Advancements in Gene Therapy – Potential Cures on the Horizon

A pair of recent clinical trials aimed at treating sickle cell disease and Duchenne muscular dystrophy thanks to gene therapies promise patiences, but how exactly will such therapies get to patients?

Cost is also prohibitive; medicines that retail for tens of thousands of dollars are unaffordable in low and middle income countries.


Gene therapy, as a way to treat disease caused by a person’s genes, had seemed like a pipe dream to researchers for years.

The first unexpected failure was that of Jesse Gelsinger, who died in 1999 from an adverse immune reaction following the infusion of gene therapy for his ornithine transcarbamylase deficiency (OTD), a rare metabolic disorder. A second challenge has been finding the optimal delivery vehicle to enable the therapeutic gene to enter cells safely while avoiding the immune system reactions that could make it toxic.

Thanks to CRISPR-Cas9, the molecular scissors that enable scientists to operate so precisely on DNA, cures for some inherited genetic diseases are closer than ever. Gene therapies that use CRISPR-Cas9 now enable us, first, to cut out a faulty gene or, second, to ‘cut and paste’ by inserting a new gene inside the individual’s body. Two gene therapies were approved this year to treat two completely different diseases: Talimogene abeparvovec-xioi (Zolgensma) is approved here in the US, EU and China for a form of muscular atrophy, involving deletions and mutations of SMN1, a gene known to be essential for survival of lower motor neurons during early development; and Voretigene neparvovec-rzyl (Casgevy) is being developed to treat anaemia as in sickle cell disease/betalassemia.

Nonviral Vectors

Gene therapy has also become more sophisticated, treating only the desired cells – such as the very specific ones in retinas that must be working properly in order to see – in contrast with previous iterations trying to replace all ‘bad’ genes in the body with one injection. Luxturna was the first gene therapy to be approved, for inherited retinal disorders that cause blindness.

Scientists use vectors – often viruses – to carry the healthy genes past the cell membrane. Yet occasionally, it incites the immune system to react.

Investigators are working to address this problem. Limited activation of the immune system can be achieved in nonviral vectors. Those chemically modified in order to minimise the immune stimulatory potential, comprise the most advanced therapeutic product (in a phase II clinical trial allowing patients with sickle cell disease to be treated with stem cells: CTX001) and the most advanced therapeutic RNA-based product (in phase I clinical trials offering patients with spinal muscular atrophy the potential for treatment: TALEN).

Tissue-Specific Gene Delivery

They enable faulty genes that cause disease to be replaced with normal ones; they enable created cells to help mend broken hearts, rebuild blood cells that have died after strokes, and assist in treating degenerative conditions such as spinal muscular atrophy and haemophilia.

The trick in gene therapy is getting that new gene into cells. But that’s a challenge because most gene therapies use viruses to carry the necessary genetic material. Their immune systems might mount a reaction that views the virus as foreign, or even harmful (the possible side effects can range from swelling and organ failure).

Scientists have also worked to develop delivery systems that avoid an immune response. One approach uses adeno-associated viruses, which only infect certain cell types; others use artificial RNA molecules to direct the viruses to infect only certain cells. This all means that patients can now benefit from gene therapy directed at a single cell type without risking the serious side-effects seen with earlier attempts.


Using genetically engineered stem cells could easily lead to gene therapy – for instance, by incorporating genes into stem cells that embryos would normally have but that somehow mutated out in the affected patients, such as genes that are mutated degeneration) and other genetic nerve diseases.

For it to work, this process will require a genetically safe delivery vehicle that can ferry therapeutic genes to cells without triggering immune responses that could provoke life-threatening reactions, and without provoking mutations or other changes in the cells that could leave that ability irreversibly altered.

For instance, 7,000 monogenetic (one gene) diseases that we know how to trace to single mutations, such as sickle cell disease and beta thalassaemia (for which current treatments involve the regular infusion of missing clotting protein, at costs prohibitive to poor countries) can also be treated through gene editing.

The most recent clinical trial in human subjects using a lentiviral vector-based gene therapy for SCD engineered human blood stem cells that carried functional factor IX genes and was quite successful at preventing the sickling of red blood cells and reducing haemorrhagic events.

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