Table 3.

Summary of A1ATD Treatment Targets Under Investigation

Target Pathway	Treatment	Studies	Current Status	Limitations
Prevent polymerization	siRNA to downregulate endogenous Z mutant A1AT*	Cruz et al. 200723	Clinical trials phases 1 and 2 (Alnylam Pharmaceuticals and Arrowhead Research Corporation)	Will suppress all A1AT production and require lifelong supplementation or augmentation therapy unless concurrent gene therapy is done to transfect patients with normal A1AT
		Guo et al. 201424
	AAV‐gene vector transfer of normal A1AT to muscle cells*	Multiple studies	Clinical trials phases 1 and 2
	Autologous grafting of iPSC from Pi*ZZ individuals reprogrammed using CRISPR technology to correct Z mutation	Rashid et al. 201025	In vitro studies using iPSCs
		Yusa et al. 201126
		Tafaleng et al. 201527
		Wilson et al. 201528
Detect and improve protein misfolding	Histone deacetylase 7 inhibitor suberoylanilide hydroxamic acid can restore secretion of Z‐type A1AT from epithelial cells	Bouchecareilh et al. 201229	In vitro study	Difficulties creating medicine molecules for use in animal models
Use of chemical chaperones stabilizes native A1AT and combats misfolded proteins	4‐Phenylbutyric acid*	Burrows et al. 200030	Clinical trials phase 2
		Teckman et al. 200431
	Trimethylamine N‐oxide	Devlin et al. 200132	In vitro study
Increase degradation via autophagy	Carbamazepine*	Hidvegi et al. 201033	Clinical trials phase 2, PiZZ‐associated cirrhosis	Lowest effect doses needed to impact A1ATD exceed safety profiles for humans
	Bile acid 24‐norursodeoxycholic acid	Tang et al. 201634	In vivo study in PiZ mice
	Sirolimus	Kaushal et al. 201035	In vivo study in PiZ mice; appears to be more effective when given in weekly doses rather than daily
	Ezetimibe	Yamamura et al. 201436	In vitro study
	Other agents: lithium, valproic acid, pimozide, fluphenazine, fluspirilene, cantharidin, tamoxifen, glucosamine, N‐acetylglucosamine	Gosai et al. 201037	In vivo study in C. elegans
	Tat‐beclin 1 peptide	Mallya et al. 200738
	Gene transfer of transcription factor TFEB using adenovirus‐mediated approaches	Pastore et al. 201339	In vivo study in PiZ mice
Increase clearance of accumulated protein	Small‐molecule therapy using bile duct ligation	Khan et al. 201740	In vivo study in PiZ mice
	Glucosidase inhibitors: castanospermine
	Mannosidase inhibitors
Reducing hepatic injury/inflammation	Cyclosporin A reduces mitochondrial injury	Teckman et al. 200441	In vitro study with HeLa cells
			In vivo study in PiZ mice
	Immunosuppressants (cyclophosphamide, cyclosporine) with variable results	Multiple studies

^*Treatments undergoing clinical trial.