‘Ex vivo’ Autologous Gene Therapy Very Promising for Sickle Cell Disease

Dr. Bobby Gaspar

“We are entering an era where gene therapies are being developed and have been approved for genetic disorders of the blood system,” said Professor Bobby Gaspar, MD, PhD, co-founder and Chief Scientific Officer of Orchard Therapeutics and Director of the Zayed Centre for Rare Diseases in the United Kingdom.         

“This is also happening for Sickle Cell Disease (SCD) and there are approaches being taken by academic and commercial entities.  Early data from some of these trials look very promising so I would anticipate that at some point in the near future, there will be approved genetic therapies for SCD that will benefit both children and adults,” adds Gaspar.

Dr. Bobby Gaspar

Professor Bobby Gaspar, MD; PhD, co-founder and Chief Scientific Officer of Orchard Therapeutics and Director of the Zayed Centre for Rare Diseases in Children in the United Kingdom – Photo courtesy of Dr. Gaspar

“More than 6,000 rare diseases, 80% with a genetic component, affect more than 300 million people worldwide.  While an individual disease might be classed as rare (defined as affecting 1 in 2,000 of the general population in the European Union or fewer than 200,000 people in the USA), the sheer number of rare diseases means that the overall numbers quickly stack up - 3.5 million people in the UK, 30 million across Europe and 30 million in the USA are affected.”  

“Whether a single rare disease affects thousands or just one person, the impact on the affected individual and those around them can be devastating: 50% of rare diseases affect children, 30% of whom will die before 5 years of age.”  ~, excerpts from ‘Spotlight on Rare Diseases’ published by The Lancet.

There are over 7,000 known rare diseases in Canada, wherein 1 in 12 Canadians are affected, reports The Canadian Organization for Rare Disorders (CORD).

Sickle cell anaemia is one of those rare diseases. 

Sickle Cell Disease (SCD) Statistics

  • 250 million people worldwide carry the gene responsible for sickle cell disease and other blood disorders.
  • Every year, 300,000 infants are born with a major haemoglobin disease globally.
  • Every day, 1,000 children in Africa are born with SCD and more than 50% of these children will die before their 5th birthday.
  • 90% of children with SCD do not survive to adulthood in poor countries.
  • Over 100,000 American people have Sickle Cell Disease and about one in every 500 African Americans is born with it.
  • There are approximately 5,000 people living with SCD in Canada.
  • By 2050, the number of people with SCD is expected to increase by 30% globally according to the World Health Organization and United Nations.
  • SCD can affect people of ANY race or ethnicity.

National Institute Health (NIH)

Between 2004 and 2013, thirty patients from 16 to 65 years-of-age with severe SCD enrolled in a clinical trial conducted by researchers from NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Heart, Lung, and Blood Institute (NHLBI) in Bethesda, Maryland.  They received a less toxic regimen to kill off some of their marrow cells and then underwent a stem cell transplant donated by a healthy sibling.

“The stem cell transplant reversed SCD in 26 of 30 patients (87%). The patients had normal haemoglobin, fewer hospitalizations and lower use of narcotics to treat pain from the disease. The patients didn’t experience graft-versus-host disease - in which donor cells attack the recipient - after a median follow up of 3 to 4 years,” states NIH.

gene therapy


“Fifteen patients successfully stopped immunosuppressant medications a year after the transplant. The treatment was unsuccessful in four patients where complications, such as infection, occurred.”

“Side effects caused by immunosuppressants can endanger patients already weakened by years of organ damage from sickle cell disease,” says senior author Dr. John Tisdale.

“Not having to permanently rely on this medication, along with use of the relatively less-toxic partial stem cell transplant, means that even older patients and those with severe sickle cell disease may be able to reverse their condition,” adds Tisdale.

26-year-old Revée Agyepong was in the emergency room five times within a seven-month span suffering from chronic pain caused by sickle cell anaemia.  Her gall bladder was excised and her spleen was non-functioning.  Every eight weeks she underwent a red blood cell exchange to manage her disease.

In April 2018, Agyepong became the first Canadian cured of sickle cell anaemia at the Tom Baker Cancer Centre in Calgary, Alberta, with the help of stem cells donated by her sister.

Since 2009, stem cell transplants on children with SCD have been performed successfully because, “…children are far more resilient,” says Dr. Andrew Daly, Director of the Alberta Bone Marrow Transplant Program and Clinical Associate Professor of the Zone Clinical Section Chief for Alberta Health Services.

Stem cell research and studies on adult success rates with transplants only started in 2015.

Sickle Cell Disease Treatments

Blood transfusions; Hydroxycarbamide (hydroxyurea), the only approved disease-modifying therapy in 1998; and Endari (L-glutamine) have provided treatment and relief for patients but not without risks and side effects, especially for adults.

While bone marrow or cord blood transplants are an alternative method of therapy, there is a risk of mortality and morbidity, especially when there is not a good match between the donor and the patient.  Standard stem cell transplantation requires a suitable third-party donor and carries a substantial risk of complications such as graft-versus-host disease or graft rejection.

Thankfully, times have changed and so has medical technology. 

Orchard Therapeutics: ‘Ex vivo’ Autologous Gene Therapy

After 20 years of academic research, doctors and scientists at Orchard Therapeutics in the UK have developed ‘unique expertise’ in the manufacturing, preclinical and clinical development of gene therapies for rare diseases. 

Ex vivo autologous gene therapy provides a perfect match using the patient’s own cells so there is no risk of graft-versus-host disease or graft rejection.

Orchard Therapeutics invented a potentially new way of treating transfusion-dependent beta-thalassemia.  First, they make a ‘working copy’ of the missing HBB gene in the laboratory and then insert the genetically modified stem cells into a sample of the patient’s own blood or bone marrow stem cells using a viral vector that carries the normal and healthy gene.  These genetically modified stem cells grow and divide into new cells that produce increased levels of haemoglobin.


Over 150 patients with primary immune deficiencies, neuro metabolic disorders and hemoglobinopathies were treated with ex vivo autologous gene therapy in the development phase.  Some patients have sustained clinical effects for 18 years post treatment.

double helix

Dr. Bobby Gaspar is also the professor of paediatrics and immunology at the UCL Institute of Child Health and Honorary Consultant in paediatric immunology at Great Ormond Street Hospital (GOSH) in London, England.

With a special interest in the treatment of severe primary immune deficiencies, including bone marrow transplantation, and gene and cell therapy, Gaspar has led multiple clinical trials that have shown gene therapy is successful in correcting the genetic defect in immune deficiencies.

Gaspar is currently leading UK and European-wide initiatives for newborn screening in severe combined immune deficiency. 

National Institute of Health (NIH) & the Bill and Melinda Gates Foundation:  Most Recent Report on Gene Therapies

Over the next four years, NIH and the Bill & Melinda Gates Foundation will each invest $100 million towards the development of affordable gene therapies for sickle cell disease (SCD) and the human immunodeficiency virus (HIV) on a global scale.

75% of babies born with SCD live in sub-Saharan Africa.  Within the next 7 to 10 years, experimental gene therapies could be advanced to clinical trials in the United States and relevant African countries.

Researchers from the National Institute of Health created a new viral vector (a virus-based vehicle) to improve genomic therapy for sickle cell disease, which is up to 10 times more efficient at ‘incorporating corrective genes into bone marrow stem cells and has a carrying capacity of up to 6 times higher than the current conventional vectors.

 “Our new vector is an important breakthrough in the field of gene therapy for sickle cell disease,” said Dr. John Tisdale, senior author for this study and chief of the Cellular and Molecular Therapeutic Branch at the National Heart, Lung and Blood Institute.

“It’s the new kid on the block and represents a substantial improvement in our ability to produce high capacity, high efficiency vectors for treating this devastating disorder.”

The new vectors also have a greater capacity for longevity - remaining in place for four years after transplantation.

27 people with SCD have undergone experimental gene therapy using conventional vectors.

“These findings bring us closer to a curative gene therapy approach for haemoglobin disorders,” adds Tisdale.

The National Institute of Health (NIH) is working hard to accelerate the development of these and other new genetic therapies including gene editing, with the goal of finding a cure for SCD.

Clinical Trials

People who have SCD can visit www.clinictrials.gov and Clinical Trials Canada to find a clinical trial that is actively enrolling.

Please scroll down to the 'Resources' section to find clinical trials for SCD in the United States.

What is Sickle Cell Disease?

Sickle cell disease (SCD) is an inherited, rare blood disorder or mutation of the beta-globin gene.  Genetic diseases are determined by two genes – one received from the mother and the other, from the father.  Recessive genetic disorders occur when a baby receives the same mutated gene for the same trait from each parent.  If a baby receives one normal gene and one gene for the disease, then the baby will be a carrier for that particular disease called ‘sickle cell trait’ and usually not experience symptoms.

Sickle Cell disease causes haemoglobin, the main ingredient in red blood cells, to produce crescent shaped cells, which often become rigid and stick to the walls of blood vessels.  They then clot in the bloodstream and block blood flow in blood vessels preventing normal, healthy delivery of nutrition and oxygen.

Sickle Cell Gene Variants

lab technician

Sickle cell haemoglobin S disease or homozygous SS disease, often referred by doctors as HbSS, is the most common and severe type of sickle cell disease where the person has very little or no normal haemoglobin (HbA). 

Sickle cell haemoglobin C disease has both HbS and HbC (HbSC) and people don’t suffer symptoms of sickle cell anaemia but when the HbS and C genes combine, people will develop sickle cell disease.  Sickle cells block blood vessels, resulting in organ damage and other complications commonly associated with HbSS.

Sickle cell haemoglobin E disease is common in Southeast Asia.  People who have this variant may experience mild to moderate anaemia symptoms or no symptoms at all.

Haemoglobin S-beta-thalassemia occurs when a person inherits the gene for thalassemia and has sickle cell disease, which causes milder symptoms than those associated with sickle cell disease but can also have complications as dangerous as those of sickle cell disease. 

Haemoglobin S-beta-thalassemia requires regular blood transfusions to replenish the level of haemoglobin in the red blood cells but regular transfusions over time cause iron to accumulate in various organs, which can lead to risk of heart or liver failure.  To remove excess iron, patients undergo iron chelation therapy that has its own nasty side effects. 

What are Sickle Cell Disease symptoms?

Common symptoms include excruciating bone and chest pain, which can last for days on end (acute) or continue long term (chronic), severe infections, fatigue and jaundice.  Blocked blood flow can also cause damage to the brain, lungs, kidneys and joints.  Infants and children are prone to irritability, swollen hands and feet, and severe infections.

The spleen often becomes enlarged because red blood cells are trapped and unable to move.  The function of the spleen is to filter out abnormal red blood cells and fight bacterial infections but when people have sickle cell anaemia their spleen is not functioning properly and so typical, mild infections can become life threatening.  Something as simple as a cold or dehydration can trigger extremely painful episodes.

Children as young as two-years-of-age have suffered stroke from SCD.

As people with SCD age, they experience additional complications, which then become common:  increased ‘pain’ episodes, infections, pulmonary hypertension and embolisms, splenic sequestration, leg ulcers, vision loss, stroke, deep vein thrombosis and damage to organs.

In Conclusion

“We've made considerable progress in this field over the past decade.  Gene therapy has been refined, trialled in patients and we've learned a huge amount.  Studies we have designed here are now open in Los Angeles, Boston, Paris and other international centres, “said Dr. Adrian Thrasher, Professor of Paediatric Immunology and Honorary Consultant Immunologist and co-founder of Orchard Therapeutics.

“I believe…gene therapy will be able to improve the life and health of many children with life-threatening diseases, where other treatment methods are either ineffective or non-existent.  It's a very exciting time to be working in this field,” adds Thrasher.

Professor Thrasher is Head of the Infection, Inflammation, and Immunity at UCL Great Ormond Street Institute of Child Health, and Lead for the Cell, Stem Cell, and Gene Therapy theme at the NIHR Great Ormond Street Hospital NHS Trust Biomedical Research Centre (BRC).  

Thrasher is currently board member for the European society (ESGCT) and was appointed to the planning committee for the International Summit on Human Gene editing at the National Academy of Sciences in Washington DC in 2015.


For additional information, Diligencia Investigative Reporting recommends the following websites:

Orchard Therapeutics - www.orchard-tx.com

Sickle Cell Anemia News – lists twelve clinical trials in the United States, and the approved and experimental treatments

Sickle Cell Disease Association of Canada

Sickle Cell Disease Coalition

CDC: Complications and Treatments for Sickle Cell Disease

National Organization for Rare Diseases (NORD): Sickle Cell Disease

NORD – Rare Diseases database

National Heart, Lung and Blood Institute – Sickle cell patient’s recovery after gene therapy heightens hopes for a cure

National Center for Biotechnology Information: Systematic Review: Hydroxyurea for the Treatment of Adults with Sickle Cell Disease

Nature.com - Latest Research and Reviews for Sickle Cell Disease

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