Breakthroughs in regenerative children's medicine

Breakthroughs in children’s medicine

REGENERATIVE MEDICINE

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WELCOME 20_12_DM_Legacy_Regenerative_Breakthrough_Guide_Mailing_UPDATE_ST4.indd 2

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Welcome

Welcome to the tenth guide in our series of breakthroughs in children’s medicine, featuring regenerative medicine. Officially recognised as a medical discipline in the 1990s, this rapidly evolving field is already shaping the future of care for seriously ill children at Great Ormond Street Hospital (GOSH), across the UK and around the world.

Regenerative medicine is defined as any treatment that restores normal function to tissues or organs, with an emphasis on harnessing the body’s natural ability to repair itself. It tells us that treating symptoms is only a temporary solution, and that tackling the root cause of disease is the path to real progress.

As a paediatric surgeon at GOSH, I can see regenerative techniques in surgery changing and improving all the time. Along with advances in technology, we’re developing a better understanding of different tissues in the body and how we might better heal or replace them. Because younger tissue is more able to regenerate and repair, regenerative medicine holds huge potential for children.

Alongside clinical work, I’m passionate about research. We’re using new ways of sourcing stem cells, growing tissue from scratch in the lab, and modifying DNA inside cells to make them work better.

We’re seeing a shift away from a reliance on organ and tissue donors – a process that often requires finding a good match fast – towards a future in which the same, or perhaps better, results could be achieved using the child’s own cells, or ready-made banks of patient-matched cells and organs.

I hope you enjoy reading about some of the key breakthroughs in regenerative medicine at GOSH, and that you continue to support our crucial work. Thank you.

Professor Paolo De Coppi Consultant Paediatric Surgeon at GOSH and Head of Stem Cells and Regenerative Medicine at the UCL Great Ormond Street Institute of Child Health (ICH).

Left: Professor Paolo De Coppi.

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CONTENTS

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Yesterday

Page

Early pioneers of surgical repair .......................................................................................................................................................................................................................................................... 8 From isolation to donation ............................................................................................................................................................................................................................................................................ 10 Making transplants safer .................................................................................................................................................................................................................................................................................... 12

Today

Entering a new era ................................................................................................................................................................................................................................................................................................................ 16 Rebooting the immune system ........................................................................................................................................................................................................................................................... 18 Meet Guy ............................................................................................................................................................................................................................................................................................................................................................. 20 Giving cells superpowers .................................................................................................................................................................................................................................................................................... 22 Meet Kieran ............................................................................................................................................................................................................................................................................................................................................... 24 Meet the team: Fetal surgery ................................................................................................................................................................................................................................................................... 26 Meet Tulsi ........................................................................................................................................................................................................................................................................................................................................................ 30

Tomorrow

Off the shelf immune systems ............................................................................................................................................................................................................................................................... 34 Bridging the gap ........................................................................................................................................................................................................................................................................................................................ 36 Meet Jake ........................................................................................................................................................................................................................................................................................................................................................ 38 Growing new organs ........................................................................................................................................................................................................................................................................................................ 40 Thank you ........................................................................................................................................................................................................................................................................................................................................................ 42

Cover image: Tulsi at 20-months-old with mum Laxmi.

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YESTERDAY

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Georgia was born with spina bifida and was treated at GOSH for her entire childhood.

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Yesterday

Early pioneers of surgical repair Life was incredibly tough for ill children living in 19th century London. In some districts, a third of children under the age of five lost their lives to illness or injury. Recognising that with specialised care many of these children could recover, in 1852 physician Dr Charles West founded the Hospital for Sick Children on Great Ormond Street.

Even with dedicated paediatric care, children with a failing organ or condition requiring surgical repair had little hope of recovery before the late 1800s.

Anaesthesia was not in widespread use and little was known about the spread of infection. Undergoing a surgical procedure to repair tissue was extremely painful, unpleasant and risky.

In 1883, Sir William Arbuthnot Lane joined GOSH and was instrumental in improving surgical techniques. He established

the ‘no touch’ technique, in which only sterilised instruments were used and fingers were kept at least four inches away. With anaesthesia now widely used and infection risks reduced, surgeons at GOSH could finally take their time to figure out new ways of repairing tissue.

Surgeons at GOSH knew that repairing tiny bodies would require specialised techniques. Sir Denis Browne, Consultant Surgeon at GOSH from 1929, advocated the need to use bespoke skills for children.

A prolific innovator with tremendous technical skill, he introduced pioneering techniques for abdominal surgery, including methods to repair obstruction and shortening of the intestine. Sir Denis helped to found the British Association of Paediatric Surgeons in 1953, which became a major forum for sharing new ideas and teaching surgery of unborn and newborn babies and children.

1943 Dr David Matthews, who would later become GOSH’s leading plastic surgeon, publishes The Surgery of Repair: Injuries and Burns, a book outlining pioneering techniques to repair tissue that he learned while treating injured aircrew during World War II. 8

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Medical staff at GOSH, 1924. Denis Browne (bottom row, second from right) would become the first surgeon in Britain to focus solely on the care of children.

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Yesterday

From isolation to donation While surgical techniques were advancing rapidly throughout the 20th century, there were still few treatment options for children born with weakened immune systems. The most severely affected, known as ‘bubble babies’, had no immune cells at all and were so vulnerable that even a common cold could be fatal. The only approach to care for these children was to isolate them completely, making a normal childhood impossible.

A breakthrough in restoring immune function came in the 1970s, when GOSH Immunologist Professor Roland Levinsky developed a technique to isolate vital immune cells in the blood. This made it possible to extract working immune cells from a healthy donor and transplant

them into a child. Known as a bone marrow transplant, this treatment offered children born without an immune system their first hope of a normal life.

Professor Levinksy carried out the UK’s first successful bone marrow transplant in a child in 1979. That child was Andrew, a four-month-old whose life hung in the balance after he was born with no immune system. Andrew received bone marrow from his threeyear-old brother, and despite his body initially rejecting the foreign cells, Andrew went on to recover and enjoy a normal childhood with a regenerated, functioning immune system.

1999 Dr Paul Veys develops a new kind of bone marrow transplant for children born with weakened immune systems. The new technique is gentler and can help children who are too sick for standard doses of drugs.

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Professor Lewinsky with Andrew as a baby. Right: Andrew today.

Andrew says: “As I reached my 40th Birthday I was mindful that it is not just a milestone for me, but a milestone for the NHS and for regenerative medicine in general. If it hadn’t been for the pioneering procedures of the team at Great Ormond Street Hospital, I wouldn’t be looking forward to a birthday at all. I am humbled by the ongoing research allowing countless others to get a chance at a full and happy life.”

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Making transplants safer Thanks to advances in surgery and the development of immunosuppressants – drugs to stop the immune system from rejecting donor tissue, organ transplantation finally became a viable option from the 1950s onwards. It marked a major turning point in the approach to failing organs, inspiring a shift from attempted repair to replacement.

With effective immunosuppressants, children could safely receive replacement kidneys, lungs and other organs. But by dialling down their immune system, the drugs left children susceptible to infection. And in some cases, rejection of the donor tissue was inevitable.

In 1988, surgeon Professor Marc de Leval set up the GOSH heart transplant unit, performing the hospital’s (and one of the

UK’s) first paediatric heart transplants.

Before this, many serious heart defects were unavoidably fatal. For the first time, children with heart failure had a chance.

Despite this incredible progress, major issues remained. By the early 1990s, 30 to 50% of all patients waiting for a heart transplant would pass away before a suitable donor could be found, and the rest – those lucky enough to find a match – would all experience rejection at some point. This was managed, where possible, by switching from one powerful immune-suppressing medication to another. Today, thanks to advances in devices that act as a bridge to transplant, the number of children who pass away while on the waiting list for a new heart has dropped to around 20%.

1950s Richard Bonham Carter and David Waterston establish the GOSH Thoracic Unit, the UK’s first joint medical and surgical ward devoted entirely to the diagnosis and treatment of children with chest and heart diseases.

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At age 13, Faye got what seemed to be a very bad chest infection that made her short of breath and unable to sleep on her back. But when her parents noticed her heart pumping out of her chest, they realised something more serious was wrong.

“Our local A&E couldn’t figure out what was happening, so I was rushed to Great Ormond Street Hospital where I was diagnosed with dilated cardiomyopathy.

My heart was enlarged and too weak to pump blood properly. It was failing, and I needed a transplant. Fortunately, I was able to get a new heart very quickly. Without it, I would have died.”

“I’m now 27 and I’m doing really well, but I’ll have to take immunosuppressants for the rest of my life. They help regulate my immune system and make sure my body doesn’t reject my heart.

Otherwise, I’m living life like any other young professional and am about to buy a house with my partner!”

1970 The discovery of powerful immunosuppressant cyclosporine helps to prevent organ rejection after transplant. The drug is still in widespread use today.

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TODAY 20_12_DM_Legacy_Regenerative_Breakthrough_Guide_Mailing_UPDATE_ST4.indd 14

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Nina had gene therapy treatment at GOSH and is pictured here a happy, healthy seven-year-old.

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Today

Entering a new era In 1992, American futurist Leland Kaiser predicted that “a new branch of medicine will develop that attempts to change the course of chronic disease and in many instances will regenerate tired and failing organ systems.” This is the first known reference to regenerative medicine, a field of research that has since expanded to represent a broad and incredibly promising area of medicine.

New knowledge is inspiring incredible laboratory techniques, from modifying faulty DNA sequences to growing human tissue from just a few patient cells. These methods harness the body’s natural ability to repair and tackle the causes of conditions at their source, decreasing our reliance on organ transplant and symptom management. Some of the key techniques are outlined in the diagram opposite.

Advances in regenerative medicine are being driven by a growing understanding of the cells that make up our bodies and the instructions within – our DNA. Mutations or ‘mistakes’ in that DNA can cause disease, as they alter the instructions the body is given and disrupt the normal cell processes that keep us healthy.

1981 For the first time, surgeons transplant tissue grown from a patient’s own cells to treat burn wounds.

1990 A child in the US receives the world’s first gene therapy treatment – a corrected sequence of DNA is delivered into her cells to fix the genetic fault causing her immune system condition.

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Key regenerative medicine techniques Cells from a donor

Take cells from patient

Reprogramme to create stem cells

Induced pluripotent stem cells (IPSCs)

Gene therapy and editing Reprogramme to create desired cells

Return cells to patient

Therapeutic cells Tissue engineering

Use cells to create new organs/tissue 17

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Rebooting the immune system Immunologists Professor Bobby Gaspar and Professor Adrian Thrasher first met at GOSH in 1994. This encounter would spark a groundbreaking programme of research into gene therapy, a technique that involves replacing a faulty section of DNA (a gene) with a working copy.

In 2001, the team began a trial that would become the second ever successful trial of gene therapy for any disease, anywhere in the world. Their patients were children born with a genetic fault that left them without a functioning immune system.

“These children were some of the sickest we’d ever seen,” says Professor Gaspar.

“We knew that our best treatment at the time – a bone marrow transplant – would be very risky in a significant number of these cases, especially those

children for whom we couldn’t find a well matched bone marrow donor.”

The team took a sample of each child’s bone marrow and, in the lab, used modified viruses to deliver a healthy copy of the faulty gene. The corrected cells were then given back to the child, where they could get to work rebuilding a healthy immune system. And it worked.

All the children recovered with fewer side effects than a bone marrow transplant.

Since then, more than 60 children with immune system conditions have been treated and GOSH has become one of the world’s leading centres for gene therapy. Research teams are now working to improve the technique, reduce side effects and develop gene therapies for other conditions including muscle-wasting diseases, metabolic conditions and sight loss.

2001 GOSH patient Rhys becomes the first child in the UK, and one of the first people in the world, to be treated with revolutionary gene therapy.

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GOSH Immunologist Professor Bobby Gaspar and Rhys.

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Meet Guy Guy from Nottingham was born healthy, but at around four months old his health started to deteriorate. He was diagnosed at Great Ormond Street Hospital with X-SCID, which meant his body was not developing the right cells to fight infections and he needed a bone marrow transplant. But sadly, a match couldn’t be found.

“However, when we returned to GOSH, they spoke to us about gene therapy.

The doctors explained that it was currently a trial and only eight children in the country had had it before. But it was an easy decision to make because it was Guy’s only hope,” says Guy’s mum Gaynor. “It took around a year to see the effects of the gene therapy as Guy was still having his antibody injections twice a week.”

“We had a great sense of relief as all the results seemed so positive.” Guy is now a typical teenager and doing brilliantly; “he can do all the things his friends can and more,” says Gaynor.

“Without the gene therapy, the injections wouldn’t be enough, and he wouldn’t have the quality of life that he has now. In fact, if it wasn’t for research, Guy wouldn’t be here today. If GOSH didn’t have the money to look into these conditions, they wouldn’t be able to help the thousands of children who need them.”

“We are incredibly grateful to the whole team at Great Ormond Street Hospital, but especially Adrian Thrasher and Bobby Gaspar who pioneered this work,” says Gaynor.

Professor Adrian Thrasher is a Professor of Paediatric Immunology at GOSH. His areas of expertise include primary immunology and gene therapy.

Professor Bobby Gaspar is an expert in paediatrics and immunology at GOSH; seeing patients and developingnew gene therapy treatments.

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Guy underwent gene therapy at GOSH.

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Giving cells superpowers Regenerative medicine could go beyond simply fixing faults. It could actually enhance the body’s natural processes, adding an extra line of defence against disease.

Our immune systems are programmed to fight off the viruses and bacteria we encounter every day. But there’s a problem. Cancer is caused by our own cells multiplying uncontrollably, so the immune system tolerates them better than invading viruses.

In the last decade, researchers have discovered a way to remove the body’s cancer blindfold. The technique involves ‘editing’ the DNA inside immune cells, adding genetic instructions for them to recognise, hunt down and destroy cancer cells. These modified immune cells are known as CAR-T cells.

In 2015, GOSH Immunologist Professor Waseem Qasim used CAR-T cells to treat a one-year-old patient with ‘incurable’ leukaemia. This incredible world-first sparked a new wave of CAR-T research around the world.

In an ideal scenario the child’s own cells are extracted, engineered in the lab to fight cancer, and returned to the child. But for children who are too ill to spare those cells, another approach is needed. “We’re testing ‘universal’ CAR-T cells, known as UCART, in ongoing clinical trials” says Professor Qasim. “These are sourced from volunteer donors but are modified so that they can be used without being matched to the child. We hope to move the next generation of this treatment towards clinical trial in the near future and extend the approach to other types of leukaemia.”

2018 A study led by GOSH researcher Dr Karin Straathof shows for the first time that CAR-T cells have the potential to target solid tumours in the nervous system.

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Professor Waseem Qasim is pioneering new treatments that teach immune cells to target cancer.

2018 GOSH becomes the first hospital in the UK to offer Kymriah, a pioneering CAR-T cancer treatment, to patients with an aggressive blood cancer called B-cell acute lymphoblastic leukaemia. GOSH expert Professor Persis Amrolia is leading a UK-wide trial of another CAR-T therapy for blood cancer patients.

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Meet Kieran Using a child’s own tissue to repair the body has clear benefits: no waiting for a matching donor, and little risk of rejection. In some cases, repurposing tissue can provide a surprisingly elegant solution.

“Kieran was born without any ears – a condition called bilateral microtia,” says Kieran’s mum Louise. “It means he’s deaf and looks a little different to other children. We were worried about whether we’d find a way to help his hearing and also cosmetically to make him feel confident.

“He was fitted with bone-anchored hearing aids at GOSH when he was about one year old. When he was 11 Kieran had a seven-hour operation at GOSH to reconstruct his ears. They removed cartilage from his ribs, sculpted it into the shape of ears, made a cut on both sides of his head and fitted the cartilage under the skin.

Then they sucked out the air, and all of a sudden, you see ears. It’s amazing.

They were the most beautiful ears I’d ever seen.”

“It might seem like what we do is very Blue Peter-ish,” says Neil Bulstrode, Kieran’s surgeon. “But it’s an incredibly effective technique. Ideally, we wouldn’t have to take rib cartilage from patients, because it means a longer operation and recovery. And cartilage won’t regenerate, so children are left with a permanent chest deformity.

“We’re now working on growing a 3D ear shape in the lab, without the need for rib cartilage. We’ll use cells taken from the patient to grow cartilage, which could give the same, if not better results for children like Kieran.”

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Kieran says: “Before the operations I thought I might get elephant ears or mouse ears, but I’ve got my mum’s ears. It’s weird but I feel great. Mr Bulstrode is the best surgeon as he made my wishes come true – I’ve got ears and can wear sunglasses!”

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Meet the team: Fetal surgery Young tissue has a remarkable ability to repair and regenerate itself. In many cases this means the earlier the diagnosis and treatment, the better the outcome for the child. At one end of that spectrum is the budding field of fetal surgery – operations that take place while a baby is still in the womb.

In 2018, GOSH and University College London Hospital (UCLH) conducted the UK’s first pioneering surgery to help reduce the long-term symptoms of spina bifida by operating on a baby while it was still in the womb. This incredible surgery was only made possible thanks to an experienced 30-strong multidisciplinary team and a panEuropean collaboration.

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The overseas expert “Spina bifida is caused when the structures covering the spinal cord, like the muscles and surrounding vertebrae, don’t form properly, leaving the spinal cord exposed as the baby develops in the womb. Surgery after birth isn’t always effective and children with the condition can have a range of disabilities including paralysis of the legs.

One major issue is the build-up of fluid on the brain, which can require draining.

Having conducted more than 40 fetal operations in Leuven, Belgium, I’ve seen firsthand that the surgery can help to reduce some of these symptoms. It’s been a great pleasure to spend the last few years guiding the multidisciplinary team at GOSH, University College London (UCL) and UCLH to bring this service to patients in the UK through the creation of the UCLH and GOSH Centre for Prenatal Therapy. This was only possible thanks to funding from GOSH Charity, UCLH Charity and UCL.”

The coordinator “My role involved coordinating the 30-strong team.

We’ve been working for three years to bring this service to UK patients. Our resolve to offer this service was based on the findings of a large trial in the US, which compared prenatal closure to postnatal closure. They found that prenatal closure was associated with a 50% reduction in the need for surgery to drain fluid from the brain after the baby is born, and a significant improvement in movement at 30 months of age. Some of these children are able to walk, which you might not expect if they hadn’t had the fetal surgery.”

Anna David Professor of Obstetrics and Fetal Medicine at UCLH

“ Over the summer of 2018, we repaired the defects in three babies’ spines, each in a 90-minute operation.” “ Jan Deprest

Jan Deprest Professor of Obstetrics and Fetal Medicine, UCLH and KU Leuven 27

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The baby’s surgeon “It’s been a privilege to be part of this amazing project and wonderful collaboration between GOSH, the ICH, UCLH and colleagues in Belgium.

For our first fetal surgeries, the GOSH team included myself, Professor Paolo DeCoppi and Zubair Tahir, assisted by a team of GOSH neurosurgical nurses.

“Surgery begins by anaesthetising the mother, which passes to the baby.

The medical team carefully monitors the baby’s vital signs throughout the procedure. The obstetric team then opens the abdomen and the womb – in a similar way to a caesarean section – and exposes the baby’s spina bifida defect . I then cut around the spinal cord, which is protruding through a hole in the back of the fetus, and put it back into the spinal canal. I create a new protective tube around the spinal cord and bring the muscles and skin together and stitch them closed. This protects the spinal cord and prevents further leakage of spinal fluid. The obstetric team then closes up mum, and the mother and baby are taken back to the recovery area. The surgery itself does not cure spina bifida completely, but research has shown that the severity of disabilities can be significantly reduced.”

Dominic Thompson Consultant Paediatric Neurosurgeon, GOSH

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Today

The nurse

The innovator

As part of my training I was fortunate enough to observe the surgery being carried out in Philadelphia and Leuven. Collaboration between GOSH and UCLH theatre staff was absolutely vital for the success of these procedures in the UK. Having the two hospitals in such close proximity was key. On the day of surgery, myself and another GOSH theatre nurse travel to UCLH to act as scrub nurse and circulating nurse for the fetal repair. We assist the neurosurgeon by passing the correct instruments and ensuring that vital equipment for every eventuality is available. We ensure the total wellbeing of our patients whilst they are in our care. The teamwork that has developed between UCLH and GOSH grows each time we carry out the procedure. For me, it has been both incredibly enjoyable and professionally satisfying to see that relationship grow.”

“I’m a general surgeon specialising in minimally invasive procedures, which is our ultimate goal for fetal surgery.

Currently, I assist Mr Dominic Thompson and am on hand if any conditions arise in my area of expertise. In the future, we hope to carry out the surgery through a small incision, which should help to reduce risks to the mother. We’re currently developing instruments and testing tissue engineering methods to make this possible. We also hope to introduce fetal intervention very soon, in collaboration with UCLH, for unborn babies with congenital diaphragmatic hernia, a life-threatening condition that causes abdominal organs to move into the chest cavity, restricting the growth of the lungs.”

Paolo De Coppi Professor of Paediatric Surgery, GOSH

Cecelia Carney Lead Theatre Nurse, GOSH 29

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Today

Meet Tulsi While she was developing inside the womb, Tulsi developed a defect – spina bifida – that stopped her spinal cord from forming properly. She was left with a hole in her spine and a sack of spinal fluid exposed on her back. Her mum Laxmi was told that her baby girl might be paralysed, need a tube in her brain to relieve pressure, or worse, not survive.

Tulsi’s best chance at life was to have delicate spinal surgery at Great Ormond Street Hospital within hours of being born. After eight hours of surgery and two days of recovery, Laxmi was finally able to hold her new baby girl. But unfortunately, not long after being home, Tulsi’s wound became infected and she needed to return to GOSH for a second operation.

Laxmi says: “I stayed by Tulsi’s side for the whole five weeks. It was a difficult time, but there were fantastic nurses that took really good care of us both.

We’ve been home for 18 months now and Tulsi is doing really great. She’s crawling and standing up, and she loves going to play group. She’s so strong, and it’s been remarkable to see her overcome so much trauma.

“We know she’ll face challenges, but we’re not focusing on the negatives. We see her for who she is, not that she has physical difficulties. Though, Tulsi will need to be monitored for the rest of her life so we come back to GOSH for regular appointments for physio and to check her brain, bladder, back and legs. We take comfort in the fact that she’s in the very best hands at GOSH.”

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Tulsi’s mum, Laxmi says: “It’s incredible what these doctors can do, like the new spina bifida surgery at GOSH that repairs the baby’s spine while it’s still in the womb. It’s just fantastic. It gives families another treatment choice, which is so important. When you’re receiving so much bad news, it’s really encouraging to hear that with surgery, your baby will survive, that they’ll smile, and maybe walk.”

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TOMORROW

Ela was born with a severely weakened immune system and comes to GOSH for treatment.

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Tomorrow

Off-the-shelf immune systems While regenerative techniques ultimately aim to use a patient’s own cells to repair the body, researchers are also finding new ways of using donor tissue to achieve personalised results.

prevent these cells from attacking the patient’s body. That’s very difficult to do.

The thymus is a complex organ made up of lots of different cells types. We’re battling to modify something that is tailored specifically for another person.”

The thymus is an organ in the chest that produces cells that form the basis of our immune system, and teaches the body to recognise the difference between harmful ‘invaders’ and its own tissue. “At GOSH we see children born without a thymus, a condition known as DiGeorge syndrome,” says Dr Paola Bonfanti, Stem Cell Biology Researcher at the ICH. “They can’t survive for more than a year or two because they’re so vulnerable to infection.

“I’m working towards building a thymus from scratch in the lab. We can use donor thymus tissue to create banks of all the cell types found inside it. Then it would be a case of pick and mix – selecting the cells we need to create an entire thymus structure. This could then be transplanted into a child with DiGeorge syndrome and help to build a strong immune system.

“It can be an anxious time for families waiting for a suitable donor,” says Dr Bonfanti. “If we find one, before the thymus can be transplanted it must be stripped of all donor immune cells, to

“It could also benefit organ transplants more generally. When a person receives an organ, they could get a piece of thymus with cells from the donor, massively reducing the risk of rejection.”

2019 GOSH is one of only two places in the world where children with DiGeorge syndrome can have a thymus transplant.

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Dr Paola Bonfanti is developing techniques to help children born without a key organ of the immune system.

2020 The British government plans to implement Max’s Law, a change to organ donation legislation that would consider everyone a potential donor unless they choose to opt out.

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Tomorrow

Bridging the gap Duchenne muscular dystrophy (DMD) is the most common and lethal musclewasting disease, affecting around 1 in 3,500 boys in the UK (very rarely affecting girls). It leaves children in a wheelchair by their teenage years and, with no cure, most do not live past their early thirties.

“When I joined GOSH in 2008, there were no clinical trials or therapies for children with DMD,” says Professor Francesco Muntoni, Director of the hospital’s Dubowitz Neuromuscular Centre. “But a decade later things are very different.

We’re involved in dozens of trials, and GOSH is really paving the way in an area known as ‘genetic patching’.

“I ask families to imagine the Golden Gate Bridge. If you cut out a tiny section in the middle, the bridge would collapse.

It’s the same with the dystrophin gene, which is crucial for building and

repairing muscle. It is a huge stretch of DNA, and most children with DMD have a tiny section missing that means they can’t produce dystrophin.

“What we’re trying to do with patching is rest a plank across the gap. It’s not as good as having the original bridge, but it’s enough to re-establish the connection between the two parts of the gene and allow production of some dystrophin.”

The ‘plank’ – known as an antisense oligonucleotide – is being evaluated in Europe and some children have already had access through clinical trials.

“We’re pushing forward as quickly and safely as we can,” says Professor Muntoni.

“There’s real hope that one day we could repair the genetic code to slow or even stop muscle wastage in these children.”

2016 An antisense oligonucleotide becomes the first drug for Duchenne muscular dystrophy to be approved for use in the United States

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Professor Francesco Muntoni is developing new treatments for musclewasting conditions.

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Tomorrow

Meet Jake “We knew something was wrong when Jake wasn’t hitting his milestones,” says Jake’s dad Carl. “He had trouble crawling and walking. Then, at about four years old and after numerous tests, the doctors told us it was Duchenne muscular dystrophy. We were devastated, but we made the decision that we would travel to the ends of the Earth for anything that helps him.”

Jake’s family learned about Professor Muntoni’s clinical trial through their local hospital and met with him to discuss the study in detail. Carl says: “To be asked to participate was absolutely brilliant.

Treatment options for the boys were basically zero at that point, and the use of steroids, which control inflammation of the muscles, can cause weight gain, mood swings and bone thinning.

“Jake had a little operation to put a port into his chest and a nurse comes out to us every week to give him his medicine.

He goes to GOSH every three months and has regular muscle biopsies. They’re still analyzing the results of the trial, but since Jake started taking the medication I feel like I’ve noticed an improvement.

He seems more active. As a family we understand how vital research is. We need to find out whether these things work. If it doesn’t, we’ll move onto the next stage.”

“The older Jake gets, the more he knows about his condition. He knows he can’t keep up with his friends at school and he can lose his balance sometimes. But most of the time he’s just a determined, happy little boy, which is brilliant. He is absolutely fearless. He’s a lot braver than I am!”

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Jake and his dad Carl.

Jake says: “I like playing on my bike and my scooter in the garden. And playing football with friends too.”

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Tomorrow

Growing new organs As treatments like gene therapy and CAR-T therapy take off, Professor De Coppi is driving regenerative medicine towards its next big breakthrough: using a patient’s own cells to grow personalised tissue and organs.

the stomach to meet the oesophagus.

This can be successful, but has long-term implications. Our new tissue engineering approach goes beyond repairing damaged tissue and offers the possibility of rejection-free organs for transplant.”

Historically, stem cells – cells with the potential to turn into almost any other type of cell in the body – were sourced from embryos. But times have changed. Researchers can now isolate stem cells found naturally in the adult body, and even create new stem cells perfectly matched to a patient, by ‘reprogramming’ skin or hair cells.

“Simple, tube-like organs like the oesophagus and intestine are easier to engineer than larger and more complex organs like the liver or lung. Other teams are working on growing retinal tissue that could help to preserve or restore a child’s sight. Of course, before we move forward with these treatments, we’re ensuring that all of our research is validated, ethical and safe.

Professor De Coppi says, “In 2018, we grew the world’s first oesophagi engineered from stem cells and successfully transplanted into mice.

That success could pave the way for clinical trials of lab-grown food pipes for children born without an oesophagus.

“One current treatment for these children is gastric pull-up – pulling up

“Our long-term goal is to actually make stem cells learn how to build these new structures inside the body, without having to remove them. We’re working on an incredible technique that would allow us to ‘grow’ new tissue within the body with a simple injection and no surgery, potentially helping many children born with parts of their organs missing.”

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Meet Hudson

Hudson was born with oesophageal atresia, where his oesophagus didn’t form properly and was disconnected from his stomach. He was referred to Great Ormond Street Hospital where Professor Paolo De Coppi recommended a gastric pullup procedure. As a result, Hudson can now enjoy some of the same foods as his twin. Though, he still needs continued feeding support.

Nicola, Hudson’s mum says: “Professor De Coppi’s latest research has the potential to change the lives of children with the condition.

In a case like Hudson’s an entirely new, functioning food pipe would be a game changer without a doubt.

It would give him a sense of normalcy, so that he can enjoy mealtimes and his life as fully and independently as any other child. We’re excited and hopeful to see where this goes.”

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THANK YOU Expert teams at GOSH care for children with rare and complex conditions, many of which are life-limiting or life-threatening.

There is an urgent need to improve the outlook for these children with new solutions and treatment approaches.

Thank to your ongoing support, we’re investing funds into pioneering areas like regenerative medicine to develop the treatments of tomorrow, giving seriously ill children the chance of a brighter future.

In 2018, we appointed a new GOSH Charity Professor of Stem Cell Biology.

Professor Rick Livesey will drive forward research in this incredibly promising area, including using cells from a patient’s hair or skin to create a whole range of life-saving stem cells and build tissue in the laboratory.

Professor Livesey says: “My research team and I are excited by the opportunity to contribute to GOSH’s mission. These are exciting times for translational research at GOSH, and we are very much looking forward to working together with everyone at GOSH, UCL and the ICH to help advance children’s health.”

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Lily was treated at GOSH for a rare type of leukaemia called AML.

We’ve opened new state-ofthe-art laboratories where researchers are growing patient-matched stem cells to understand more about how faulty genes cause disease.

Research in these labs could reveal how these genetic faults could be corrected using new gene editing technology.

GOSH Charity is the UK’s largest dedicated funder of child health research. With our partner charity Sparks, we fund pioneering regenerative medicine projects at GOSH, the ICH and around the UK. Thanks to donations and gifts in Wills from our supporters, we can bring hope for generations to come.

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FIND OUT MORE Our website has more information about the specialists, patients and treatments you’ve read about in this guide, as well as pioneering research at Great Ormond Street Hospital (GOSH) and the UCL Great Ormond Street Institute of Child Health.

If you’d like to find out more or share your stories with us, please visit gosh.org/breakthroughs.

We need to raise money to help create a better future for seriously ill children.

Your donations are used to rebuild and refurbish wards and facilities, to fund up-to-date medical equipment, support pioneering research to find new treatments, and fund accommodation and other support services for patients and their families.

These are just some of the developments that have taken place since the hospital opened in 1852. Extraordinary things continue to happen at GOSH every day.

Great Ormond Street Hospital Children’s Charity. Registered charity number 1160024.

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