Bringing gene therapy to Manchester Clinical Research Facility to improve the lives of patients with rare disease

To help raise awareness of “Rare Disease Day,” research nurses Lebina Pinto and Preety Roberts talk about an exciting gene therapy trial to help patients with haemophilia A. They provide insight into how Manchester’s NIHR infrastructure, combined with Manchester University NHS Foundation Trust (MFT), has been central to the successful delivery of the study – which, through a
one – time treatment aims to stop the spontaneous, excessive bleeding associated with this rare condition.  

Haemophilia is a rare disease that affects the blood’s ability to clot. It’s usually inherited, and mostly affects males (one in 10,000 males). Normally, when you cut yourself, substances in the blood known as clotting factors combine with blood cells called platelets to make the blood “sticky”. This eventually makes the bleeding stop. People with haemophilia have lower levels of clotting factor in their blood. This means they bleed for longer than usual. Someone with severe haemophilia may have frequent spontaneous bleeds into their muscles or joints which can be painful, damage the joints, restrict movement and lead to haemophilic arthritis in the long term.

The body’s clotting factors are numbered using the Roman numerals I through XII. They work together in a specialized sequence, almost like pieces of a puzzle. When the last piece is in place, the clot develops — but if even one piece is missing or defective, the puzzle can’t come together.

In haemophilia A, a faulty gene the liver means it doesn’t make enough of clotting factor VIII. Current treatment replaces the missing clotting factor VIII in the blood through frequent injections (every 24 – 48 hours) for life.

This study used an experimental technique that utilises genes to treat or prevent disease using the adeno–associated virus, a virus that doesn’t cause disease and can be modified to deliver the missing DNA to the faulty gene in the liver cells. By replacing the faulty gene with one single injection, the liver could produce enough factor VIII by itself – preventing future bleeding episodes.

Bringing gene therapy to Manchester CRF

This was the first time we had delivered a gene therapy trial at the Manchester CRF at Manchester Royal Infirmary. We worked with the trial sponsor, clinical research associates and the wider MFT team to identify the key requirements and operational challenges, unique to this trial. These included pharmacy and specialist aseptic (sterile) capabilities, biobank availability and physiotherapy support (to measure mobility and joint swelling).

As we were relying on the support of other departments we had to ensure that they were all aware of our priorities and they were both supportive of what we needed to achieve and able to provide the service needed.

We met with each Trust service regularly so we could keep the lines of communication open and it helped us to drive the set-up process along with clear plans. From the set-up process we learnt a lot about the importance of two-way interaction and how important it was to ensure the needs of our project were kept on everyone’s radar. Without us doing that the demands on the clinical departments for normal NHS services could impact on the research. Although, it’s essential to point out that every department we worked with showed great interest in what we were doing and we couldn’t have delivered the trial without them.

We’re using this learning to develop guidelines for managing complex trials within MFT which we will be able to share with colleagues.

Being hosted by MFT has been key to supporting the the delivery of this trial.  Through MFT’s infrastructure, the CRF has been at the centre of this multi-disciplinary collaboration.

Trial set-up

Staff from MFT’s Haemophillia Centre, including the centre coordinator and the haemophillia nurses, worked very hard to support this trial and they helped to support us with the identification and initial meeting with our first patient.

When patients are moving from one team to another within clinical specialities it’s important they feel confident that they are making the right choice. This is critical when there is a routine clinical need, but perhaps even more so when they are volunteering to be part of research. The Haemophillia Team have been with us every step of the way and are a good example of how research and clinical services can have a symbiotic relationship.

We are delighted to have recruited the first global patient on a second cohort for this study.

Charles Hay, Clinical Professor of Haemostasis and Thrombosis, and Consultant Haematologist at Manchester University Foundation Trust has said he was very pleased to be able to offer this study to his patients and that without access to the CRF it wouldn’t be possible to run such trials within the clinical service.

We’re delighted that since receiving the gene therapy our patient has been able to play properly with his children for the first time. This is fantastic news as in the past, even simple family activities like playing football or giving his children a hug could have caused him to bleed.  

Before taking part in the trial our patient had to inject himself regularly to keep his factor VIII levels up. Since taking part in the trial he hasn’t had to do this. He will only need to treat himself if he has a bleed and, as this hasn’t happened yet he’s currently classed as ‘free of treatment.’

This trial was supported by the NIHR Greater Manchester Clinical Research Network and iMATCH (Innovate Manchester Advanced Therapy Centre Hub), and funded by Bayer PLC.