Comparison of Therapeutic Efficacy of Gene Therapy for Tuberous Sclerosis Type 2 with Standard of Care Everolimus in Preclinical Model
Edwina Abou Haidar1, Shilpa Prabhakar1, Pike See Cheah2, Sevda Lule1, Roberta L. Beauchamp3, Akiko Yoshinaga1, Alexandra L. Geffrey1, Anat Stemmer-Rachamimov4, Vijaya Ramesh3, Casey A. Maguire1, Xandra O. Breakefield1
1Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, MGH, and Program in Neuroscience, HMS, Boston, MA USA, 2Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Malaysia, 3Center for Human Genetics Research, MGH, Boston, MA USA, 4Department of Pathology, Boston, MA USA, Massachusetts General Hospital
Objective:
Therapeutic efficacy of gene therapy using an adeno-associated viral vector encoding cTuberin to treat brain lesions in a TSC2 mouse model.
Background:
Tuberous sclerosis complex is an autosomal dominant disorder caused by a hereditary loss of function mutation in one of two tumor suppressor genes, TSC1 and TSC2, encoding for hamartin or tuberin respectively. These proteins form a complex that constitutively inhibits the mammalian target of rapamycin signaling pathway. In TSC-related lesions, the loss of either proteins due to a somatic mutation in the normal allele in susceptible tissues causes over activation of mTOR signaling, leading to cellular proliferation in many vital organs, especially in the brain. Neurological features include seizures, cognitive impairment and autism.
Design/Methods:
We have recently demonstrated in a mouse model, that gene therapy using an adeno-associated virus vector carrying a “condensed” form of human tuberin (cTuberin) is a promising therapeutic strategy for TSC2. Here, we compare and contrast our gene therapy strategy to the standard of care for TSC patients, the mTOR inhibitor everolimus.
Results:
A mouse model of TSC2 generated by AAV1-Cre recombinase disruption of homozygous Tsc2-floxed alleles at birth (P0) via intracerebroventricular injections has a shortened lifespan (mean 50 days) and brain pathology consistent with TSC, including overgrowth of ependymal/subependymal tissue and enlarged ventricles. When these mice were then single injected intravenously at post natal day 21 (P21) with an AAV9 vector encoding cTuberin, most survived for more than 120 days. Post treatment neuropathologic assessment resulted in near normal brain with reduction in ventricular volume and abnormal overgrowths. Interestingly, continuous treatment with everolimus, used in TSC patients, extended survival for up to 75 days but failed to maintain life after discontinuation.
Conclusions:
This study shows the potential of treating life-threatening TSC2 lesions with a single intravenous injection of AAV9-cTuberin as compared to the alternative drug treatment available clinically.