Gene Therapy for Prevention of Esophageal Cancer and Osteoporosis in ALDH2-Deficient Patients

Background & Unmet Need

• Aldehyde dehydrogenase type 2 (ALD2), a key enzyme in ethanol metabolism, processes toxic acetaldehyde to nontoxic acetate
• ALDH2 deficiency affects 8% of the world population and 35–45% of East Asians
• In the acute setting, ALDH2 deficiency causes “Asian flush syndrome,” presenting as alcohol-induced facial flushing, tachycardia, nausea, and headaches
• With chronic ethanol ingestion, mutations in ALDH2 are associated with a variety of hematological, neurological, and dermatological abnormalities, and an increased risk for esophageal cancer and osteoporosis
• Unmet Need: Therapies that supply functional ALDH2 to reduce the risk of esophageal cancer and osteoporosis in ALDH2-deficient patients

Technology Overview

• The Technology: AAV gene therapy that provides sustained expression of wild-type human ALDH2 to eliminate the symptoms of ALDH2 deficiency
• The DNA sequence encoding for human ALDH2 was inserted into an AAV gene transfer vector (AAVrh.10hALDh2) and administered intravenously to mice in a single dose
• The AAVrh.10 serotype was chosen because it predominately targets the liver, the primary site of ethanol and acetaldehyde metabolism
• PoC Data: Delivery of the gene therapy to the liver reconstitutes wild-type enzymatic activity and normalizes acetaldehyde levels and behavior after acute ethanol consumption to near wild-type levels
• In a mouse model of chronic ALDH2 deficiency, the gene therapy prevented reduced performance in locomotor activity tests, loss of body weight, accumulation of esophageal DNA damage, and development of osteopenia

Technology Applications

• Preventative therapy for the increased risk of chronic disorders associated with ALDH2 deficiency and chronic alcohol exposure

Technology Advantages

• Only requires a single dose
• Reduces patient risk of developing esophageal cancer or osteoporosis