Table-1:

Oral delivery of therapeutic proteins for induction of tolerance, enhance metabolic functions or immunity through booster vaccines.

Disease	Plant	Antigen	Antibiotic	Expression system	Expression level	Animal model /human	Functional Evaluation	References
Peanut allergy	Peanut	AR003	n/a	n/a	n/a	Human	Oral delivery of Arah proteins showed tolerating 600mg peanut flour dose in 500 allergic subjects (67.2%)- suppressed SPT reactivity and enhanced IgG4 production to modify peanut-specific immune responses	[4]
Pollen allergy	Rice	Destructed Cry j 1 and Cry j 2	n/a	Seed	n/a	Mice	Oral delivery of rice seeds suppressed allergen-specific Cd4 (+) T-Cell proliferation in mice and reduced allergy symptoms including sneezing, eosinophils etc.	[95]
Pollen allergy	Rice	Cry j 1 and Cry j 2	n/a	Seed	n/a	Mice	Oral immunotherapy decreased allergic conjunctivitis and IFN-γ production in mice splenocytes	[96]
Allergic asthma	Rice	Mite allergen (Der p 1)	n/a	Seed	7.5% TSP	Mice	Oral gavage of rice mite allergen expressed in rice seed reduced serum level allergen Especific IgE and IgG without bystander suppression.	[75]
Rheumatoid arthritis	Rice	Type II collagen (CII)	mALS	Seed	Up to 24 mg/g	Mice	Oral delivery of APL7 transgenic rice suppressed the development of arthritis and delayed onset of disease in mice model	[73]
Hemophilia A	Lettuce Tobacco	FVIII	Marker free	Chloroplast	3622 μg/g DW	Mouse	Oral gavage of C2, LC and HC fused with CTB suppressed inhibitor formation in animal model	[19, 20]
Hemophilia B	Lettuce	FIX	Marker free	Chloroplast	1000 μg/g DW	Mice/dog	Orally delivered FIX inhibited formation of anti-drug antibodies in hemophilia A mice	[33, 47]
Pompe disease	Tobacco	GAA	aadA	Chloroplast	190 μg/g DW	Mice	Oral delivery of CTB-GAA suppressed significantly Immunoglobulin formation against GAA in Pompe mice	[43]
Diabetes fracture	Lettuce	Pro-IGF-1	Marker free	Chloroplast	370 μg/g DW	Mice	The oral delivery of IGF-1 promoted musculoskeletal cell proliferation, differentiation and fracture healing in diabetic mice.	[18]
Diabetes	Lettuce	Extendin-1	aadA	Chloroplast	14.3% TLP	mice	Oral delivery of extendin-4 lowered blood glucose levels and stimulated insulin secretion in mice	[38]
Diabetes	Lettuce Tobacco	Pro-insulin	aadA	Chloroplast	Tobacco: ~16%TSP Lettuce: 72% TLP	Mice	Oral delivery of pro-insulin resulted in lower blood or urine glucose levels, and preserved insulin-producing β-cells in mice	[29, 35]
Hypertension	Lettuce	CTB-ACE2	aadA	Chloroplast	8600 μg/g DW	Mice	Oral delivery of CTB-ACE2/ANG-(1–7) reduced development of pulmonary hypertension, decreased right ventricular RV hypertrophy, total pulmonary resistance index, RV systolic pressure and pulmonary artery remodeling	[21]
Hypertension	Lettuce	CTB-Ang1–7	Marker free	Chloroplast	1900 μg/g DW	Rats
Alzheimer’s disease	Tobacco	Myelin basic protein (MBP)	aadA	Chloroplast	2% TSP	Mice	Oral delivery of CTB-MBP resulted in increased level of MBP levels in brain, and amyloid plaque intensity was reduced up to 70% in mice	[97]
Gaucher’s disease	Carrot cells	glucocerebrosidase	n/a	Plant cell	3 mg kg−1	Rat and pig	The orally delivered dose was inadequate due to low levels of expression.	[98]
Cancer	Tobacco	IFN-α2b	aadA	Chloroplast	20% TSP	Mice	Increased expression of MHC-I on splenocytes, and improved number of natural killer (NK) cells. The IFN-α2b also protected mice from metastatic tumor line.	[99]
Polio	Tobacco	VP1	aadA	Chloroplast	5.5mg/g DW	Mice	VP1-specific IgG1, VP1-IgA titres and neutralization (80%−100% seropositivity of Sabin-1,2, 3). VP1-specific IgG1, VP1-IgA titres and neutralization (80%−100% seropositivity of Sabin-1,2, 3). VP1-specific IgG1, VP1-IgA titres and neutralization (80%−100% seropositivity of Sabin-1,2, 3). Oral boost in mice resulted in high levels of VP1 specific IgG1 and VP1-IgA titers and neutralization and seropostivity against all three polio virus serotypes.	[6, 7]
Dengue	Lettuce	EDIII-1–4	aadA	Chloroplast	3.5% TSP	Rabbit	The injection of vaccine antigen EDIII-1–4 produced in lettuce elicited antibody production.	[100]
Plague	Lettuce	F1-V	aadA	Chloroplast	14.1% TSP	Mice	Oral gavage of lettuce produced F1-V showed survival rate of 88% in aerosolized Y. pestis challenge.	[101]
Tuberculosis	Carrot	ESAT6	nptII	Root	0.056% TSP	Mice	Mice fed with ESAT6 induced cell-mediated and humoral immunities	[102]
Anthrax	Lettuce	pagA	aadA	Chloroplast	14.2%	Mice	Subcutaneous immunization of lettuce produced pagA resulted in 100% survival of lethal dose of lethal toxin doses.	[103]
Hepatitis B	Lettuce	HBcAg	n/a	Nuclear	3.5 μg/g DW	Mice	Oral delivery of lyophilized lettuce containing HBcAg elicited a specific and efficient response in mice model	[104]
Hepatitis C	Lettuce	E1E2	nptII	Nuclear	n/a	Mice	Injections with oral boosts with the lettuce E1E2 developed systemic response.	[105]