Comparison of Therapeutic Efficacy of Gene Therapy for Tuberous Sclerosis Type 2 with Standard of Care Everolimus in Preclinical Model (S14.002)

Abstract

<h3>Objective:</h3> Therapeutic efficacy of gene therapy using an adeno-associated viral vector encoding cTuberin to treat brain lesions in a TSC2 mouse model. <h3>Background:</h3> Tuberous sclerosis complex is an autosomal dominant disorder caused by a hereditary loss of function mutation in one of two tumor suppressor genes, <i>TSC1</i> and <i>TSC2</i>, 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. <h3>Design/Methods:</h3> 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. <h3>Results:</h3> 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. <h3>Conclusions:</h3> 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. <b>Disclosure:</b> Dr. Abou Haidar has nothing to disclose. Miss Prabhakar has nothing to disclose. The institution of Dr. CHEAH has received research support from MInistry of Higher Education, MALAYSIA. Dr. Lule has received personal compensation for serving as an employee of Codiak Biosciences. Ms. Beauchamp has nothing to disclose. Dr. Yoshinaga has nothing to disclose. Dr. Geffrey has received personal compensation for serving as an employee of Massachusetts General Hospital. Anat Stemmer-Rachamimov has nothing to disclose. Vijaya Ramesh has nothing to disclose. Dr. Maguire has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Chameleon Biosciences. Dr. Maguire has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sphere Gene Therapeutics. Dr. Maguire has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Skylark Bio. Dr. Maguire has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sphere Gene Therapeutics. Dr. Maguire has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for CLS Therapeutics. Dr. Maguire has received stock or an ownership interest from Chameleon Biosciences. Dr. Maguire has received stock or an ownership interest from Sphere Gene Therapeutics. Dr. Maguire has received stock or an ownership interest from Skylark Bio. Dr. Maguire has received research support from SwanBio. Dr. Maguire has received research support from BridgeBio. Dr. Maguire has received research support from Wayvector Inc. Dr. Maguire has received intellectual property interests from a discovery or technology relating to health care. Dr. Breakefield has nothing to disclose.