A South African researcher has helped lead a breakthrough in the treatment of a rare and life-threatening genetic disorder, offering new hope to patients in developing countries.
Wits University professor and haematologist Johnny Mahlangu was part of an international team that explored a new type of gene therapy for haemophilia A, a rare genetic bleeding disorder that affects the blood’s ability to clot.
The study, published in the New England Journal of Medicine, presents early but hopeful results from a small phase-one trial in India. Patients who received the lentiviral therapy experienced no bleeding episodes for more than 27 months, a striking outcome in a condition where spontaneous or trauma-induced bleeding is common.
We’ve done a relatively large number of gene therapies using AAV. But it does not integrate into the DNA, and in recent studies the expression of the protein seems to be going down over time
— Prof Johnny Mahlangu
Haemophilia A is caused by a deficiency in clotting factor VIII. Traditionally, patients require regular infusions of the missing factor to manage bleeding. More recently, gene therapies using adeno-associated virus (AAV) have allowed the body to produce the factor on its own. However, Mahlangu has noted that this method comes with serious limitations.
“We’ve done a relatively large number of gene therapies using AAV,” he said. “But it does not integrate into the DNA, and in recent studies the expression of the protein seems to be going down over time.”
Another concern is that up to 90% of patients have pre-existing antibodies against AAV, disqualifying them from treatment. AAV therapy is also only suitable for adults, leaving younger patients behind.
Lentiviral gene therapy may solve many of these problems. “Lentivirus is agnostic to anti-AAV antibodies,” said Mahlangu. “It also integrates into the DNA, meaning it may offer longer-lasting and potentially be used in children whose livers are still developing.”
In the study, researchers harvested patients’ stem cells, inserted the factor VIII gene using a lentiviral vector, and reinfused the cells. “Magic happens,” said Mahlangu. “Those stem cells start to produce the protein the individuals were born unable to make.”
Over the 27-month follow-up period, there were no bleeding episodes or serious side effects. “This is very significant,” said Mahlangu. “It actually means that though we don’t often talk about cure, potentially these patients have achieved a functional cure.”
Still, affordability remains a major barrier. “The current AAV gene therapy costs about $3.2m, more than R60m per treatment,” he said. “This is clearly not feasible for most patients in low- and middle-income countries.”
But there is hope. The study was conducted in India, a country known for making expensive therapies more affordable. “We’ve seen this with antiretrovirals and the Covid-19 vaccine. Our hope is that lentiviral gene therapy follows the same path, made affordable and accessible.”
Efforts are already under way to repurpose existing vaccine infrastructure in Africa for gene therapy manufacturing. Mahlangu said, “The CDC in Africa is running a project looking to empower African countries to use existing expertise and resources to produce gene therapies locally.”
The promise of lentiviral vectors goes beyond haemophilia. “If we can prove it works in rare diseases like this one, we could apply it to many other genetic disorders,” he said.
For Mahlangu, who has spent more than two decades treating haemophilia patients, the results are deeply personal. He said he has seen the treatment of haemophilia move from using blood products to synthetic clotting factors, and now advanced therapies like gene editing.
“Five years down the line, the patients I gave gene therapy to stopped bleeding when they had been bleeding all their lives. That is fulfilling.”
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