AAV vectors accumulate in the pineal gland after injections into the brain or spinal cord

Molecular Therapy: Methods & Clinical Development, 2021 · DOI: https://doi.org/10.1016/j.omtm.2021.09.016 · Published: December 1, 2021

Pharmacology Neurology Genetics

Simple Explanation

AAV vectors, used for gene therapy in neurological disorders, surprisingly accumulate in the pineal gland after injections into the brain, spinal cord, or cerebrospinal fluid (CSF). This was observed following focal injections of AAV2/9-shPTEN-zsGreen into the sensorimotor or hippocampus of rats and injections of AAV2/Cre into the spinal cord of transgenic mice. Pineal transduction occurred even when AAV2/Cre injections were made into the lumbar spinal cord, distant from the pineal gland. Further investigation revealed that pinealocytes, the main cells of the pineal gland, were transduced. Intracerebroventricular (i.c.v.) injections of AAV2/9-shPTEN-zsGreen also led to pineal transduction, suggesting that AAV vectors may diffuse from injection sites into the CSF and accumulate in the pineal gland. These findings highlight the need for vigilance regarding potential off-target effects of therapeutic AAVs in the pineal gland.

Study Duration

4 Months

Participants

Adult female Fisher 344 or female Sprague-Dawley rats and transgenic tdT reporter mice

Evidence Level

Not specified

Key Findings

1
AAV vectors accumulate in the pineal gland following injections into the brain, spinal cord, or cerebrospinal fluid.
2
Pinealocytes are the primary cell type transduced by AAV vectors in the pineal gland.
3
AAV vectors can reach the pineal gland through diffusion into the cerebrospinal fluid and subsequent accumulation, or potentially through migration of transduced cells.

Research Summary

This study reports the unexpected finding that AAV vectors accumulate in the pineal gland following injections into the brain, spinal cord, or cerebrospinal fluid (CSF). Different AAV serotypes, including AAV2/9 and AAV2-retro, were found to transduce cells in the pineal gland, particularly pinealocytes. The researchers explored potential mechanisms for AAV accumulation in the pineal gland, suggesting that AAV particles diffuse from the injection site into the CSF and then reach the pineal gland directly or indirectly. They also considered the possibility of transduced cells migrating from the injection site to the pineal gland. The study emphasizes the need for vigilance regarding the functional consequences and potential adverse effects of off-target accumulation of therapeutic AAVs in the pineal gland. It suggests including the pineal gland in routine biodistribution screens for AAV-based therapies.

Practical Implications

Safety Considerations for Gene Therapy

The accumulation of AAV vectors in the pineal gland raises safety concerns for AAV-based therapies, particularly regarding potential disruption of melatonin production and sleep/wake cycles.

Inclusion in Biodistribution Screens

The pineal gland should be included in routine screens for off-target accumulation of therapeutic candidate AAVs delivered into the CNS or systemically, given its lack of a blood-brain barrier.

Potential Therapeutic Delivery

The efficient accumulation of AAVs in the pineal gland could be leveraged to deliver therapeutic cargos for treating pineal tumors.

Study Limitations

1
The exact mechanisms by which AAVs reach the pineal gland from different injection sites are not fully established.
2
The study's findings may not be generalizable to all AAV serotypes, as the accumulation may be unique to certain serotypes.
3
The functional consequences of AAV accumulation and gene cargo expression in pinealocytes require further investigation.

Your Feedback

Was this summary helpful?

Back to Pharmacology