Gene Therapy to Treat Osteopenia Associated With Chronic Ethanol Consumption and Aldehyde Dehydrogenase 2 Deficiency.

Aldehyde dehydrogenase 2 (ALDH2) deficiency affects 35% to 45% of East Asians and 8% of the world population. ALDH2 is the second enzyme in the ethanol metabolism pathway. The common genetic variant ALDH2*2 allele has a glutamic acid-to-lysine substitution at position 487 (E487K) that reduces the enzyme activity, resulting in an accumulation of acetaldehyde after ethanol consumption. The ALDH2*2 allele is associated with increased risk of osteoporosis and hip fracture. Our prior study showed that administration of an adeno-associated virus (AAV) serotype rh.10 gene transfer vector expressing the human ALDH2 cDNA (AAVrh.10hALDH2) before initiation of ethanol consumption prevented bone loss in ALDH2-deficient homozygous knockin mice carrying the E487K mutation (Aldh2 E487K+/+). We hypothesized that AAVrh.10hALDH2 administration after establishment of osteopenia would be able to reverse bone loss due to ALDH2 deficiency and chronic ethanol consumption. To test this hypothesis, male and female Aldh2 E487K+/+ mice (n = 6) were given ethanol in the drinking water for 6 weeks to establish osteopenia and then administered AAVrh.10hALDH2 (1011 genome copies). Mice were evaluated for an additional 12 weeks. AAVrh.10hALDH2 administration after osteopenia was established corrected weight loss and locomotion phenotypes and, importantly, increased midshaft femur cortical bone thickness, the most important component of bone in the resistance to fractures, and showed a trend toward increased trabecular bone volume. AAVrh.10hALDH2 is a promising therapeutic for osteoporosis in ALDH2-deficient individuals. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Gene therapy for alpha 1-antitrypsin deficiency with an oxidant-resistant human alpha 1-antitrypsin.

Alpha 1-antitrypsin (AAT) deficiency, a hereditary disorder characterized by low serum levels of functional AAT, is associated with early development of panacinar emphysema. AAT inhibits serine proteases, including neutrophil elastase, protecting the lung from proteolytic destruction. Cigarette smoke, pollution, and inflammatory cell-mediated oxidation of methionine (M) 351 and 358 inactivates AAT, limiting lung protection. In vitro studies using amino acid substitutions demonstrated that replacing M351 with valine (V) and M358 with leucine (L) on a normal M1 alanine (A) 213 background provided maximum antiprotease protection despite oxidant stress. We hypothesized that a onetime administration of a serotype 8 adeno-associated virus (AAV8) gene transfer vector coding for the oxidation-resistant variant AAT (A213/V351/L358; 8/AVL) would maintain antiprotease activity under oxidant stress compared with normal AAT (A213/M351/M358; 8/AMM). 8/AVL was administered via intravenous (IV) and intrapleural (IPL) routes to C57BL/6 mice. High, dose-dependent AAT levels were found in the serum and lung epithelial lining fluid (ELF) of mice administered 8/AVL or 8/AMM by IV or IPL. 8/AVL serum and ELF retained serine protease-inhibitory activity despite oxidant stress while 8/AMM function was abolished. 8/AVL represents a second-generation gene therapy for AAT deficiency providing effective antiprotease protection even with oxidant stress.