Kidney organoids could help reduce gene therapy side effects

Side effects of viral-delivered gene therapies have been elucidated using human stem-cell-derived kidney organoids.

Researchers have used kidney organoids, lab-grown mini-kidneys, to understand how gene therapy delivery can cause organ damage. The work, published in Signal Transduction and Targeted Therapy, shows how adeno-associated viruses (AAVs), used to deliver the therapies, can cause inflammation and damage in target tissues, helping to inform strategies to improve their safety.

Dr Ryuji Morizane, leading the team who did the work at the Department of Medicine at Massachusetts General Hospital, explained: 'We investigated whether human stem cell-derived kidney organoids, an emerging and increasingly recognised technology, can serve as a more accurate preclinical model for evaluating the therapeutic efficacy and potential side effects of AAVs used in gene therapy'.

Part of the lifecycle of a virus involves getting its genetic material inside a host cell, which it needs to do to replicate. As such, many gene therapies and genome-editing therapies use the outer parts of viruses as packaging to deliver the therapeutic components into target cells – known as a viral vector. There are several AAVs which are used as vectors, with some enabling precise delivery to specific organs, such as the kidneys.

However, some clinical trials have had to be stopped because patients have had side effects which are thought to have been caused by AAV viral vectors, notably three patients who received two different gene therapies for muscular dystrophies died from acute liver failure earlier this year (see BioNews 1282, 1293 and 1299). Patients on a previous clinical trial for a different AAV-based gene therapy experienced side effects, including acute kidney injury (see BioNews 1024).

Animal models are used to assess the safety of treatments before they are licensed for use in patients. However, fewer than 15 percent of drugs make it past human clinical trials due to the failure of animal models to accurately predict side effects which occur in humans. Human stem-cell-derived organoids offer a method to detect human-specific side effects of treatments.

'Importantly, organoid-based approaches are not meant to replace animal models entirely, but to complement them, adding a layer of human-specific insight that current animal testing often cannot provide,' Dr Morizane said.

Dr Morizane's team discovered that AAV2 – a variant of the AAV virus used to deliver gene therapy treatment – induced an inflammatory response in the kidney organoids, leading to DNA damage and fibrosis. This response was a result of the AAV delivery mechanism, rather than the gene therapy itself. Treating the organoids with the anti-inflammatory drug, bardoxolone methyl, alongside AAV delivery reduced these effects.

The researchers plan to develop more sophisticated kidney organoids in the future, incorporating vascular structures and other mature kidney cell types, in order to increase their physiological relevance in therapy testing. They hope that these will enable better testing of AAVs to facilitate their broader use in gene therapy.