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Updated: Jan 10, 2026
Author Spotlight: Assessing Intrathecal Gene Therapy Efficacy in Juvenile Rats
Published on: March 29, 2024
First-in-human high dose AAV9 intrathecal gene therapy for paediatric CLN7 disease: a phase 1, open-label, single
Benjamin M Greenberg1, Berge Minassian1, Souad Messahel2
1Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Paediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA; Peter O'Donnell Brain Institute, University of Texas Southwestern, Dallas, TX, USA.
Insights
This study shows high-dose intrathecal adeno-associated virus serotype 9 (AAV9) gene therapy is safe for Neuronal Ceroid Lipofuscinoses type 7 (CLN7) disease. Preliminary findings suggest potential efficacy, warranting further investigation with immunosuppression.
Area of Science:
- Neurology
- Genetics
- Immunology
Background:
- Neuronal Ceroid Lipofuscinoses type 7 (CLN7) is a fatal pediatric lysosomal storage disease caused by MFSD8 gene mutations.
- CLN7 leads to progressive cognitive, motor, and visual decline, with no current effective therapies.
- Adeno-associated virus serotype 9 (AAV9) gene therapy offers potential but faces dose limitations and immune responses.
Purpose of the Study:
- To evaluate the safety of high-dose intrathecal AAV9 gene therapy for CLN7 disease.
- To assess the impact of a comprehensive immunosuppression regimen on gene therapy safety.
- To gather preliminary efficacy data for AAV9 gene therapy in CLN7 patients.
Main Methods:
- A two-year, open-label, dose-escalation Phase 1 clinical trial.
- Intrathecal administration of AAV9 gene therapy in four CLN7 patients (one low dose, three high dose).
- Regular monitoring included blood work, cerebrospinal fluid analysis, EEG, MRI, and neurological/neuropsychological assessments.
Main Results:
- The study demonstrated the safety of high-dose intrathecal AAV9 gene therapy under a specific immunosuppression protocol.
- Preliminary evidence suggests potential therapeutic efficacy of this gene therapy approach for CLN7.
- No major safety concerns were reported related to the high-dose gene therapy with immunosuppression.
Conclusions:
- High-dose intrathecal AAV9 gene therapy is a viable option for CLN7 disease when combined with adequate immunosuppression and monitoring.
- Long-term monitoring of immune responses during immunosuppression tapering is crucial to detect potential reactions to the gene product.
- Further research is needed to confirm long-term safety and efficacy, and optimize immunosuppression strategies.
Background:
Neuronal Ceroid Lipofuscinoses type 7 (CLN7) is a paediatric lysosomal storage disease caused by mutations of the MFSD8 gene. Affected children have normal early development, but then suffer from progressive cognitive, motor, verbal, and visual decline. Ataxia and myoclonic epilepsy are predominant features of the condition, and there are no effective therapies. Death usually occurs by approximately age 11 years. While adeno-associated virus serotype 9 (AAV9) based gene therapy holds promise for treating monogenetic neurologic disorders, the impact of this intervention is limited by the maximum safe tolerable dose and the host immune response to the capsid and gene product. This study sought to confirm the safety of high dose intrathecal AAV-based gene therapy under a comprehensive immunosuppression regimen.
Methods:
This was a two-year open label, dose escalation, phase 1 first-in-human study of AAV9-based intrathecal gene therapy for CLN7. 4 participants (1 low dose, 3 high dose) were followed at regular intervals with blood work, CSF analysis, EEG, MRI, and measures of neurologic and neuropsychological function.
Findings:
This study provided evidence of safety for high dose intrathecal AAV9 based gene therapy in CLN7 disease under a specific immunosuppression regimen. Additionally, this study provides preliminary evidence of efficacy for this gene therapy.
Interpretation:
High dose intrathecal AAV based gene therapy can be pursued with adequate immunosuppression and monitoring for immune responses to the gene product. Additional long-term monitoring of the immune system during tapering of immunosuppression is needed to identify potential reactions to the gene product.
Funding:
This study was funded by The Batten's Hope Foundation, Mila's Miracle Foundation, Children's Health Dallas and Philanthropic Gifts to UT Southwestern. In addition, Emily R. Nettesheim received funding from NIH training grant 5T32GM131945-03 and Hamza Dahshi was supported in part by NIH award T32 GM152319.
