The subject of these headlines is Libmeldy, but the media seems obsessed with its cost, rather than what Libmeldy actually is. And, by the way, Libmeldy is no more a drug than my bird-watching binoculars are the James Web Space Telescope, but we’ll come to that in a moment.
Libmeldy is the brand name for Atidarsagene autotemcel, made by Orchard Therapeutics, a company based in London, UK and Boston, US, and developed in partnership with the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy. Libmeldy is used in treating a neurodegenerative disorder known as metachromatic leukodystrophy or MLD for short. The “metachromatic” part of the name, incidentally, is because under the microscope diseased cells have a different colour to their surroundings.
MLD is an autosomal recessive disorder, meaning that it’s caused by two malfunctioning genes. Humans have 46 chromosomes arranged in 23 pairs (chromosomes 1-22 plus the X/Y, chromosome, XX for female and XY for male). We inherit one chromosome in the pair from our father and the other from our mother. If we inherit a faulty gene from either parent, then there’s a reasonable chance we’ll have a functioning gene from the other parent. Those suffering autosomal recessive disorders however, have inherited faulty genes from both parents. MLD is extremely rare – in fact, so rare that it’s hard to pin down how often it presents. Best estimates put it at one in 40,000, totalling about 160,000 individuals worldwide (equivalent to about 5 children born with MLD per year in the UK). Despite its rarity, it’s nevertheless devastating for sufferers and their families. Symptoms start as a child, with difficulty walking, muscle wastage, loss of vision, dementia, and death usually occurring within 10 years of onset.
The cause is with a faulty ARSA gene on chromosome 22. Genes make proteins and proteins are the toolbox of life; everything from muscles to enzymes, from antibodies to receptors on the surface of cells. The ARSA gene makes an enzyme called arylsufatase-A which breaks down fatty chemicals in the body called sulfatides. Sulfatides are important in maintaining nerve function, particularly the myelin sheath which coats nerve cells and acts something akin to the insulation on domestic wiring. (Multiple sclerosis is perhaps the best known disease caused by the breakdown of the myelin sheath). Like most chemicals in the body, healthy levels of sulfatides are maintained by a balance between their manufacture and their breakdown. Without the arylsufatase-A enzyme however, sulfatides build up, leading to nerve damage.
Not that long ago, medical science thought it impossible to treat genetic disorders such as MLD, but medical science never stands still. Libmeldy in that respect is very likely a game changer, but as I said above, it’s not a drug, it’s far more than that, it’s a gene therapy treatment. It’s made from stem cells derived from the patient’s own bone marrow (known technically as haematopoietic stem cells, which are destined to become white blood cells). Medical scientists then insert a working copy of the ARSA gene into these cells, which are re-injected into the patient. A few days before treatment another medicine, busulfan, is given to clear out existing bone marrow cells so they can be replaced with the modified cells in Libmeldy.
Stem cells are a kind of proto-cell and have no specific role other than to differentiate into more specialised cells. We might liken them to substitute players in a game of rugby. Sitting on the benches, they play no part in the game until called upon to substitute for an injured player. But once on the field, the fresh player becomes part of the team just as much as his injured predecessor. You can’t however, just inject a gene into the body and expect it to work – you also need what’s known a vector. The vector in the case of Libmeldy is a modified Lentivirus. This family of viruses is well known for inserting DNA into host cells, and they are responsible for diseases such as HIV. Before conspiracy theorists start Tweeting that the pharmaceutical industry is giving children aids, the viral vector is deactivated and used only for insertion of the ARSA gene.
Libmeldy therefore takes the patient’s own stem cells, adds a working gene and uses an inactivated virus to insert that gene into the body’s cells. This is medical science at the cutting edge, putting the cost of the treatment into context – you are buying a therapy based on years of scientific research. A fact that much of the general media seemed to have missed as they got lost in the fog of the price.
With MLD being so rare, it’s difficult to conduct the usual clinical trials with many thousands of patients. So far they have tested it on around 30 individuals over about 10 years and have shown it restores in the order of 70% of motor neurone function. Libmeldy is approved in the European Union and the UK (which are sadly separated these days) and is an investigational therapy in the United States. But it’s under scrutiny so a more complete assessment won’t come, perhaps for several years. At the very least however, it offers hope and it may even offer a solution.