Gene therapy’s next frontier lies beyond rare, monogenic diseases

How gene therapy is transitioning from single gene disorders to a modality of general use

As in vivo gene therapies continue notching approvals for rare monogenic diseases, the next frontier for the modality will be in treating complex indications without obvious genetic drivers. At least seven companies have clinical or preclinical gene therapies for non-monogenic diseases, with a flurry of data expected this year.

Two in vivo gene therapies have been approved since 2017, Luxturna voretigene neparvovec-rzyl from Spark Therapeutics Inc. and Zolgensma onasemnogene abeparvovec-xioi from Novartis AG (NYSE:NVS; SIX:NOVN). Another eight are in Phase III or Phase II/III testing. All address rare monogenic diseases where a single gene is mutated, and the goal is to deliver a functional copy of the gene to compensate for the defective one (see “AAVs on the Brink”).

The step change will come when the modality is broadened to treatment of more complex diseases not driven by single defective genes, which affect millions rather than thousands of patients.

The challenge in those diseases is choosing which gene to deliver.

“The rationale for a monogenic disease is very simple and very clear. If you can put the correct gene into the right cell at the right level, you can treat the disease,” Yatish Lad told BioCentury. Lad is head of early development at gene therapy company Oxford BioMedica plc.

For non-monogenic diseases, the “one-shot” nature of gene therapies heightens the stakes of selecting the correct gene.

Small molecules or antibodies modulating a target’s function can be withdrawn if the therapy is ineffective or unsafe, but so far, gene therapies don’t have built-in mechanisms to control when and how much they are expressed.


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