Tackling chronic disease with gene and cell therapies

Repair of old, damaged or disease tissues promises future where people live longer

The CCMI is affiliated with NUI Galway’s School of Medicine and serves as a key translational outlet for research carried out in NUI Galway’s Regenerative Medicine Institute.

The CCMI is affiliated with NUI Galway’s School of Medicine and serves as a key translational outlet for research carried out in NUI Galway’s Regenerative Medicine Institute.

 

The repair of old, damaged, or diseased tissues using gene or cell therapies promises a future where people live longer, healthier lives – and Ireland is well placed to become a manufacturing hub for products based on this technology.

Gene therapy is the technology used to correct a gene defect that is causing an inherited genetic disease. Cell therapy is the use of living cells from the patient or a donor, to repair tissue or treat an inflammatory condition or disease. These therapies can be used alone or combined for greater effect.

“We’ve been interested, for a very long time in the development of new treatments for patients involving cell and gene therapy,” says professor of cellular therapy at NUI Galway Frank Barry – a co-founder of the Regenerative Medicine Institute (Remedi) in 2004.

“Over the last several decades there have been some extraordinary, transformative developments in medicine; for example, antibiotics and monoclonal antibodies and these have had a dramatic impact on how diseases were treated,” says Barry. “Many people believe that cell and gene therapy represent the next transformative innovation that will change medicine.

“There are many examples of outstanding success stories, where diseases which were previously untreatable are now actually being treated and we’re very anxious to continue to play a role in this,” says Barry.

The combination of cell and gene therapy has been successful in treating cancers that were thought incurable. For example, stem cells have been taken from the blood of patients with specific cancers, genetically modified so they target a particular cancer, and are delivered back into the patient’s blood.

Troubled history

Gene therapy has had a troubled history with some adverse outcomes reported from early clinical trials two decades ago. Most notably, and tragically, was the case of 18-year-old Jesse Gelsinger, who died in 1999 during a University of Pennsylvania run gene therapy trial. Jesse suffered from a genetic disease affecting his liver which meant that he was unable to metabolise ammonia.

“The learnings from that have proven to be very helpful – not to diminish the impact of his death on his family and the tragedy of that,” says Prof Tim O’Brien, head of medicine at NUI Galway, an Irish pioneer of this field.

In Ireland, the origins of cell and gene therapy research go back to 2004, when Remedi was set up with funding from Science Foundation Ireland (SFI). Then in 2014, the Centre for Cell Manufacturing in Ireland (CCMI) was established. Barry and O’Brien have been the key figures driving the process.

From the beginning, the dream of Barry and O’Brien was to convert promising gene and cell therapy research into new therapies that could then be tested in clinical trials. Galway was a good place to do it, as it was known as a leading hub for medical device research and manufacturing, and it had the laboratories, hospital tissue facilities and clinical trial expertise that would be required.

The Centre for Cell Manufacturing (CCMI) at NUI Galway is the first facility on the island of Ireland to receive regulatory authorisation from the Health Products Regulatory Authority to manufacture Advanced Therapy Medicinal Products
The Centre for Cell Manufacturing (CCMI) at NUI Galway is the first facility on the island of Ireland to receive regulatory authorisation from the Health Products Regulatory Authority to manufacture Advanced Therapy Medicinal Products

Almost two decades down the road, the next step, they say, requires putting in place a national plan for developing a cell and gene therapy industry across the island similar to what has been achieved for medical devices and other high areas dependent on advanced technology, like ICT and pharmaceuticals. The UK offers a model of what can be achieved as it benefits from a decision by government to heavily invest in gene and cell therapy 15 years ago through an independent body it established called the Cell and Gene Therapy Catapult.

The opportunity for gene and cell therapy to grow here in coming years helped attract Dr Meadhbh Brennan, a post-doctoral researcher at Harvard University, back to Ireland. She also worked at the National Institute of Health and Inserm in France before returning to NUIG to set up her own research group.

In France, Brennan had worked on a clinical trial using stem cells to treat bone defects, while in the US her research focused on factors secreted by stem cells which could be used as a therapeutic. While in the US, she was awarded funding from SFI and that provided impetus for her move home, to take up a position at NUIG working at the interface between engineering and medicine.

She has a European Research Council starting grant award to investigate ways of regenerating bone defects, building on her work in this area. There are more than one million bone grafting procedures performed annually in Europe, and after blood, bone is the most transplanted tissue. There are issues with these procedures, however, as bone tissue is limited in quantity and quality – and there is often pain at the surgical site for patients.

Brennan and her team are seeking alternatives to bone grafting through the use of byproducts from the manufacturing of stem cells called extracellular vesicles (EVs). These EVs are tiny biological packages that each contain a therapeutic cargo that has been shown to be capable of enhancing healing processes in tissues by delivering “healing messages” from cell to cell.

Up to now, EVs have been disposed of as waste products from commercial stem cell manufacturing. “We want to divert these discarded products and harness their therapeutic potential,” Brennan says, “This will make the whole stem cell manufacturing process more efficient and sustainable.”

Trials

Remedi scientists have experience running patient cell therapy trials, with a trial to treat arthritis of the knee using patients’ own cells having finished and its results set to be reported during 2022. “We don’t have the formal results yet, but every piece of information that we’ve seen about this kind of effort suggests that there is a positive benefit associated with delivering cells to these arthritic joints,” Barry says. The next step would be to conduct a larger, well controlled, multinational trial of the therapy, which could be led in Ireland.

There is a huge need for new therapies to treat bone defects, given that about 10 per cent of all bone fractures won’t heal if left alone, while bone infection and surgery can leave big voids in bone that need to be healed. This is where new approaches based on EVs can come in, says Brennan. “These tiny particles hold huge promise for regenerating not only bone tissue, but also older tissues and organs, and have healing potential in other diseases too.”

The idea of Ireland becoming a global hub for cell and gene therapy and manufacturing is something we should talk about seriously
 

A key challenge to sort out with EV-based therapies is to find a way to safely transport them from the stem cell manufacturing facility to the clinic. Brennan and her team are investigating ways to allow the vesicles to be stored for longer durations at room temperature. The ultimate goal is to develop novel EV treatments that are inexpensive and available “off the shelf” when a patient has an injured or damaged tissue or needs an anti-inflammatory treatment.

“The whole idea about these technologies is that they are regenerative, stimulate repair or correct defects which are chronic,” Barry notes. “If they work then you are saving years and years of care associated with chronic illness. The economics of this make an awful lot of sense, and the investment that is needed is very much worth it in terms of the long term.

“This is a huge new industry which is exploding worldwide and will require advanced manufacturing capacity in all corners of the world,” Barry points out. “There is an opportunity for Ireland to become a major centre of this, and we have the people, expertise, and infrastructure to allow the industry to develop here. We need to move with lightning speed to capture the opportunity.

“The idea of Ireland becoming a global hub for cell and gene therapy and manufacturing is something we should talk about seriously,” he adds.