Cell and gene therapy for genetic diseases: inherited disorders affecting the lung and those mimicking sudden infant death syndrome

Abstract

Some of the first human gene therapy trials targeted diseases of the lung and provided important information that will continue to help shape future trials. Here we describe both cell and gene therapies for lung diseases such as cystic fibrosis and alpha-1 antitrypsin disorder as well as fatty acid oxidation disorders that mimic sudden infant death syndrome (SIDS). Human clinical gene therapy trials for cystic fibrosis and alpha-1 antitrypsin have been performed using a variety of vectors including adenovirus, adeno-associated virus, and nonviral vectors. No human clinical gene therapy trials have been performed for disorders of fatty acid oxidation; however, important proof-of-principle studies have been completed for multiple fatty acid oxidation disorders. Important achievements have been made and have yet to come for cell and gene therapies for disorders of the lung and those mimicking SIDS.

FIG. 1.

Serum anti-adenovirus (Ad) antibodies elicited by administration of AdCFTR to the respiratory tract. (Originally published in Crystal et al. [1994] and reprinted by permission [license number 2891420070068].) Serum was evaluated for anti-Ad antibodies before and after administration of AdCFTR. Anti-AdCFTR antibodies detected by enzyme-linked immunosorbent assay (ELISA). The ordinate is presented as the inverse of the maximum dilution of serum yielding a value higher than the highest value observed during the baseline and/or vehicle control period (pre-Rx).

FIG. 2.

Serum M-specific alpha1-antitrypsin (AAT) concentration after injection of rAAV1-CB-hAAT produced by plasmid transfection (TFX) or the herpes simplex virus (HSV) method. (Originally published in Flotte et al. [2011] and reprinted with permission by Flotte et al.) Values shown represent means±SD. The dose of vector administered to subjects is indicated in the figure legend. Values for the TFX group are from a previous study (Brantly et al., 2009). Values for the 6×10¹¹ vg/kg HSV group do not include results for subject 303 who had an AAT phenotype of SZ; the monoclonal antibody used to determine serum M-specific AAT concentrations had little cross-reactivity with Z-type AAT but cross-reacted strongly with S-type AAT, causing results for this assay in this subject to be spuriously high. vg, viral genome.

FIG. 3.

Phenotypic correction with rAAV9-very long-chain acyl-coA dehydrogenase (VLCAD)- treated mice after cold fast challenge. (Originally published in Keeler et al. [2012] and reprinted with permission by Keeler et al.) Core body temperature of mice undergoing cold fast challenge, temperatures were recorded every 20 min by rectal thermometer. Mice were humanely sacrificed if body temperatures dropped below 20°C, n=4. Error bars are SEM. p=value by two-way analysis of variance (ANOVA) ****p<0.0001.