laboratory that discovered the CFTR gene. She and Professor Alton, who share a keen focus on taking science beyond the lab and into the clinic, have worked together for over 20 years.

They and their colleagues adopted a multi-pronged strategy in their search for improved cystic fibrosis treatment. Their non-viral approach involved encasing healthy versions of the CFTR gene in lipid coatings called liposomes. They completed the world’s largest cystic fibrosis gene therapy trial in 2015. “We showed for the first time that repeated doses of gene therapy can make a difference to lung function compared to placebo,” says Professor Alton.

While this was promising, the effects were seen as too modest to form the basis for a commercially viable product. In parallel, the group had been working with Japanese researchers on an alternative viral vector-based approach. Using a process called pseudotyping, they added proteins from the murine Sendai virus to a simian lentivirus to produce a vector that could effectively enter cells that make up airway linings while evading the immune reactions that reduce the efficacy of other viral vectors.

 “Adenoviruses and adeno-associated viruses are widely used as vectors, but when you come to give second and third doses they induce immune responses, so they don’t work as well,” says Professor Griesenbach. “We and others have shown lentiviruses seem to be immunologically privileged, so you can give repeated doses without losing efficacy.”

Professor Griesenbach has also shown their lentivirus-based gene therapy platform can drive efficient secretion of proteins. Based on this work, she and Professor Alton received a large Wellcome Trust grant to investigate the technology’s potential to treat a number of other lung conditions, such as alpha-1 antitrypsin deficiency, interstitial lung disease and pulmonary alveolar proteinosis, as well as blood disorders including thrombotic thrombocytopenic purpura.

Automated chemistry

Dr Elena Sanna, a Research Associate in Imperial’s Department of Chemistry, is already working in collaboration with a commercial partner, a startup called Sixfold Bioscience, in her work to improve the efficacy of RNA nanoparticle-based drugs.

A growing body of research has shown how short sections of double-stranded RNA called small interfering RNAs (siRNAs) can be used to turn off the expression of genes linked to disease. While groups around the world are seeking to use the technique to develop new cancer therapies, a remaining obstacle is that, because of their relatively large size, most siRNAs that make it into tumour cells get stuck within cellular waste disposal systems called endosomes, undermining their efficacy.

Dr Sanna is trying to discover compounds called endosomal escape molecules (EEMs) that can be attached to RNA nanoparticles to give them a helping hand to break free of the lysosome. She is doing so using facilities at the Centre for Rapid Online Analysis of Reactions (ROAR), based in Imperial’s Molecular Sciences Research Hub at the White City Campus.

ROAR, launched in 2019, provides access to a wide range of automated rapid-throughput instruments. This allows Dr Sanna to rapidly carry out huge numbers of experiments, varying conditions such as temperature, solvents, reagents and reaction times, to identify EEMs and the best ways to chemically bond them to RNA nanoparticles. The ultimate goal is for Dr Sanna’s EEMs to be used to improve the efficacy of siRNAs currently being developed by Sixfold as novel cancer treatments, and the technology could also be applied more broadly.

It has been estimated that getting a new drug through clinical trials and to regulatory approval costs around $1 billion. Using facilities like ROAR, researchers can identify new treatments more quickly and cheaply. Most importantly, that means patients getting access to more effective therapies more quickly.

 Tissue engineering

Sian Harding, Professor of Cardiac Pharmacology in Imperial's National Heart and Lung Institute, is also working at the cutting edge of tissue engineering. The treatment of heart attacks has improved in recent years; however, the muscle damage they cause leaves survivors unable to pump blood around the body effectively, resulting in symptoms such as fatigue and breathlessness. The body does a poor job of replacing the missing muscle tissue. Professor Harding’s team, along with collaborators in Nottingham and Hamburg, are growing patches of engineered cardiac muscle tissue to help patients following heart attacks.

The patches start out as stem cells, the body’s master cells that can grow into many different types. These can be mature skin cells that have been reprogrammed into stem cells or stem cells taken from embryos. Once large numbers have been grown, changes to the medium in which they are grown drive them to turn into heart muscle cells. Pushed together onto scaffolds, these form thumb-sized patches that begin to beat in synchrony and release compounds that help repair and regenerate existing heart tissue.

In research presented at a conference in 2019, Professor Harding’s group showed patches implanted into rabbits after heart attacks were being nourished by blood vessels growing into them from the heart. “We were able to show improved function, decreased scar sizes, and importantly, no arrhythmias.” Arrhythmias are abnormal heart rhythms and side effects seen in other experimental stem cell-based treatments.

Supported by funding from the British Heart Foundation, Professor Harding’s group is now seeking to better understand how the patches become synchronised with recipient hearts and is investigating the use of devices to ensure this happens safely. If successful, they hope to test the safety and efficacy of their patches in pigs and ultimately to a trial them in humans.

Following earlier work that helped reveal the molecular mechanisms underpinning the contraction of the heart, Professor Harding went on to lead the UK’s first myocardial gene therapy clinical trial, but the levels of gene transfer achieved were too low and the treatment failed to produce significant benefit in participants. She is now working with collaborators at King’s College London and UCL to use small, single-stranded sections of RNAs called microRNAs to improve the efficiency of adeno-associated viruses for future potential use in gene therapy to repair heart damage.

Professor Harding says the Centre for Advanced Therapeutics and its collaborators in the field at King’s and UCL are laying the groundwork for the adoption of novel treatments by facilitating conversations between scientists and healthcare professionals. “We’re talking about the use of cells, viruses and other live constructs,” says Professor Harding, “which are quite different to drugs. There’s a lot of infrastructure and training needed to make that happen, and so we need to work with healthcare professionals in the NHS to understand how best we can deliver these complex products.”

Spinal cord injury

While ATMPs have been transforming the lives of patients with blood disorders for many years, research on them is at an earlier stage in other fields. Professor Simone di Giovanni, Chair in Restorative Neuroscience at Imperial, is seeking to better understand the mechanisms that underpin repair and regeneration in the nervous system following following injury.

Professor Di Giovanni’s team does so by investigating some of the key cellular and molecular pathways responsible for the regeneration failure. One experimental approach his group uses is to compare what happens after injury in the peripheral nervous system, in which nerves have some capacity to grow back, with what happens in the spinal cord and brain, where damage is generally irreparable. Other techniques include providing animals with stimulating environments to increase their brain activity or making changes to their diets or exercise patterns to see how this affects the ability to repair damage. 

By introducing genetic modifications in target populations of neurons using adeno-associated viral vectors, Professor Di Giovanni has identified a number of key molecular pathways that could be targeted with interventions. In research published in December 2020, for example, his team observed that mice provided with stimulating environments saw greater regeneration of their dorsal root ganglia sensory neurons following spinal cord injury. They went on to identify the NOX2 gene as playing a key role in this finding. “We showed that gene transfer using this gene enhances axonal regeneration, synaptic function and sensory recovery in animals,” says Professor Di Giovanni. “You could in principle do this in humans.”

Professor Di Giovanni says there remain significant obstacles to overcome before clinical trials of gene therapy for spinal cord injury can begin, and highlights that his work could also inform the discovery of new small molecule drugs. As an associate of the Centre for Advanced Therapeutics, Professor Di Giovanni has access to a network of leading researchers in related fields to discuss his efforts to tackle these challenges.

This feature was commissioned by Enterprise, an Imperial team that helps industry partners benefit from the expertise of Imperial researchers, and helps Imperial staff and students turn ideas into world-changing innovations.

Learn more about how Imperial helps businesses in healthcare and other industries address their challenges at the Enterprise website.