Gene Therapy for the Treatment of Hereditary Angioedema

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant) Hereditary angioedema (HAE) is a chronic, debilitating and potentially life-threatening autosomal dominant disease that has a dramatic impact on the affected individual's quality of life. HAE is characterized by recurrent, often unpredictable and variable submucosal edema of cutaneous tissues, the gastrointestinal and respiratory tracts and is associated with a high mortality risk secondary to asphyxiation. More than 99% of HAE cases are caused by functional deficiency of the plasma serine protease inhibitor C1-esterase inhibitor (C1-INH). C1-INH controls vascular homeostasis and low levels in plasma leads to accumulation of the vasoactive peptide bradykinin, with consequent increase in vascular permeability. Current approved therapies are targeted at reducing the number, frequency and severity of at- tacks. While these therapies have proven effective, compliance is limited by a high side effect profile, high cost of therapy, drug interactions and medication contraindications. Further, given the complex nature of the disease, individuals often require tailored, individualized therapeutic regimens. Low plasma functional levels of C1-INH are caused by mutations on the SERPING1 gene, thus a therapy that pro- vides a correct copy of the human C1-INH cDNA is a promising approach to restore functional C1-INH levels in plasma. We propose to develop an experimental therapeutic for the treatment of HAE that will be delivered as a one-time administration of a gene therapy vector expressing the normal human hC1-INH protein. The goal is to reach sustained, long-term plasma C1-INH therapeutic levels to prevent angioedema attacks without the need of repeated protein administration. We have cloned the normal hC1-INH cDNA sequence into an adeno-associated serotype rh.10 (AAVrh.10) viral vector to generate the AAVrh.10hC1-INH vector, and designed a C1-INH deficient mouse model to test therapeutic efficacy. We propose 3 specific aims: Aim 1. Demonstrate functional human C1-INH protein levels in vivo in wild type mice after parenteral administration of AAVrh.10hC1-INH. Aim 2. Characterize a C1-INH-deficient mouse model with a phenotype similar to HAE. Aim 3. Using the mouse model from aim 2, demonstrate that a single systemic administration of AAVrh.10hC1-INH reverts the mouse C1-INH deficiency phenotype and restores normal functional levels of C1-INH. If studies are successful, AAVrh.10hC1-INH vector will produce high, long lasting levels of functional hC1-INH in mice, at vector doses that scale to a safe human dose. Further success will be demonstrated by a normal phenotype in C1-INH deficient mice, demonstrated by normal plasma C4 levels, decreased vascular permeability and submucosal edema. The proposal is the translational development of an AAVrh.10 gene transfer vector encoding C1-INH cDNA such that a single administration will provide sustained, long-term therapeutic benefit for the treatment of HAE, thus obviating the need for repeated C1-INH protein administration.