Drug delivery systems comprising neurotrophic agent, apoptosis signaling fragment inhibitor (FAS) or fas ligand (FASL) inhibitor, tumor necrosis factor α (TNF-α) or TNF receptor inhibitor, mitochondrial peptide, oligonucleotide, chemokine inhibitor, or cysteine-aspartic protease

Abstract

To provide a drug delivery system for treating a medical condition such as an inherited or age-related choroid, retina or optic nerve disorder, or optic nerve degeneration; an otic disorder; a neurologic or CNS disorder; or a related condition; or a condition related to occlusion or obstruction of a blood vessel or blood circulation such as a stroke or myocardial or renal infarction.SOLUTION: A drug delivery system comprises a first active pharmaceutical ingredient (API) and a sustained delivery component. The first API is a neurotrophic agent, a FAS / FASL inhibitor, a TNF-α / TNFR inhibitor, a mitochondrial peptide, a chemokine inhibitor, a cysteine-aspartic protease, or a combination thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority based on U.S. Provisional Patent Application No. 62 / 687,173 filed on 19 June 2018, U.S. Provisional Patent Application No. 62 / 725,972 filed on 31 August 2018, U.S. Provisional Patent Application No. 62 / 747,575 filed on 18 October 2018, and U.S. Provisional Patent Application No. 62 / 787,873 filed on 3 January 2019, the entire contents of which are incorporated herein by reference. PCT / US19 / 37774 filed on 18 June 2019 is also incorporated herein by reference in its entirety.

[0002] (Sequence Listing) This application includes a sequence listing submitted electronically in ASCII format, which is thereby referenced in its entirety. A copy of that ASCII file, created on June 18, 2019, is filenamed V3563_10002WO01_SL.txt and has a size of 4,697 bytes. [Overview of the project] [Problems that the invention aims to solve]

[0003] This disclosure relates to a drug delivery system comprising neurotrophic agents, apoptosis signaling fragment inhibitors (FAS) or FAS ligand (FASL) inhibitors, tumor necrosis factor α (TNF-α) or TNF receptor (TNFR) inhibitors, mitochondrial peptides, oligonucleotides, chemokine inhibitors, or cysteine-aspartate proteases (including any combination of these compounds), and optionally a sustained delivery component. This type of drug delivery system can be used to treat conditions such as hereditary or age-related choroid, retinal, or optic nerve diseases, or optic nerve degeneration; hearing impairment; neurological or CNS disorders; or related symptoms; or conditions related to occlusion or impairment of blood vessels or blood circulation, such as stroke, myocardial infarction, or renal infarction. [Means for solving the problem]

[0004] Some embodiments include a drug delivery system comprising a first pharmaceutically active ingredient (API) and a sustained-delivery component, the first API being a neurotrophic agent, a FAS / FASL inhibitor, a TNF-α / TNFR inhibitor, a mitochondrial peptide, a chemokine inhibitor, a cysteine-aspartate protease, or a combination thereof.

[0005] Some embodiments include methods for treating medical conditions including 1) hereditary or age-related disorders or degeneration of the choroid, retina, or optic nerve, 2) ear disorders, or 3) neurological or CNS disorders, which involve administering the drug delivery system described herein to a mammal in need of treatment.

[0006] 1) hereditary or age-related disorders or degeneration of the choroid, retina, or optic nerve; 2) ear disorders; or 3) the use of FAS / FASL inhibitors, TNF-α / TNFR inhibitors, mitochondrial peptides, chemokine inhibitors, cysteine-aspartate proteases, or combinations thereof in the manufacture of a drug delivery system for the treatment of neurological or CNS disorders, wherein the drug delivery system further includes sustained delivery components.

[0007] A kit comprising a drug delivery system as described herein and a label for instructions on the use of the drug delivery system for the treatment of 1) hereditary or age-related disorders or degeneration of the choroid, retina, or optic nerve, 2) eye disorders, or 3) neurological or CNS disorders. [Modes for carrying out the invention]

[0008] Regarding the drug delivery system of the subject, neurotrophic agents may include CNTF compounds or other neurotrophic agents, and CNTF compounds include any compound having a similar structure or activity to ciliary neurotrophic factor (CNTF), including CNTF, a protein derivative of CNTF, or a CNTF peptide. Examples include CNTF, peptide 6 (P6; Ac-VGDGGLFEKKL-NH2 (SEQ ID NO: 1)) and peptide 21 (P21; Ac-DGGL A This includes peptides containing a portion of the sequence of CNTF, such as G-NH2 (SEQ ID NO: 2), recombinant CNTF (rhCNTF), or neurotrophic peptides having adamant groups at the C-terminus and / or N-terminus, as described in U.S. Patent No. 8,592,374, which is incorporated herein by reference, or any other peptide having biological activity similar to CNTF. Other neurotrophic agents include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), etc.

[0009] Any appropriate amount of neurotrophic agents such as CNTF compounds, NGF, BDNF, and GDNF can be used in the drug delivery system. For example, the drug delivery system can be used in doses of approximately 0.01-1 μg, 1-2 μg, 2-3 μg, 3-4 μg, 4-5 μg, 5-6 μg, 6-7 μg, 7-8 μg, 8-9 μg, 9-10 μg, 0.01-3 μg, 3-6 μg, 6-10 μg, 0.01-10 μg, and 10-20 μg. μg, approx. 20-30 μg, approx. 30-40 μg, approx. 40-50 μg, approx. 50-60 μg, approx. 60-70 μg, approx. 70-80 μg, approx. 80-90 μg, Approximately 90-100μg, approximately 0.01-30μg, approximately 30-60μg, approximately 60-100μg, approximately 0.01-100μg, approximately 0.1-100μg, approximately 10 It may contain 0-200 μg, approximately 200-300 μg, approximately 300-400 μg, approximately 400-500 μg, approximately 500-600 μg, approximately 600-700 μg, approximately 700-800 μg, approximately 800-900 μg, approximately 900-1,000 μg, approximately 0.01-300 μg, approximately 300-600 μg, approximately 600-1,000 μg, approximately 0.01-1 mg, approximately 1-2 mg, approximately 2-3 mg, approximately 3-4 mg, approximately 4-5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 0.01-3 mg, approximately 3-6 mg, approximately 6-10 mg, or approximately 0.01-10 mg of one of these compounds. These amounts may also apply to situations where the drug exists in a covalent form with other drugs or sustained delivery components.

[0010] The use of the above-mentioned amounts of neuronutrient agents such as CNTF compounds, NGF, BDNF, and GDNF in a drug delivery system may provide a drug delivery system that delivers therapeutic concentrations of neuronutrient agents for periods of approximately 1-4 weeks, 1-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 2-5 years, 5-10 years, or longer.

[0011] Useful FAS or FASL inhibitors include bicyclol, FLIP;MET12(HHIYLGAVNYIY (SEQ ID NO: 3), HHIYLGATNYIY (SEQ ID NO: 4), or H 60 HIYLGATNYIY 71Shorter fragments thereof, such as tetramers, having sequence (SEQ ID NO: 4), or sequence YLGA (SEQ ID NO: 5), or fragments having sequences such as compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, or compound 11, ONL1204 (for example, a peptide containing or consisting of sequence HHIYLGATNYIY (SEQ ID NO: 4)), as shown in Table 1 below, having homology with MET12 of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%; sequence H 60 HIYLGATNYIY 71 Other MET12 derivatives such as compounds containing -NH2 (SEQ ID NO: 4); FAS apoptosis inhibitory molecules [FAIM]; NOL3 [nucleolar protein 3 (apoptosis inhibitory factor [ARC] mediated by the CARD domain), etc.]; starfish decoy receptor 1 (DcR1); starfish decoy receptor 2 (DcR2); or starfish decoy receptor 3 (DcR3).

[0012] [ka]

[0013] [Table 1]

[0014] Any appropriate amount of bicyclol, FLIP, compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, ONL1204, H 60 HIYLGATNYIY 71FAS or FASL inhibitors such as -NH2 (SEQ ID NO: 4), FAIM, NOL3, DcR1, DcR2, DcR3 can be used in drug delivery systems. For example, the drug delivery system can contain one of these compounds in amounts of about 0.01 - 1 μg, about 1 - 2 μg, about 2 - 3 μg, about 3 - 4 μg, about 4 - 5 μg, about 5 - 6 μg, about 6 - 7 μg, about 7 - 8 μg, about 8 - 9 μg, about 9 - 10 μg, about 0.01 - 3 μg, about 3 - 6 μg, about 6 - 10 μg, about 0.01 - 10 μg, about 10 - 20 μg, about 20 - 30 μg, about 30 - 40 μg, about 40 - 50 μg, about 50 - 60 μg, about 60 - 70 μg, about 70 - 80 μg, about 80 - 90 μg, about 90 - 100 μg, about 0.01 - 30 μg, about 30 - 60 μg, about 60 - 100 μg, about 0.01 - 100 μg, about 0.1 - 100 μg, about 100 - 200 μg, about 200 - 300 μg, about 300 - 400 μg, about 400 - 500 μg, about 500 - 600 μg, about 600 - 700 μg, about 700 - 800 μg, about 800 - 900 μg, about 900 - 1,000 μg, about 0.01 - 300 μg, about 300 - 600 μg, about 600 - 1,000 μg, about 0.01 - 1 mg, about 1 - 2 mg, about 2 - 3 mg, about 3 - 4 mg, about 4 - 5 mg, about 5 - 6 mg, about 6 - 7 mg, about 7 - 8 mg, about 8 - 9 mg, about 9 - 10 mg, about 0.01 - 3 mg, about 3 - 6 mg, about 6 - 10 mg, or about 0.01 - 10 mg. These amounts can also be applicable to situations where the drug exists in a form covalently bonded to other agents or sustained release components, etc.

[0015] The above amounts of bicyclol, FLIP, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, ONL1204, H in the drug delivery system 60 HIYLGATNYIY<000,0009>The use of FAS or FASL inhibitors such as -NH2 (SEQ ID NO: 4), FAIM, NOL3, DcR1, DcR2, DcR3 can provide a drug delivery system that provides a therapeutic concentration of the FAS or FASL inhibitor for a period of about 1 - 4 weeks, about 1 - 3 months, about 3 - 6 months, about 6 - 9 months, about 9 - 12 months, about 12 - 18 months, about 18 - 24 months, about 2 - 5 years, about 5 - 10 years, or longer.

[0016] Useful TNF-α or TNFR inhibitors include etanercept, infliximab, golimumab, certolizumab, adalimumab, TNF variants that selectively antagonize TNFR1 (R1antTNF), DMS5540, TNF receptor 1 silencer (TROS), and ARROSAB.

[0017] Any appropriate amount of TNF-α or TNFR inhibitors such as etanercept, infliximab, golimumab, certolizumab, adalimumab, R1antTNF, DMS5540, TROS, and ATROSAB can be used in the drug delivery system. For example, the drug delivery system may contain approximately 0.01-1 μg, 1-2 μg, 2-3 μg, 3-4 μg, 4-5 μg, 5-6 μg, 6-7 μg, 7-8 μg, 8-9 μg, 9-10 μg, 0.01-3 μg, 3-6 μg, 6-10 μg, 0.01-10 μg, or 10-20 μg. μg, approximately 20-30 μg, approximately 30-40 μg, approximately 40-50 μg, approximately 50-60 μg, approximately 60-70 μg, approximately 70-80 μg, approximately 80-90 μg, Approximately 90-100μg, approximately 0.01-30μg, approximately 30-60μg, approximately 60-100μg, approximately 0.01-100μg, approximately 0.1-100μg, approximately 10 It may contain 0-200 μg, approximately 200-300 μg, approximately 300-400 μg, approximately 400-500 μg, approximately 500-600 μg, approximately 600-700 μg, approximately 700-800 μg, approximately 800-900 μg, approximately 900-1,000 μg, approximately 0.01-300 μg, approximately 300-600 μg, approximately 600-1,000 μg, approximately 0.01-1 mg, approximately 1-2 mg, approximately 2-3 mg, approximately 3-4 mg, approximately 4-5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 0.01-3 mg, approximately 3-6 mg, approximately 6-10 mg, or approximately 0.01-10 mg of one of these compounds. These amounts may also apply to situations where the drug exists in a covalent form with other drugs or sustained delivery components.

[0018] The use of the above-mentioned amounts of TNF-α or TNFR inhibitors such as etanercept, infliximab, golimumab, certolizumab, adalimumab, R1antTNF, DMS5540, TROS, and ATROSAB in a drug delivery system may provide a drug delivery system that delivers therapeutic concentrations of TNF-α or TNFR inhibitors for periods of approximately 1-4 weeks, 1-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 2-5 years, 5-10 years, or longer.

[0019] Useful mitochondrial peptides include humanin and humanin analogs (e.g., s14G-humanin, MTP101, ellamipretide, etc.).

[0020] Any appropriate amount of mitochondrial peptides such as humanin, humanin analogs, s14G-humanin, MTP101, and ellamipretide can be used in drug delivery systems. For example, drug delivery systems can use approximately 0.01-1 μg, 1-2 μg, 2-3 μg, 3-4 μg, 4-5 μg, 5-6 μg, 6-7 μg, 7-8 μg, 8-9 μg, 9-10 μg, 0.01-3 μg, 3-6 μg, 6-10 μg, 0.01-10 μg, and 10-20 μg. g, about 20-30μg, about 30-40μg, about 40-50μg, about 50-60μg, about 60-70μg, about 70-80μg, about 80-90μg, about 90~100μg, approx. 0.01~30μg, approx. 30~60μg, approx. 60~100μg, approx. 0.01~100μg, approx. 0.1~100μg, approx. 100 It may contain one of these compounds in amounts of ~200 μg, approximately 200~300 μg, approximately 300~400 μg, approximately 400~500 μg, approximately 500~600 μg, approximately 600~700 μg, approximately 700~800 μg, approximately 800~900 μg, approximately 900~1,000 μg, approximately 0.0100~300 μg, approximately 300~600 μg, approximately 600~1,000 μg, approximately 0.01~1 mg, approximately 1~2 mg, approximately 2~3 mg, approximately 3~4 mg, approximately 4~5 mg, approximately 5~6 mg, approximately 6~7 mg, approximately 7~8 mg, approximately 8~9 mg, approximately 9~10 mg, approximately 0.01~3 mg, approximately 3~6 mg, approximately 6~10 mg, or approximately 0.01~10 mg. These amounts may also apply to situations where the drug exists in a covalent form with other drugs or sustained delivery components.

[0021] The use of the above-mentioned amounts of mitochondrial peptides such as humanin, humanin analogs, s14G-humanin, MTP101, and ellamipretide in a drug delivery system may provide a drug delivery system that delivers therapeutic concentrations of mitochondrial peptides for periods of approximately 1-4 weeks, 1-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 2-5 years, 5-10 years, or longer.

[0022] Useful oligonucleotides include DNA, RNA, etc. In some embodiments, the oligonucleotide is a short-chain inhibitory RNA or "siRNA." siRNA can induce the RNA interference (RNAi) pathway. siRNAs vary in length (typically 20-25 base pairs) and in degree of complementarity with the target mRNA in the antisense strand. Some, but not all, siRNAs have unpaired protruding bases at the 5' or 3' end of the sense strand and / or antisense strand. siRNAs include double helixed structures of two separate strands, as well as single strands that can form hairpin structures containing the double-stranded region. In some embodiments, the siRNA targets FAS (as FAS-targeted siRNA), such as FAS siRNA sense ((5'-GAAACGAACUGCACCCGGAU-3' (SEQ ID NO: 16)) or negative siRNA sense (5'-UAGCGACUAAACACAUCAA-3' (SEQ ID NO: 17)). In some embodiments, the siRNA targets TNF-α.

[0023] Any appropriate amount of oligonucleotides such as DNA, RNA, siRNA, FAS-targeted siRNA, FAS siRNA sense, negative siRNA sense, and TNF-α-targeted siRNA can be used in the drug delivery system. For example, the drug delivery system can use approximately 0.01-1 μg, 1-2 μg, 2-3 μg, 3-4 μg, 4-5 μg, 5-6 μg, 6-7 μg, 7-8 μg, 8-9 μg, 9-10 μg, 0.01-3 μg, 3-6 μg, 6-10 μg, 0.01-10 μg, and 10-20 μg. μg, approximately 20-30 μg, approximately 30-40 μg, approximately 40-50 μg, approximately 50-60 μg, approximately 60-70 μg, approximately 70-80 μg, approximately 80-90 μg, Approximately 90-100μg, approximately 0.01-30μg, approximately 30-60μg, approximately 60-100μg, approximately 0.01-100μg, approximately 0.1-100μg, approximately 10 It may contain 0-200 μg, approximately 200-300 μg, approximately 300-400 μg, approximately 400-500 μg, approximately 500-600 μg, approximately 600-700 μg, approximately 700-800 μg, approximately 800-900 μg, approximately 900-1,000 μg, approximately 0.01-300 μg, approximately 300-600 μg, approximately 600-1,000 μg, approximately 0.01-1 mg, approximately 1-2 mg, approximately 2-3 mg, approximately 3-4 mg, approximately 4-5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 0.01-3 mg, approximately 3-6 mg, approximately 6-10 mg, or approximately 0.01-10 mg of one of these compounds. These amounts may also apply to situations where the drug exists in a covalent form with other drugs or sustained delivery components.

[0024] The use of the above-mentioned amounts of oligonucleotides such as DNA, RNA, siRNA, FAS-targeted siRNA, FAS siRNA sense, negative siRNA sense, and TNF-α-targeted siRNA in a drug delivery system may provide a drug delivery system that delivers therapeutic concentrations of oligonucleotides for periods of approximately 1-4 weeks, 1-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 2-5 years, 5-10 years, or longer.

[0025] Useful chemokine inhibitors include NR58.3-14-3.

[0026] [ka]

[0027] Any appropriate amount of chemokine inhibitors such as NR58.3-14-3 can be used in the drug delivery system. For example, the drug delivery system can use approximately 0.01-1 μg, approximately 1-2 μg, approximately 2-3 μg, approximately 3-4 μg, approximately 4-5 μg, approximately 5-6 μg, approximately 6-7 μg, approximately 7-8 μg, approximately 8-9 μg, approximately 9-10 μg, approximately 0.01-3 μg, approximately 3-6 μg, approximately 6-10 μg, approximately 0.01-10 μg, approximately 10-20 μg μg, approximately 20-30 μg, approximately 30-40 μg, approximately 40-50 μg, approximately 50-60 μg, approximately 60-70 μg, approximately 70-80 μg, approximately 80-90 μg, Approximately 90-100μg, approximately 0.01-30μg, approximately 30-60μg, approximately 60-100μg, approximately 0.01-100μg, approximately 0.1-100μg, approximately 10 It may contain 0-200 μg, approximately 200-300 μg, approximately 300-400 μg, approximately 400-500 μg, approximately 500-600 μg, approximately 600-700 μg, approximately 700-800 μg, approximately 800-900 μg, approximately 900-1,000 μg, approximately 0.01-300 μg, approximately 300-600 μg, approximately 600-1,000 μg, approximately 0.01-1 mg, approximately 1-2 mg, approximately 2-3 mg, approximately 3-4 mg, approximately 4-5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 0.01-3 mg, approximately 3-6 mg, approximately 6-10 mg, or approximately 0.01-10 mg of one of these compounds. These amounts may also apply to situations where the drug exists in a covalent form with other drugs or sustained delivery components.

[0028] The use of the above-mentioned amounts of chemokine inhibitors such as NR58.3-14-3 in a drug delivery system may provide a drug delivery system that delivers therapeutic concentrations of the chemokine inhibitor for periods of approximately 1-4 weeks, 1-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 2-5 years, 5-10 years, or longer.

[0029] Useful cysteine-aspartate proteases (caspases) include caspase 2, caspase 3, caspase 8, caspase 9, and others.

[0030] Any appropriate amount of caspase 2, caspase 3, caspase 8, caspase 9, etc., can be used in the drug delivery system. For example, the drug delivery system can use approximately 0.01-1 μg, approximately 1-2 μg, approximately 2-3 μg, approximately 3-4 μg, approximately 4-5 μg, approximately 5-6 μg, approximately 6-7 μg, approximately 7-8 μg, approximately 8-9 μg, approximately 9-10 μg, approximately 0.01-3 μg, approximately 3-6 μg, approximately 6-10 μg, approximately 0.01-10 μg, approximately 10-20 μg μg, approximately 20-30 μg, approximately 30-40 μg, approximately 40-50 μg, approximately 50-60 μg, approximately 60-70 μg, approximately 70-80 μg, approximately 80-90 μg, Approximately 90-100μg, approximately 0.01-30μg, approximately 30-60μg, approximately 60-100μg, approximately 0.01-100μg, approximately 0.1-100μg, approximately 10 It may contain 0-200 μg, approximately 200-300 μg, approximately 300-400 μg, approximately 400-500 μg, approximately 500-600 μg, approximately 600-700 μg, approximately 700-800 μg, approximately 800-900 μg, approximately 900-1,000 μg, approximately 0.01-300 μg, approximately 300-600 μg, approximately 600-1,000 μg, approximately 0.01-1 mg, approximately 1-2 mg, approximately 2-3 mg, approximately 3-4 mg, approximately 4-5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 0.01-3 mg, approximately 3-6 mg, approximately 6-10 mg, or approximately 0.01-10 mg of one of these compounds. These amounts may also apply to situations where the drug exists in a covalent form with other drugs or sustained delivery components.

[0031] The use of the above-mentioned amounts of caspases such as caspase 2, caspase 3, caspase 8, and caspase 9 in a drug delivery system may provide a drug delivery system that delivers therapeutic concentrations of caspases for periods of approximately 1 to 4 weeks, 1 to 3 months, 3 to 6 months, 6 to 9 months, 9 to 12 months, 12 to 18 months, 18 to 24 months, 2 to 5 years, 5 to 10 years, or longer.

[0032] The drug delivery system includes two different compounds, which are neurotrophic agents, FAS / FASL inhibitors, TNF-α / TNFR inhibitors, mitochondrial peptides, oligonucleotides, chemokine inhibitors, or cysteine-aspartate proteases. For example, the first and second compounds may be those identified in Table 2.

[0033] [Table 2]

[0034] For each combination identified in Table 2, in some embodiments, the first and second compounds are covalently bonded to each other. In some embodiments, the first and second compounds are not covalently bonded to each other via bonding groups.

[0035] For example, some combinations linked by linking groups are given by formulas 1, I, 2, A, B, D, E, F, G, H, J, K, M, N, O, P, Q, R, S, T, and U. [ka] It is represented as follows.

[0036] In some embodiments, the drug delivery system includes the following combinations of drugs covalently bonded (by a binding group L, etc., including a group represented by formula L-1, L-2, L-3, L-4, L-5, L-6, L-7, or L-8) containing a salt of the drug, a free acid, or a free base: CNTF and CNTF protein derivatives; CNTF and CNTF peptides; CNTF and peptide 21; CNTF and peptide 21; CNTF and rhCNTF; CNTF and NGF; CNTF and BDNF; CNT F and GDNF; CNTF and Bicyclol; CNTF and FLIP; CNTF and MET12; CNTF and Compound 1 from Table 1; CNTF and Compound 2 from Table 1; CNTF and Compound 3 from Table 1; CNTF and Compound 4 from Table 1; CNTF and Compound 5 from Table 1; CNTF and Compound 6 from Table 1; CNTF and Compound 7 from Table 1; CNTF and Compound 8 from Table 1; CNTF and Compound 9 from Table 1; CNTF and Compound 10 from Table 1; CNTF and Compound 11 from Table 1; CNTF and ONL1204; CNTF and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO 4); CNTF and FAIM; CNTF and NOL3; CNTF and DcR1; CNTF and DcR2; CNTF and DcR3; CNTF and etanercept; CNTF and infliximab; CNTF and golimumab; CNTF and certolizumab; CNTF and adalimumab; CNTF and R1antTNF; CNTF and DMS5540; CNTF and TROS; CNTF and ATROSAB; CNTF and humanin; CNTF and humanin analog; CNTF and s14G-humanin; CNTF and MT P101; CNTF and ellamipretide; CNTF and DNA; CNTF and RNA; CNTF and siRNA; CNTF and siRNA targeting FAS; CNTF and FAS siRNA sense; CNTF and negative siRNA sense; CNTF and siRNA targeting TNF-α; CNTF and NR58.3-14-3; CNTF and caspase 2; CNTF and caspase 3; CNTF and caspase 8; CNTF and caspase 9; CNTF protein derivatives and CNTF peptides; CNTF protein derivatives and peptide 21; CNTF protein derivative and peptide 21; CNTF protein derivative and rhCNTF; CNTF protein derivative and NGF; CNTF protein derivative and BDNF; CNTF protein derivative and GDNF; CNTF protein derivative and bicyclol; CNTF protein derivative and FLIP; CNTF protein derivative and MET12; CNTF protein derivative and compound 1 of Table 1; CNTF protein derivative and compound 2 of Table 1; CNTF protein derivative and compound 3 of Table 1; CNTF protein derivative and compound 4 of Table 1; CNTF protein derivative and compound 5 of Table 1; CNTF protein derivative and compound 6 of Table 1; CNTF protein derivative and compound 7 of Table 1; CNTF protein derivative and compound 8 of Table 1; CNTF protein derivative and compound 9 of Table 1; CNTF protein derivative and compound 10 of Table 1; CNTF protein derivative and / or compound 11 of Table 1; CNTF protein derivative and ONL1204; CNTF protein derivative and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO. 4); CNTF protein derivative and FAIM; CNTF protein derivative and NOL3; CNTF protein derivative and DcR1; CNTF protein derivative and DcR2; CNTF protein derivative and DcR3; CNTF protein derivative and etanercept; CNTF protein derivative and infliximab; CNTF protein derivative and golimumab; CNTF protein derivative and certolizumab; CNTF protein derivative and adalimumab; CNTF protein derivative and R1antTNF; CNTF protein derivative and DMS5540; CNTF protein derivative and TROS; CNTF protein derivative and ATROSAB; C NTF protein derivatives and humanin; CNTF protein derivatives and humanin analogs; CNTF protein derivatives and s14G-humanin; CNTF protein derivatives and MTP101; CNTF protein derivatives and ellamipretide; CNTF protein derivatives and DNA; CNTF protein derivatives and RNA; CNTF protein derivatives and siRNA; CNTF protein derivatives and FAS-targeted siRNA; CNTF protein derivatives and FASsiRNA sense; CNTF protein derivatives and negative siRNA sense; CNTF protein derivatives and TNF-α-targeted siRNA; CNTF protein derivatives and NR58.3-14-3; CNTF protein derivative and caspase 2; CNTF protein derivative and caspase 3; CNTF protein derivative and caspase 8; CNTF protein derivative and caspase 9; CNTF peptide and peptide 21; CNTF peptide and rhCNTF; CNTF peptide and NGF; CNTF peptide and BDNF; CNTF peptide and GDNF; CNTF peptide and bicyclol; CNTF peptide and FLIP; CNTF peptide and MET12; CNTF peptide and compound 1 from Table 1; CNTF peptide and compound 2 from Table 1; CNTF peptide and compound 3 from Table 1; CNTF peptide and compound 4 from Table 1; CNTF peptide and compound 5 from Table 1; CNTF peptide and compound 6 from Table 1; CNTF peptide and compound 7 from Table 1; CNTF peptide and compound 8 from Table 1; CNTF peptide and compound 9 from Table 1; CNTF peptide and compound 10 from Table 1; CNTF peptide and / or compound 11 from Table 1; CNTF peptide and ONL1204; CNTF peptide and H. 60 HIYLGATNYIY 71-NH2 (SEQ ID NO. 4); CNTF peptide and FAIM; CNTF peptide and NOL3; CNTF peptide and DcR1; CNTF peptide and DcR2; CNTF peptide and DcR3; CNTF peptide and etanercept; CNTF peptide and infliximab; CNTF peptide and golimumab; CNTF peptide and certolizumab; CNTF peptide and adalimumab; CNTF peptide and R1antTNF; CNTF peptide and DMS5540; CNTF peptide and TROS; CNTF peptide and ATROSAB; CNTF peptide and humanin; CNTF peptide and humanin analog; CNTF peptide and s14G-humanin; CNTF peptide and MTP101; CNTF peptide and ellamipretide; CNTF peptide and DNA; CNTF peptide and RNA; CNTF peptide and siRNA; CNTF peptide and FAS-targeted siRNA; CNTF peptide and FASsiRNA sense; CNTF peptide Butide and negative siRNA sense; CNTF peptide and TNF-α-targeted siRNA; CNTF peptide and NR58.3-14-3; CNTF peptide and caspase 2; CNTF peptide and caspase 3; CNTF peptide and caspase 8; CNTF peptide and caspase 9; peptide 21 and rhCNTF; peptide 21 and NGF; peptide 21 and BDNF; peptide 21 and GDNF; peptide 21 and bicyclol; peptide 21 and FLIP; peptide Tide 21 and MET12; Peptide 21 and compound 1 from Table 1; Peptide 21 and compound 2 from Table 1; Peptide 21 and compound 3 from Table 1; Peptide 21 and compound 4 from Table 1; Peptide 21 and compound 5 from Table 1; Peptide 21 and compound 6 from Table 1; Peptide 21 and compound 7 from Table 1; Peptide 21 and compound 8 from Table 1; Peptide 21 and compound 9 from Table 1; Peptide 21 and compound 10 from Table 1; Peptide 21 and compound 11 from Table 1; Peptide 21 and ONL1204; Peptide 21 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO. 4); Peptide 21 and FAIM; Peptide 21 and NOL3; Peptide 21 and DcR1; Peptide 21 and DcR2; Peptide 21 and DcR3; Peptide 21 and etanercept; Peptide 21 and infliximab; Peptide 21 and golimumab; Peptide 21 and certolizumab; Peptide 21 and adalimumab; Peptide 21 and R1antTNF; Peptide 21 and DMS5540; Peptide 21 and TROS; Peptide 21 and ATROSAB; Peptide 21 and humanin; Peptide 21 and humanin analog; Peptide 21 and s14G-humanin; Peptide 21 and MTP101; Peptide 21 and ellamipretide; Peptide 21 and DNA; Peptide 21 and RNA; Peptide 21 and siRNA; Peptide 21 and FAS-targeted siRNA; Peptide 21 and FASsiRNA sense; Peptide 21 and negative siRNA NA sense; siRNA targeting peptide 21 and TNF-α; peptide 21 and NR58.3-14-3; peptide 21 and caspase 2; peptide 21 and caspase 3; peptide 21 and caspase 8; peptide 21 and caspase 9; rhCNTF and NGF; rhCNTF and BDNF; rhCNTF and GDNF; rhCNTF and bicyclol; rhCNTF and FLIP; rhCNTF and MET12; rhCNTF and compound 1 from Table 1; rhCNTF and compound 2 from Table 1; rhCNTF and compound 3 from Table 1; rhCNTF and compound 4 from Table 1; rhCNTF and compound 5 from Table 1; rhCNTF and compound 6 from Table 1; rhCNTF and compound 7 from Table 1; rhCNTF and compound 8 from Table 1; rhCNTF and compound 9 from Table 1; rhCNTF and compound 10 from Table 1; rhCNTF and compound 11 from Table 1; rhCNTF and ONL1204; rhCNTF and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO 4); rhCNTF and FAIM; rhCNTF and NOL3; rhCNTF and DcR1; rhCNTF and DcR2; rhCNTF and DcR3; rhCNTF and etanercept; rhCNTF and infliximab; rhCNTF and golimumab; rhCNTF and certolizumab; rhCNTF and adalimumab; rhCNTF and R1antTNF; rhCNTF and DMS5540; rhCNTF and TROS; rhCNTF and ATROSAB; rhCNTF and humanin; rhCNTF and humanin analog; rhCNTF and s14G-humanin; rhCNTF and MTP101; rhCNTF and ellamipretide; rhCNTF and DNA; rhCNTF and RNA; rhCNTF and siRNA; rhCNTF and siRNA targeting FAS; rh CNTF and FASsiRNA sense; rhCNTF and negative siRNA sense; rhCNTF and TNF-α targeted siRNA; rhCNTF and NR58.3-14-3; rhCNTF and caspase 2; rhCNTF and caspase 3; rhCNTF and caspase 8; rhCNTF and caspase 9; NGF and BDNF; NGF and GDNF; NGF and bicyclol; NGF and FLIP; NGF and MET12; NGF and compound 1 from Table 1; NGF and compound 2 from Table 1; NGF and compound 3 from Table 1; NGF and compound 4 from Table 1; NGF and compound 5 from Table 1; NGF and compound 6 from Table 1; NGF and compound 7 from Table 1; NGF and compound 8 from Table 1; NGF and compound 9 from Table 1; NGF and compound 10 from Table 1; NGF and compound 11 from Table 1; NGF and ONL1204; NGF and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO 4); NGF and FAIM; NGF and NOL3; NGF and DcR1; NGF and DcR2; NGF and DcR3; NGF and etanercept; NGF and infliximab; NGF and golimumab; NGF and certolizumab; NGF and adalimumab; NGF and R1antTNF; NGF and DMS5540; NGF and TROS; NGF and ATROSAB; NGF and humanin; NGF and humanin analog; NGF and s14G-humanin; NGF and MTP101; NGF and ellamipretide; NGF and DNA; NGF and RNA; NGF and siRNA; NGF and FAS-targeted siRNA; NGF and FAS siRNA sense; NGF and negative siRNA sense; NGF and TNF-α-targeted SIRN A; NGF and NR58.3-14-3; NGF and caspase 2; NGF and caspase 3; NGF and caspase 8; NGF and caspase 9; BDNF and GDNF; BDNF and bicyclol; BDNF and FLIP; BDNF and MET12; BDNF and compound 1 from Table 1; BDNF and compound 2 from Table 1; BDNF and compound 3 from Table 1; BDNF and compound 4 from Table 1; BDNF and compound 5 from Table 1; BDNF and compound 6 from Table 1; BDNF and compound 7 from Table 1; BDNF and compound 8 from Table 1; BDNF and compound 9 from Table 1; BDNF and compound 10 from Table 1; BDNF and compound 11 from Table 1; BDNF and ONL1204; BDNF and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO 4); BDNF and FAIM; BDNF and NOL3; BDNF and DcR1; BDNF and DcR2; BDNF and DcR3; BDNF and etanercept; BDNF and infliximab; BDNF and golimumab; BDNF and certolizumab; BDNF and adalimumab; BDNF and R1antTNF; BDNF and DMS5540; BDNF and TROS; BDNF and ATROSAB; BDNF and humanin; BDNF and humanin analog; BDNF and s14G-humanin; BDNF and MTP101; BDNF and ellamipretide; BDNF and DNA; BDNF and RNA; BDNF and siRNA; BDNF and FAS-targeted siRNA; BDNF and FASsiRNA sense ;BDNF and negative siRNA sense;BDNF and TNF-α targeted siRNA;BDNF and NR58.3-14-3;BDNF and caspase 2;BDNF and caspase 3;BDNF and caspase 8;BDNF and caspase 9;GDNF and bicyclol;GDNF and FLIP;GDNF and MET12;GDNF and compound 1 from Table 1;GDNF and compound 2 from Table 1;GDNF and compound 3 from Table 1;GDNF and compound 4 from Table 1;GDNF and compound 5 from Table 1;GDNF and compound 6 from Table 1;GDNF and compound 7 from Table 1;GDNF and compound 8 from Table 1;GDNF and compound 9 from Table 1;GDNF and compound 10 from Table 1;GDNF and compound 11 from Table 1;GDNF and ONL1204;GDNF and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO 4); GDNF and FAIM; GDNF and NOL3; GDNF and DcR1; GDNF and DcR2; GDNF and DcR3; GDNF and etanercept; GDNF and infliximab; GDNF and golimumab; GDNF and certolizumab; GDNF and adalimumab; GDNF and R1antTNF; GDNF and DMS5540; GDNF and TROS; GDNF and ATROSAB; GDNF and humanin; GDNF and humanin analog; GDNF and s14G-humanin; GDNF and MTP101; GDNF and ellamipretide; GDNF and DNA; GDNF and RNA; GDNF and siRNA; GDNF and FAS-targeted siRNA; GDNF and FASsiRNA sense; GDNF and negative siRNA sense; siRNA targeting GDNF and TNF-α; GDNF and NR58.3-14-3; GDNF and caspase 2; GDNF and caspase 3; GDNF and caspase 8; GDNF and caspase 9; Bicyclol and FLIP; Bicyclol and MET12; Bicyclol and compound 1 from Table 1; Bicyclol and compound 2 from Table 1; Bicyclol and compound 3 from Table 1; Bicyclol and compound 4 from Table 1; Bicyclol and compound 5 from Table 1; Bicyclol and compound 6 from Table 1; Bicyclol and compound 7 from Table 1; Bicyclol and compound 8 from Table 1; Bicyclol and compound 9 from Table 1; Bicyclol and compound 10 from Table 1; Bicyclol and / or compound 11 from Table 1; Bicyclol and ONL1204; Bicyclol and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO. 4); Bicyclol and FAIM; Bicyclol and NOL3; Bicyclol and DcR1; Bicyclol and DcR2; Bicyclol and DcR3; Bicyclol and etanercept; Bicyclol and infliximab; Bicyclol and golimumab; Bicyclol and certolizumab; Bicyclol and adalimumab; Bicyclol and R1antTNF; Bicyclol and DMS5540; Bicyclol and TROS; Bicyclol and ATROSAB; Bicyclol and humanin; Bicyclol and humanin analog; Bicyclol and s14G-humanin; Bicyclol and MTP101; Bicyclol and ellamipretide; Bicyclol and DNA; Bicyclol and RNA; Bicyclol and siRNA; Bicyclol and FAS Targeted siRNA; Bicyclol and FASsiRNA sense; Bicyclol and negative siRNA sense; Bicyclol and TNF-α-targeted siRNA; Bicyclol and NR58.3-14-3; Bicyclol and caspase 2; Bicyclol and caspase 3; Bicyclol and caspase 8; Bicyclol and caspase 9; FLIP and MET12; FLIP and compound 1 from Table 1; FLIP and compound 2 from Table 1; FLIP and compound 3 from Table 1; FLIP and compound 4 from Table 1; FLIP and compound 5 from Table 1; FLIP and compound 6 from Table 1; FLIP and compound 7 from Table 1; FLIP and compound 8 from Table 1; FLIP and compound 9 from Table 1; FLIP and compound 10 from Table 1; FLIP and / or compound 11 from Table 1; FLIP and ONL1204; FLIP and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO 4); FLIP and FAIM; FLIP and NOL3; FLIP and DcR1; FLIP and DcR2; FLIP and DcR3; FLIP and etanercept; FLIP and infliximab; FLIP and golimumab; FLIP and certolizumab; FLIP and adalimumab; FLIP and R1antTNF; FLIP and DMS5540; FLIP and TROS; FLIP and ATROSAB; FLIP and humanin; FLIP and humanin analog; FLIP and s14G-humanin; FLIP and MTP101; FLIP and ellamipretide; FLIP and DNA; FLIP and RNA; FLIP and siRNA; FLIP and siRNA targeting FAS; FLIP and F ASsiRNA sense; FLIP and negative siRNA sense; FLIP and TNF-α-targeted siRNA; FLIP and NR58.3-14-3; FLIP and caspase 2; FLIP and caspase 3; FLIP and caspase 8; FLIP and caspase 9; MET12 and compound 1 from Table 1; MET12 and compound 2 from Table 1; MET12 and compound 3 from Table 1; MET12 and compound 4 from Table 1; MET12 and compound 5 from Table 1; MET12 and compound 6 from Table 1; MET12 and compound 7 from Table 1; MET12 and compound 8 from Table 1; MET12 and compound 9 from Table 1; MET12 and compound 10 from Table 1; MET12 and compound 11 from Table 1; MET12 and ONL1204; MET12 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO4); MET12 and FAIM; MET12 and NOL3; MET12 and DcR1; MET12 and DcR2; MET12 and DcR3; MET12 and etanercept; MET12 and infliximab; MET12 and golimumab; MET12 and certolizumab; MET12 and adalimumab; MET12 and R1antTNF; MET12 and DMS5540; MET12 and TROS; MET12 and ATROSAB; MET12 and humanin; MET12 and humanin analog; MET12 and s14G-humanin; MET12 and MTP101; MET12 and ellamipretide; MET12 and DNA; MET12 and RNA; MET12 and siRNA; MET12 and siRNA targeting FAS; MET 12 and FASsiRNA sense; MET12 and negative siRNA sense; MET12 and TNF-α-targeted siRNA; MET12 and NR58.3-14-3; MET12 and caspase 2; MET12 and caspase 3; MET12 and caspase 8; MET12 and caspase 9; Compound 1 and Compound 2 from Table 1; Compound 1 and Compound 3 from Table 1; Compound 1 and Compound 4 from Table 1; Compound 1 and Compound 5 from Table 1; Compound 1 and Compound 6 from Table 1; Compound 1 and Compound 7 from Table 1; Compound 1 and Compound 8 from Table 1; Compound 1 and Compound 9 from Table 1; Compound 1 and Compound 10 from Table 1; Compound 1 and / or Compound 11 from Table 1; Compound 1 and ONL1204 from Table 1; Compound 1 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO 4); Compound 1 in Table 1 and FAIM; Compound 1 in Table 1 and NOL3; Compound 1 in Table 1 and DcR1; Compound 1 in Table 1 and DcR2; Compound 1 in Table 1 and DcR3; Compound 1 in Table 1 and etanercept; Compound 1 in Table 1 and infliximab; Compound 1 in Table 1 and golimumab; Compound 1 in Table 1 and certolizumab; Compound 1 in Table 1 and adalimumab; Compound 1 in Table 1 and R1antTNF Compound 1 from Table 1 and DMS5540; Compound 1 from Table 1 and TROS; Compound 1 from Table 1 and ATROSAB; Compound 1 from Table 1 and Humanin; Compound 1 from Table 1 and Humanin analog; Compound 1 from Table 1 and s14G-Humanin; Compound 1 from Table 1 and MTP101; Compound 1 from Table 1 and Elamipretide; Compound 1 from Table 1 and DNA; Compound 1 from Table 1 and RNA; Compound 1 from Table 1 and siRNA; Compound 1 and FAS-targeted siRNA; Compound 1 from Table 1 and FASsiRNA sense; Compound 1 from Table 1 and negative siRNA sense; Compound 1 from Table 1 and TNF-α-targeted siRNA; Compound 1 from Table 1 and NR58.3-14-3; Compound 1 from Table 1 and caspase 2; Compound 1 from Table 1 and caspase 3; Compound 1 from Table 1 and caspase 8; Compound 1 from Table 1 and caspase 9; Compound 2 from Table 1 and compound 3 from Table 1; Compound 2 from Table 1 and compound 4 from Table 1; Compound 2 from Table 1 and compound 5 from Table 1; Compound 2 from Table 1 and compound 6 from Table 1; Compound 2 from Table 1 and compound 7 from Table 1; Compound 2 from Table 1 and compound 8 from Table 1; Compound 2 from Table 1 and compound 9 from Table 1; Compound 2 from Table 1 and compound 10 from Table 1; Compound 2 from Table 1 and / or compound 11 from Table 1; Compound 2 from Table 1 and ONL1204; Compound 2 from Table 1 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO. 4); Compound 2 in Table 1 and FAIM; Compound 2 in Table 1 and NOL3; Compound 2 in Table 1 and DcR1; Compound 2 in Table 1 and DcR2; Compound 2 in Table 1 and DcR3; Compound 2 in Table 1 and etanercept; Compound 2 in Table 1 and infliximab; Compound 2 in Table 1 and golimumab; Compound 2 in Table 1 and certolizumab; Compound 2 in Table 1 and adalimumab; Compound 2 in Table 1 and R1an tTNF; Compound 2 in Table 1 and DMS5540; Compound 2 in Table 1 and TROS; Compound 2 in Table 1 and ATROSAB; Compound 2 in Table 1 and Humanin; Compound 2 in Table 1 and Humanin analog; Compound 2 in Table 1 and s14G-Humanin; Compound 2 in Table 1 and MTP101; Compound 2 in Table 1 and Elamipretide; Compound 2 in Table 1 and DNA; Compound 2 in Table 1 and RNA; Compound 2 in Table 1 and s iRNA; siRNA targeting compound 2 in Table 1 and FAS; compound 2 in Table 1 and FASsiRNA sense; compound 2 in Table 1 and negative siRNA sense; compound 2 in Table 1 and TNF-α targeted siRNA; compound 2 in Table 1 and NR58.3-14-3; compound 2 in Table 1 and caspase 2; compound 2 in Table 1 and caspase 3; compound 2 in Table 1 and caspase 8; compound 2 in Table 1 and caspase 9; compound 3 in Table 1 and compound 4 in Table 1; compound 3 in Table 1 and compound 5 in Table 1; compound 3 in Table 1 and compound 6 in Table 1; compound 3 in Table 1 and compound 7 in Table 1; compound 3 in Table 1 and compound 8 in Table 1; compound 3 in Table 1 and compound 9 in Table 1; compound 3 in Table 1 and compound 10 in Table 1; compound 3 in Table 1 and / or compound 11 in Table 1; compound 3 in Table 1 and ONL1204; compound 3 in Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO. 4); Compound 3 in Table 1 and FAIM; Compound 3 in Table 1 and NOL3; Compound 3 in Table 1 and DcR1; Compound 3 in Table 1 and DcR2; Compound 3 in Table 1 and DcR3; Compound 3 in Table 1 and etanercept Compound 3 from Table 1 and infliximab; Compound 3 from Table 1 and golimumab; Compound 3 from Table 1 and certolizumab; Compound 3 from Table 1 and adalimumab; Compound 3 from Table 1 and R1antTNF; Compound 3 from Table 1 and DMS5540; Compound 3 from Table 1 and TROS; Compound 3 from Table 1 and ATROSAB; Compound 3 from Table 1 and humanin; Compound 3 from Table 1 and humanin analog; Compound 3 from Table 1 and s14G-humanin; Compound 3 from Table 1 and MTP101; Compound 3 from Table 1 and ellamipretide; Compound 3 from Table 1 and DNA; Compound 3 from Table 1 and RNA; Compound 3 from Table 1 and siRNA; Compound 3 from Table 1 and siRNA targeting FAS; Compound 3 from Table 1 and FA SsiRNA sense; Compound 3 from Table 1 and negative siRNA sense; Compound 3 from Table 1 and TNF-α-targeted siRNA; Compound 3 from Table 1 and NR58.3-14-3; Compound 3 from Table 1 and caspase 2; Compound 3 from Table 1 and caspase 3; Compound 3 from Table 1 and caspase 8; Compound 3 from Table 1 and caspase 9; Compound 4 from Table 1 and compound 5 from Table 1; Compound 4 from Table 1 and compound 6 from Table 1; Compound 4 from Table 1 and compound 7 from Table 1; Compound 4 from Table 1 and compound 8 from Table 1; Compound 4 from Table 1 and compound 9 from Table 1; Compound 4 from Table 1 and compound 10 from Table 1; Compound 4 from Table 1 and / or compound 11 from Table 1; Compound 4 from Table 1 and ONL1204; Compound 4 from Table 1 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); Compound 4 in Table 1 and FAIM; Compound 4 in Table 1 and NOL3; Compound 4 in Table 1 and DcR1; Compound 4 in Table 1 and DcR2; Compound 4 in Table 1 and DcR3; Compound 4 in Table 1 and etanercept; Compound 4 in Table 1 and infliximab; Compound 4 in Table 1 and golimumab; Compound 4 in Table 1 and certolizumab; Compound 4 in Table 1 and adalimumab; Compound 4 in Table 1 and R1antTNF; Compound 4 in Table 1 and DMS5540; Compound 4 in Table 1 and TROS; Compound 4 in Table 1 and ATROSAB; Compound 4 in Table 1 and humanin; Compound 4 in Table 1 and humanin analog; Compound 4 in Table 1 and s14G-humanin; Compound 4 in Table 1 and MTP101; Compound 4 in Table 1 and ellamipretide; Compound 4 in Table 1 and DNA; Compounds in Table 1 Compound 4 and RNA; Compound 4 from Table 1 and siRNA; Compound 4 from Table 1 and FAS-targeted siRNA; Compound 4 from Table 1 and FASsiRNA sense; Compound 4 from Table 1 and negative siRNA sense; Compound 4 from Table 1 and TNF-α-targeted siRNA; Compound 4 from Table 1 and NR58.3-14-3; Compound 4 from Table 1 and caspase 2; Compound 4 from Table 1 and caspase 3; Compound 4 from Table 1 and caspase 8; Compound 4 from Table 1 and caspase 9; Compound 5 from Table 1 and Compound 6 from Table 1; Compound 5 from Table 1 and Compound 7 from Table 1; Compound 5 from Table 1 and Compound 8 from Table 1; Compound 5 from Table 1 and Compound 9 from Table 1; Compound 5 from Table 1 and Compound 10 from Table 1; Compound 5 from Table 1 and / or Compound 11 from Table 1; Compound 5 from Table 1 and ONL1204; Compound 5 from Table 1 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO. 4); Compound 5 in Table 1 and FAIM; Compound 5 in Table 1 and NOL3; Compound 5 in Table 1 and DcR1; Compound 5 in Table 1 and DcR2; Compound 5 in Table 1 and DcR3; Compound 5 in Table 1 and etanercept; Compound 5 in Table 1 and infliximab; Compound 5 in Table 1 and golimumab; Compound 5 in Table 1 and certolizumab; Compound 5 in Table 1 and adalimumab; Compound 5 in Table 1 and R1antTNF; Compound 5 in Table 1 and DMS5540; Compound 5 in Table 1 and TROS; Compound 5 in Table 1 and ATROSAB; Compound 5 in Table 1 and humanin; Compound 5 in Table 1 and humanin analog; Compound 5 in Table 1 and s14G-humanin; Compound 5 in Table 1 and MTP101; Compound 5 in Table 1 and ellamipretide; Compound 5 in Table 1 and D NA; Compound 5 from Table 1 and RNA; Compound 5 from Table 1 and siRNA; Compound 5 from Table 1 and FAS-targeted siRNA; Compound 5 from Table 1 and FASsiRNA sense; Compound 5 from Table 1 and negative siRNA sense; Compound 5 from Table 1 and TNF-α-targeted siRNA; Compound 5 from Table 1 and NR58.3-14-3; Compound 5 from Table 1 and caspase 2; Compound 5 from Table 1 and caspase 3; Compound 5 from Table 1 and caspase 8; Compound 5 from Table 1 and caspase 9; Compound 6 from Table 1 and compound 7 from Table 1; Compound 6 from Table 1 and compound 8 from Table 1; Compound 6 from Table 1 and compound 9 from Table 1; Compound 6 from Table 1 and compound 10 from Table 1; Compound 6 from Table 1 and / or compound 11 from Table 1; Compound 6 from Table 1 and ONL1204; Compound 6 from Table 1 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO. 4); Compound 6 in Table 1 and FAIM; Compound 6 in Table 1 and NOL3; Compound 6 in Table 1 and DcR1; Compound 6 in Table 1 and DcR2; Compound 6 in Table 1 and DcR3; Compound 6 in Table 1 and etanercept; Compound 6 in Table 1 and infliximab; Compound 6 in Table 1 and golimumab; Compound 6 in Table 1 and certolizumab; Compound 6 in Table 1 and adalimumab; Compound 6 in Table 1 and R1antTNF; Compound 6 in Table 1 and DMS5540; Compound 6 in Table 1 and TROS; Compound 6 in Table 1 and ATROSAB; Compound 6 in Table 1 and humanin; Compound 6 in Table 1 and humanin analog; Compound 6 in Table 1 and s14G-humanin; Compound 6 in Table 1 and MTP101; Compound 6 in Table 1 and ellamipretide; Table Compound 6 from Table 1 and DNA; Compound 6 from Table 1 and RNA; Compound 6 from Table 1 and siRNA; Compound 6 from Table 1 and FAS-targeted siRNA; Compound 6 from Table 1 and FASsiRNA sense; Compound 6 from Table 1 and negative siRNA sense; Compound 6 from Table 1 and TNF-α-targeted siRNA; Compound 6 from Table 1 and NR58.3-14-3; Compound 6 from Table 1 and caspase 2; Compound 6 from Table 1 and caspase 3; Compound 6 from Table 1 and caspase 8; Compound 6 from Table 1 and caspase 9; Compound 7 from Table 1 and Compound 8 from Table 1; Compound 7 from Table 1 and Compound 9 from Table 1; Compound 7 from Table 1 and Compound 10 from Table 1; Compound 7 from Table 1 and / or Compound 11 from Table 1; Compound 7 from Table 1 and ONL1204; Compound 7 from Table 1 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); Compound 7 in Table 1 and FAIM; Compound 7 in Table 1 and NOL3; Compound 7 in Table 1 and DcR1; Compound 7 in Table 1 and DcR2; Compound 7 in Table 1 and DcR3; Compound 7 in Table 1 and etanercept; Compound 7 in Table 1 and infliximab; Compound 7 in Table 1 and golimumab; Compound 7 in Table 1 and certolizumab; Compound 7 in Table 1 and adalimumab; Compound 7 in Table 1 and R1antTNF; Compound 7 in Table 1 and DMS5540; Compound 7 in Table 1 and TROS; Compound 7 in Table 1 and ATROSAB; Compound 7 in Table 1 and humanin; Compound 7 in Table 1 and humanin analog; Compound 7 in Table 1 and s14G-humanin; Compound 7 in Table 1 and MTP101; Compound 7 in Table 1 and E Lamipretide; Compound 7 from Table 1 and DNA; Compound 7 from Table 1 and RNA; Compound 7 from Table 1 and siRNA; Compound 7 from Table 1 and FAS-targeted siRNA; Compound 7 from Table 1 and FASsiRNA sense; Compound 7 from Table 1 and negative siRNA sense; Compound 7 from Table 1 and TNF-α-targeted siRNA; Compound 7 from Table 1 and NR58.3-14-3; Compound 7 from Table 1 and caspase 2; Compound 7 from Table 1 and caspase 3; Compound 7 from Table 1 and caspase 8; Compound 7 from Table 1 and caspase 9; Compound 8 from Table 1 and Compound 9 from Table 1; Compound 8 from Table 1 and Compound 10 from Table 1; Compound 8 from Table 1 and / or Compound 11 from Table 1; Compound 8 from Table 1 and ONL1204; Compound 8 from Table 1 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); Compound 8 in Table 1 and FAIM; Compound 8 in Table 1 and NOL3; Compound 8 in Table 1 and DcR1; Compound 8 in Table 1 and DcR2; Compound 8 in Table 1 and DcR3; Compound 8 in Table 1 and etanercept; Compound 8 in Table 1 and infliximab; Compound 8 in Table 1 and golimumab; Compound 8 in Table 1 and certolizumab; Compound 8 in Table 1 and adalimumab; Compound 8 in Table 1 and R1antTNF; Compound 8 in Table 1 and DMS5540; Compound 8 in Table 1 and TROS; Compound 8 in Table 1 and ATROSAB; Compound 8 in Table 1 and humanin; Compound 8 in Table 1 and humanin analog; Compound 8 in Table 1 and s14G-humanin; Compound 8 in Table 1 and MTP101; Table Compound 8 from Table 1 and ellamipretide; Compound 8 from Table 1 and DNA; Compound 8 from Table 1 and RNA; Compound 8 from Table 1 and siRNA; Compound 8 from Table 1 and FAS-targeted siRNA; Compound 8 from Table 1 and FASsiRNA sense; Compound 8 from Table 1 and negative siRNA sense; Compound 8 from Table 1 and TNF-α-targeted siRNA; Compound 8 from Table 1 and NR58.3-14-3; Compound 8 from Table 1 and caspase 2; Compound 8 from Table 1 and caspase 3; Compound 8 from Table 1 and caspase 8; Compound 8 from Table 1 and caspase 9; Compound 9 from Table 1 and Compound 10 from Table 1; Compound 9 from Table 1 and / or Compound 11 from Table 1; Compound 9 from Table 1 and ONL1204; Compound 9 from Table 1 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO. 4); Compound 9 in Table 1 and FAIM; Compound 9 in Table 1 and NOL3; Compound 9 in Table 1 and DcR1; Compound 9 in Table 1 and DcR2; Compound 9 in Table 1 and DcR3; Compound 9 in Table 1 and etanercept; Compound 9 in Table 1 and infliximab; Compound 9 in Table 1 and golimumab; Compound 9 in Table 1 and certolizumab; Compound 9 in Table 1 and adalimumab; Compound 9 in Table 1 and R1antTNF; Compound 9 in Table 1 and DMS5540; Compound 9 in Table 1 and TROS; Compound 9 in Table 1 and ATROSAB; Compound 9 in Table 1 and humanin; Compound 9 in Table 1 and humanin analog; Compound 9 in Table 1 and s14G-humanin; Compound 9 in Table 1 and M TP101; Compound 9 from Table 1 and ellamipretide; Compound 9 from Table 1 and DNA; Compound 9 from Table 1 and RNA; Compound 9 from Table 1 and siRNA; Compound 9 from Table 1 and FAS-targeted siRNA; Compound 9 from Table 1 and FASsiRNA sense; Compound 9 from Table 1 and negative siRNA sense; Compound 9 from Table 1 and TNF-α-targeted siRNA; Compound 9 from Table 1 and NR58.3-14-3; Compound 9 from Table 1 and caspase 2; Compound 9 from Table 1 and caspase 3; Compound 9 from Table 1 and caspase 8; Compound 9 from Table 1 and caspase 9; Compound 10 from Table 1 and / or Compound 11 from Table 1; Compound 10 from Table 1 and ONL1204; Compound 10 from Table 1 and H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO: 4); Compound 10 in Table 1 and FAIM; Compound 10 in Table 1 and NOL3; Compound 10 in Table 1 and DcR1; Compound 10 in Table 1 and DcR2; Compound 10 in Table 1 and DcR3; Compound 10 in Table 1 and etanercept; Compound 10 in Table 1 and infliximab; Compound 10 in Table 1 and golimumab; Compound 10 in Table 1 and certolizumab; Compound 10 in Table 1 and adalimumab; Compound 10 in Table 1 and R1antTNF; Compound 10 in Table 1 and DMS5540; Compound 10 in Table 1 and TROS; Compound 10 in Table 1 and ATROSAB; Compound 10 in Table 1 and humanin; Compound 10 in Table 1 and humanin analog; Compound 10 in Table 1 and s14G-Hu Manin; Compound 10 in Table 1 and MTP101; Compound 10 in Table 1 and ellamipreletide; Compound 10 in Table 1 and DNA; Compound 10 in Table 1 and RNA; Compound 10 in Table 1 and siRNA; Compound 10 in Table 1 and FAS-targeted siRNA; Compound 10 in Table 1 and FASsiRNA sense; Compound 10 in Table 1 and negative siRNA sense; Compound 10 in Table 1 and TNF-α-targeted siRNA; Compound 10 in Table 1 and NR58.3-14-3; Compound 10 in Table 1 and caspase 2; Compound 10 in Table 1 and caspase 3; Compound 10 in Table 1 and caspase 8; Compound 10 in Table 1 and caspase 9; Compound 11 in Table 1 and ONL1204; Compound 11 in Table 1 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO. 4); Compound 11 in Table 1 and FAIM; Compound 11 in Table 1 and NOL3; Compound 11 in Table 1 and DcR1; Compound 11 in Table 1 and DcR2; Compound 11 in Table 1 and DcR3; Compound 11 in Table 1 and etanercept; Compound 11 in Table 1 and infliximab; Compound 11 in Table 1 and golimumab; Compound 11 in Table 1 and certolizumab; Compound 11 in Table 1 and adalimumab; Compound 11 in Table 1 and R1antTNF; Compound 11 in Table 1 and DMS5540; Compound 11 in Table 1 and TROS; Compound 11 in Table 1 and ATROSAB; Compound 11 in Table 1 and humanin; Compound 11 in Table 1 and humanin analog; Compound 11 in Table 1 and s14G-humanin; Compound 11 in Table 1 and MTP101; Compound 11 in Table 1 and ellamipretide; Compound 11 in Table 1 and DNA; Compound 11 in Table 1 and RNA; Compound 1 in Table 1 Compound 1 and siRNA; Compound 11 from Table 1 and siRNA targeting FAS; Compound 11 from Table 1 and FASsiRNA sense; Compound 11 from Table 1 and negative siRNA sense; Compound 11 from Table 1 and siRNA targeting TNF-α; Compound 11 from Table 1 and NR58.3-14-3; Compound 11 from Table 1 and caspase 2; Compound 11 from Table 1 and caspase 3; Compound 11 from Table 1 and caspase 8; Compound 11 from Table 1 and caspase 9; ONL1204 and H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO. 4); ONL1204 and FAIM; ONL1204 and NOL3; ONL1204 and DcR1; ONL1204 and DcR2; ONL1204 and DcR3; ONL1204 and etanercept; ONL1204 and infliximab; ONL1204 and golimumab; ONL1204 and certolizumab; ONL1204 and adalimumab; ONL1204 and R1antTNF; ONL1204 and DMS5540; ONL1204 and TROS; ONL1204 and ATROSAB; ONL1204 and humanin; ONL1204 and humanin analog; ONL12 04 and s14G-humanin; ONL1204 and MTP101; ONL1204 and ellamipreletide; ONL1204 and DNA; ONL1204 and RNA; ONL1204 and siRNA; ONL1204 and FAS-targeted siRNA; ONL1204 and FASsiRNA sense; ONL1204 and negative siRNA sense; ONL1204 and TNF-α-targeted siRNA; ONL1204 and NR58.3-14-3; ONL1204 and caspase 2; ONL1204 and caspase 3; ONL1204 and caspase 8; ONL1204 and caspase 9; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and FAIM;H60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and NOL3; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and DcR1; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and DcR2; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and DcR3; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and etanercept; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and infliximab; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and golimumab; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and certolizumab; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and adalimumab; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and R1antTNF; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and DMS5540; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and TROS; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and ATROSAB; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and humanin; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and humanin analog; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and s14G-humanin; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and MTP101; H 60 HIYLGATNYIY71 -NH2 (SEQ ID NO: 4) and Elamipretide; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and DNA; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and RNA; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and siRNA; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and siRNA targeting FAS; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and FAS siRNA sense; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and negative siRNA sense; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and siRNA targeting TNF-α; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and NR58.3 - 14 - 3; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and caspase 2; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and caspase 3; H 60 HIYLGATNYIY 71 -NH2 (SEQ ID NO: 4) and caspase 8; H 60 HIYLGATNYIY 71-NH2 (SEQ ID NO. 4) and caspase 9; FAIM and NOL3; FAIM and DcR1; FAIM and DcR2; FAIM and DcR3; FAIM and etanercept; FAIM and infliximab; FAIM and golimumab; FAIM and certolizumab; FAIM and adalimumab; FAIM and R1antTNF; FAIM and DMS5540; FAIM and TROS; FAIM and ATROSAB; FAIM and humanin; FAIM and humanin analog; FAIM and s14G-humanin; FAIM and MTP101; FAIM and ellamipretide; FAIM and DNA; FAIM and RNA; FAIM and siRNA; FAIM and siRNA targeting FAS; FAIM and FASsiRNA sense; FAIM and negative siRNA sense; FAIM and siRNA targeting TNF-α; FAIM and NR58.3-14-3; FAIM and ca caspase 2; FAIM and caspase 3; FAIM and caspase 8; FAIM and caspase 9; NOL3 and DcR1; NOL3 and DcR2; NOL3 and DcR3; NOL3 and etanercept; NOL3 and infliximab; NOL3 and golimumab; NOL3 and certolizumab; NOL3 and adalimumab; NOL3 and R1antTNF; NOL3 and DMS5540; NOL3 and TROS; NOL3 and ATROSAB; NOL3 and humanin; NOL3 and humanin analog; NOL3 and s14G-humanin; NOL3 and MTP101; NOL3 and ellamipretide; NOL3 and DNA; NOL3 and RNA; NOL3 and siRNA; NOL3 and siRNA targeting FAS; NOL3 and FASsiRNA sense; NOL3 and negative siRNA sense; NOL3 and siRNA targeting TNF-α; NOL3 and NR58.3-14-3; NOL3 and caspase 2; NOL3 and caspase 3; NOL3 and caspase 8; NOL3 and caspase 9; DcR1 and DcR2; DcR1 and DcR3; DcR1 and etanercept; DcR1 and infliximab; DcR1 and golimumab; DcR1 and certolizumab; DcR1 and adalimumab; DcR1 and R1antTNF; DcR1 and DMS5540; DcR1 and TROS; DcR1 and ATRO SAB; DcR1 and humanin; DcR1 and humanin analog; DcR1 and s14G-humanin; DcR1 and MTP101; DcR1 and ellamipretide; DcR1 and DNA; DcR1 and RNA; DcR1 and siRNA; DcR1 and siRNA targeting FAS; DcR1 and FASsiRNA sense; DcR1 and negative siRNA sense; DcR1 and siRNA targeting TNF-α; DcR1 and NR58.3-14-3; DcR1 and caspase 2; DcR1 and caspase 3; DcR1 and caspase 8; DcR1 and caspase 9; DcR2 and DcR3; DcR2 and etanercept; DcR2 and infliximab; DcR2 and golimumab; DcR2 and certolizumab; DcR2 and adalimumab; DcR2 and R1antTNF; DcR2 and DMS5540; DcR2 and TROS; DcR2 and ATROSAB; D cR2 and humanin; DcR2 and humanin analog; DcR2 and s14G-humanin; DcR2 and MTP101; DcR2 and ellamipretide; DcR2 and DNA; DcR2 and RNA; DcR2 and siRNA; DcR2 and siRNA targeting FAS; DcR2 and FASsiRNA sense; DcR2 and negative siRNA sense; DcR2 and siRNA targeting TNF-α; DcR2 and NR58.3-14-3; DcR2 and caspase 2; DcR2 and caspase 3; DcR2 and caspase 8; DcR2 and caspase 9; DcR3 and etanercept; DcR3 and infliximab; DcR3 and golimumab; DcR3 and certolizumab; DcR3 and adalimumab; DcR3 and R1antTNF; DcR3 and DMS5540; DcR3 and TROS; DcR3 and ATROSAB; DcR3 and humanin; DcR3 and human Nin analogs; DcR3 and s14G-humanin; DcR3 and MTP101; DcR3 and ellamipretide; DcR3 and DNA; DcR3 and RNA; DcR3 and siRNA; DcR3 and FAS-targeted siRNA; DcR3 and FASsiRNA sense; DcR3 and negative siRNA sense; DcR3 and TNF-α-targeted siRNA; DcR3 and NR58.3-14-3; DcR3 and caspase 2; DcR3 and ca caspase 3; DcR3 and caspase 8; DcR3 and caspase 9; etanercept and infliximab; etanercept and golimumab; etanercept and certolizumab; etanercept and adalimumab; etanercept and R1antTNF; etanercept and DMS5540; etanercept and TROS; etanercept and ATROSAB; etanercept and humanin; etanercept and humanin analog; eta Nercept and s14G-humanin; etanercept and MTP101; etanercept and ellamipretide; etanercept and DNA; etanercept and RNA; etanercept and siRNA; etanercept and FAS-targeted siRNA; etanercept and FASsiRNA sense; etanercept and negative siRNA sense; etanercept and TNF-α-targeted siRNA; etanercept and NR58.3-14-3; Etanercept and caspase 2; Etanercept and caspase 3; Etanercept and caspase 8; Etanercept and caspase 9; Infliximab and golimumab; Infliximab and certolizumab; Infliximab and adalimumab; Infliximab and R1antTNF; Infliximab and DMS5540; Infliximab and TROS; Infliximab and ATROSAB; Infliximab and humanin; Infliximab and humanin analog; Infliximab and s14G-humanin; Infliximab and MTP101; Infliximab and ellamipretide; Infliximab and DNA; Infliximab and RNA; Infliximab and siRNA; Infliximab and FAS-targeted siRNA; Infliximab. Mab and FASsiRNA sense; Infliximab and negative siRNA sense; Infliximab and TNF-α-targeted siRNA; Infliximab and NR58.3-14-3; Infliximab and caspase 2; Infliximab and caspase 3; Infliximab and caspase 8; Infliximab and caspase 9; Golimumab and certolizumab; Golimumab and adalimumab; Golimumab and R1antTNF; Golimumab and DMS5540; Golimumab and TROS; Golimumab and ATROSAB; Golimumab and Humanin; Golimumab and Humanin analog; Golimumab and s14G-Humanin; Golimumab and MTP101; Golimumab and Elamipretide; Golimumab and DNA; Golimumab and RNA; Golimumab and siRNA; Golimumab and FAS-targeted siRNA; Golimumab and FASsiRNA sense; Golimumab and negative siRNA sense; Golimumab and TNF-α-targeted siRNA; Golimumab and NR58.3-14-3; Golimumab and caspase 2; Golimumab and caspase 3; Golimumab and caspase 8; Golimumab and caspase 9; Certolizumab and adalimumab; Certolizumab and R1antTNF; Certolizumab and DMS5540; Certolizumab and TROS; Certolizumab and ATROSAB; Certolizumab and Humanin; Certolizumab and Human Nin analogs; certolizumab and s14G-humanin; certolizumab and MTP101; certolizumab and ellamipretide; certolizumab and DNA; certolizumab and RNA; certolizumab and siRNA; certolizumab and FAS-targeted siRNA; certolizumab and FASsiRNA sense; certolizumab and negative siRNA sense; certolizumab and TNF-α-targeted siRNA; certolizumab and NR58.3-14-3; Certolizumab and caspase 2; Certolizumab and caspase 3; Certolizumab and caspase 8; Certolizumab and caspase 9; Adalimumab and R1antTNF; Adalimumab and DMS5540; Adalimumab and TROS; Adalimumab and ATROSAB; Adalimumab and humanin; Adalimumab and humanin analog; Adalimumab and s14G-Humanin Manin; adalimumab and MTP101; adalimumab and ellamipretide; adalimumab and DNA; adalimumab and RNA; adalimumab and siRNA; adalimumab and FAS-targeted siRNA; adalimumab and FASsiRNA sense; adalimumab and negative siRNA sense; adalimumab and TNF-α-targeted siRNA; adalimumab and NR58.3-14-3 Adalimumab and caspase 2; Adalimumab and caspase 3; Adalimumab and caspase 8; Adalimumab and caspase 9; R1antTNF and DMS5540; R1antTNF and TROS; R1antTNF and ATROSAB; R1antTNF and Humanin; R1antTNF and Humanin analog; R1antTNF and s14G-Humanin; R1antTNF and MTP101; R1antTNF and ellamipretide; R1antTNF and DNA; R1antTNF and RNA; R1antTNF and siRNA; R1antTNF and FAS-targeted siRNA; R1antTNF and FAS siRNA sense; R1antTNF and negative siRNA sense; R1antTNF and TNF-α-targeted siRNA; R1antTNF and NR58.3-14-3; R1antTNF and caspase 2; R1antTNF and caspase 3; R1antTNF and caspase 8; R1antTNF and caspase 9; DMS5540 and TROS; DMS5540 and ATROSAB; DMS5540 and humanin; DMS5540 and humanin analog; DMS5540 and s14G-humanin; DMS5540 and MTP101; DMS5540 and ellamipretide; DMS5540 and DNA; DMS5540 and RNA; DMS5540 and s iRNA; siRNA targeting DMS5540 and FAS; DMS5540 and FASsiRNA sense; DMS5540 and negative siRNA sense; DMS5540 and TNF-α targeted siRNA; DMS5540 and NR58.3-14-3; DMS5540 and caspase 2; DMS5540 and caspase 3; DMS5540 and caspase 8; DMS5540 and caspase 9; TROS and ATROSAB; TROS and humanin; TROS and humanin analog; TRO S and s14G-humanin; TROS and MTP101; TROS and ellamipretide; TROS and DNA; TROS and RNA; TROS and siRNA; TROS and siRNA targeting FAS; TROS and FASsiRNA sense; TROS and negative siRNA sense; TROS and siRNA targeting TNF-α; TROS and NR58.3-14-3; TROS and caspase 2; TROS and caspase 3; TROS and caspase 8; TROS and caspase 9; ATROSAB Humanin and ATROSAB; Humanin analogues and ATROSAB; s14G-humanin and ATROSAB; MTP101 and ATROSAB; Elamipretide and ATROSAB; DNA and ATROSAB; RNA and ATROSAB; siRNA and FAS-targeted siRNA and ATROSAB; FASsiRNA sense and ATROSAB; Negative siRNA sense and ATROSAB; TNF-α-targeted siRNA and ATROSAB; NR58.3-14-3; ATROSAB and caspase 2; ATROSAB and caspase 3; ATROSAB and caspase 8; ATROSAB and caspase 9; Humanin and humanin analog; Humanin and s14G-humanin; Humanin and MTP101; Humanin and ellamipretide; Humanin and DNA; Humanin and RNA; Humanin and siRNA; Humanin and FAS-targeted siRNA; Humanin and FASsiRNA sense Humanin and negative siRNA sense; Humanin and TNF-α-targeted siRNA; Humanin and NR58.3-14-3; Humanin and caspase 2; Humanin and caspase 3; Humanin and caspase 8; Humanin and caspase 9; Humanin analog and s14G-humanin; Humanin analog and MTP101; Humanin analog and ellamipretide; Humanin analog and DNA; Humanin analog and RNA; Hi Humanin analog and siRNA; Humanin analog and FAS-targeted siRNA; Humanin analog and FASsiRNA sense; Humanin analog and negative siRNA sense; Humanin analog and TNF-α-targeted siRNA; Humanin analog and NR58.3-14-3; Humanin analog and caspase 2; Humanin analog and caspase 3; Humanin analog and caspase 8; Humanin analog and caspase 9; s14G - Humanin and MTP101; s14G-humanin and ellamipretide; s14G-humanin and DNA; s14G-humanin and RNA; s14G-humanin and siRNA; s14G-humanin and siRNA targeting FAS; s14G-humanin and FASsiRNA sense; s14G-humanin and negative siRNA sense; s14G-humanin and siRNA targeting TNF-α; s14G-humanin and NR58.3-14-3; s14G-humanin and caspase 2; s14G-humanin and caspase 3; s14G-humanin and caspase 8; s14G-humanin and caspase 9; MTP101 and ellamipretide; MTP101 and DNA; MTP101 and RNA; MTP101 and siRNA; MTP101 and siRNA targeting FAS; MTP101 and FASsiRNA sense; MTP101 and negative siRNA sense; MTP101 and siRNA targeting TNF-α; MTP 101 and NR58.3-14-3; MTP101 and caspase 2; MTP101 and caspase 3; MTP101 and caspase 8; MTP101 and caspase 9; ellamipretide and DNA; ellamipretide and RNA; ellamipretide and siRNA; ellamipretide and FAS-targeted siRNA; ellamipretide and FASsiRNA sense; ellamipretide and negative siRNA sense; ellamipretide and TNF-α-targeted siRNA; ellamipretide and NR58.3-14-3; ellami Pretide and caspase 2; elamipretide and caspase 3; elamipretide and caspase 8; elamipretide and caspase 9; DNA and RNA; DNA and siRNA; DNA and FAS-targeted siRNA; DNA and FAS siRNA sense; DNA and negative siRNA sense; DNA and TNF-α-targeted siRNA; DNA and NR58.3-14-3; DNA and caspase 2; DNA and caspase 3; DNA and caspase 8; DNA and caspase 9; RNA and siRNA; RNA and FAS-targeted siRNA; RNA and FAS siRNA sense; RNA and negative siRNA sense; RNA and TNF-α-targeted siRNA; RNA and NR58.3-14-3; RNA and caspase 2; RNA and caspase 3; RNA and caspase 8; RNA and caspase 9; siRNA and FAS-targeted siRNA; siRNA and FAS siRNA sense; siRNA and negative siRNA sense; siRNA and TNF-α-targeted siRNA; siRNA and NR58.3-14-3; siRNA and caspase 2; siRNA and caspase 3; siRNA and caspase 8; siRNA and caspase 9; FAS-targeted siRNA and FASsiRNA sense; FAS-targeted siRNA and negative siRNA sense; FAS-targeted siRNA and TNF-α-targeted siRNA; FAS-targeted siRNA and NR58.3-14-3; FAS-targeted siRNA and caspase 2; FAS-targeted siRNA and caspase 3; FAS-targeted siRNA and caspase 8; FAS-targeted siRNA and caspase 9; FASsiRNA sense and negative siRNA sense; FASsiRNA sense and TNF-α-targeted siRNA; FASsiRNA sense and NR58.3-14-3; FASsiRNA sense and caspase 2; FASsiRNA sense and caspase 3; FASsiRNA sense and caspase 8; FASsiRNA sense and caspase 9; negative siRNA sense and TNF-α-targeted siRNA; Negative siRNA sense and NR58.3-14-3; Negative siRNA sense and caspase 2; Negative siRNA sense and caspase 3; Negative siRNA sense and caspase 8; Negative siRNA sense and caspase 9; TNF-α-targeted siRNA and NR58.3-14-3; TNF-α-targeted siRNA and caspase 2; TNF-α-targeted siRNA and caspase 3; TNF-α-targeted siRNA and caspase 8; T This includes NF-α-targeted siRNA and caspase 9; NR58.3-14-3 and caspase 2; NR58.3-14-3 and caspase 3; NR58.3-14-3 and caspase 8; NR58.3-14-3 and caspase 9; caspase 2 and caspase 3; caspase 2 and caspase 8; caspase 2 and caspase 9; caspase 3 and caspase 8; caspase 3 and caspase 9; caspase 8 and caspase 9; or MET12 (SEQ ID NO: 3) and one of peptide 6 (SEQ ID NO: 1).

[0037] With respect to any related structural representation such as Formula 1, I, 2, D, E, or F, Neu-H is a neuronutrient such as the neuronutrient described above.

[0038] With respect to any related structural representation such as Formula 1, A, G, H, J, or K, FAS-H is a FAS / FASL inhibitor, such as the FAS / FASL inhibitors mentioned above.

[0039] With respect to any relevant structural representation of formula I, B, G, M, N, or O, TNF-H is a TNF-α / TNFR inhibitor, such as the TNF-α / TNFR inhibitors mentioned above.

[0040] In formula 2, with respect to any related structural representation such as H, M, P, Q, or R, Mit-H is a mitochondrial peptide, such as the mitochondrial peptide mentioned above.

[0041] With respect to any related structural representation of formulas A, B, D, P, S, or T, Nuc-H is an oligonucleotide such as the oligonucleotides mentioned above.

[0042] With respect to any related structural representation of formulas such as E, J, N, Q, S, or U, CK-H is a chemokine inhibitor, such as the chemokine inhibitors mentioned above.

[0043] Regarding the representation of the relevant structure such as formula F, K, O, R, T, or U, CAS-H is a cysteine-aspartate protease inhibitor, such as the cysteine-aspartate protease described above.

[0044] With respect to any related structural representation containing L, such as 1, I, 2, 3, 4, 5, 6, 7, A, B, C, C1, D, E, F, G, H, J, K, M, N, O, P, Q, R, S, T, U, II, IID, 3D, 4D, 5D, 6D, or 7D (formulas C, II, IID, 3-7 and 3D-7D are shown below), L is empirically represented as C a H b O c N d or C a H b O c This is a linking group represented by .

[0045] For any L, a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, a is 1-5, 5-10, 10-15, 15-20, 1-10, or 10-20.

[0046] For any L, b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43. In some embodiments, b is 1-10, 10-20, 20-30, 30-40, 40-43, 1-15, 15-30, or 30-43.

[0047] For any L, c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, c is 0-2, 2-4, 4-6, 6-8, 8-10, 0-3, 3-6, or 6-10.

[0048] For any L, d is 0, 1, or 2. In some embodiments, d is 0. In some embodiments, d is 1. In some embodiments, d is 2.

[0049] In some embodiments, L is formula L-1, L-2, L-3, L-4, L-5, L-6, L-7, or L-8: [ka] [ka] It can be represented as follows.

[0050] With respect to any related structural representation of formulas L-1, L-2, L-3, L-4, L-5, L-6, L-7, or L-8, L 1 This is empirical formula C e H f O g N hor C e H f O g It can be represented as follows.

[0051] Any L 1 With respect to e, e is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18. In some embodiments, e is 1-5, 5-10, 10-15, 15-20, 1-10, or 10-18.

[0052] Any L 1 With respect to f, f is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, or 38. In some embodiments, f is 1-10, 10-20, 20-30, 30-38, 1-15, 15-30, or 30-38.

[0053] Any L 1 With respect to g, g is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, g is 0-2, 2-4, 4-6, 6-8, 0-3, 3-6, or 6-8.

[0054] Any L 1 With respect to this, h is 0, 1, or 2. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, h is 2.

[0055] With respect to any related structural representation of formulas L-1, L-2, L-3, L-4, L-5, L-6, L-7, or L-8, in some embodiments, L 1 teeth, -(CH2) i -(OCH2CH2) j -O-(CH2) k - [Formula L 1 -1], -(CH2) i -(OCH2CH2) j-O-CONH-(CH2) k - [Formula L 1 -2], -(C i H 2i )-(OCH2CH2) j -O-(C k H 2k )- [formula L 1 -3], or -( C i H 2i )-(OCH2CH2) j -O-CONH-(C k H 2k )- [formula L 1 -4] That's fine.

[0056] formula L 1 -1, L 1 -2, L 1 -3, or L 1 For any related structural representation such as -4, i is 0, 1, 2, 3, or 4.

[0057] formula L 1 -1, L 1 -2, L 1 -3, or L 1 For any related structural representation such as -4, j is 0, 1, 2, 3, 4, or 5.

[0058] With respect to any related structural representation such as formulas L1-1, L1-2, L1-3, or L1-4, k is 0, 1, 2, 3, or 4.

[0059] A sustained-delivery component is part of a drug delivery system that allows a drug to remain in the body for a sustained period, for example, longer than the time it takes for the drug to be metabolized or eliminated from the body. Typically, a sustained-delivery component is a graft, such as a solid graft, that functions by encapsulating or otherwise capturing the drug within the graft. If the graft is biodegradable or bioerosive, the drug may be released as the graft biodegrades or erodes. The graft may also be porous to allow the drug to diffuse from the graft over a period of time. Biodegradable or bioerosive grafts may be porous or non-porous. Typically, non-biodegradable or non-bierosive grafts are porous, and the drug is released by diffusion. However, other mechanisms, such as osmotic pumps, may also be at work.

[0060] The drug may be physically captured by the sustained delivery component and / or covalently bonded to a molecule that is part of the sustained delivery component.

[0061] Typical examples of biodegradable materials for porous or non-porous biodegradable grafts generally include silica-based materials and organic biodegradable materials such as polymers containing poly(D,L-lactic acid) (PLA) and poly(D,L-glycolic acid copolymer) (PLGA), polyesteramide (PEA, DSM Chemical), and polycaprolactone (PCL); hydrogels such as polyvinyl alcohol (PVA), PEGamine, and PEG-N-hydroxysuccinate ester (Ocular Therapeutix, etc.); collagen-based materials (Euclid Systems); or combinations thereof.

[0062] There are many suitable silica-based sustained-delivery components available.

[0063] One type of silica-based sustained delivery component involves a silica hydrogel complex obtained by mixing silica particles containing encapsulated drugs with a silica sol, the resulting hydrogel complex being shear-thinning. This type of delivery system is an injectable, all-silica-based microparticle-silica hydrogel controlled-release system that significantly reduces bursts of different types of encapsulated therapeutic and bioactive drugs. A detailed description of this type of silica-based sustained delivery component and its manufacturing method can be found in U.S. Patent No. 9,949,922 by Jokinen et al., issued April 24, 2018, the entire contents of which are incorporated herein by reference.

[0064] Another type of silica-based sustained delivery component includes drug-containing fluid silica and gel compositions obtained by a method for producing a fluid silica composition involving a sol-gel transition in which redispersion occurs. The redispersion involves adding a liquid to the gel formed by the sol-gel transition after it has reached its gel point, with this addition occurring within a sufficiently short time after the gel point is reached, and after mixing the gel and liquid, a viscoelastically homogeneous fluid silica composition is available that remains injectable, either directly through a fine 22G needle or after a short stirring time of less than 30 seconds. Fluid and injectable sustained delivery silica compositions can enhance the stability and maintain the activity of encapsulated therapeutic agents. A detailed description of this type of silica-based sustained delivery component and a method for producing the same can be found in U.S. Patent Application No. 20140057996 by Jokinen et al., published February 27, 2014, which is incorporated herein by reference in its entirety.

[0065] Another type of silica-based sustained delivery component includes compositions comprising a bio-erosive, porous silicon-based carrier material that delivers a drug and at least one amorphous sugar, optionally further comprising a crystallization inhibitor. These delivery systems involve loading biomolecules into the pores of the silica carrier material, thereby stabilizing the biomolecules. However, these systems may also be used for small molecule therapeutic compounds. A detailed description of this type of silica-based sustained delivery component and methods for producing the same can be found in U.S. Patent No. 9,603,801 by Barnett et al., issued March 28, 2017, which is incorporated herein by reference in its entirety.

[0066] Another type of silica-based sustained delivery component includes bio-erosive devices, such as grafts, for controlled delivery of drugs. These devices include porous silicon-based carrier materials impregnated with or loaded with the drug. These particular silicon carrier materials contain at least one large molecule therapeutic agent positioned within the pores of the carrier material. It is believed that the large molecule is stabilized by loading it into the pores of the carrier material. In many embodiments, this large molecule is a protein, with pores having an average size of approximately 15 nm to 40 nm, and the protein having a molecular weight of approximately 100,000 amu to 200,000 amu. Detailed descriptions of this type of silica-based sustained delivery component and methods for producing the same can be found in U.S. Patent No. 9,808,421, issued November 7, 2017; U.S. Patent No. 9,333,173, issued May 10, 2016; and U.S. Patent Publication No. 20140271764, published September 28, 2014, all of which are incorporated herein by reference.

[0067] The sustained-delivery component is available in doses of approximately 10 μg to 100 mg, 10 to 20 μg, 20 to 30 μg, 30 to 40 μg, 40 to 50 μg, 50 to 60 μg, 60 to 70 μg, 70 to 80 μg, 80 to 90 μg, 90 to 100 μg, 100 to 200 μg, 200 to 300 μg, 300 to 400 μg, 400 to 500 μg, 500 to 600 μg, 600 to 700 μg, 700 to 800 μg, 800 to 900 μg, and 90 0-1,000 μg, approx. 1-2 mg, approx. 2-3 mg, approx. 3-4 mg, approx. 4-5 mg, approx. 5-6 mg, approx. 6-7 mg, approx. 7-8 mg, approx. 8-9 mg, approx. 9-10 mg, approx. 10-20 mg, approx. 20-30 mg, approx. 30-40 mg, approx. 40-50 mg, approx. 50-60 mg, approx. 60-70 mg, approx. 70-80 mg, approx. 80-90 mg, approx. 90-100 mg, approx. 100-200 mg, approx. 200-300 mg, approx. 300-400 mg, approx. 400- 500mg, about 500-600mg, about 600-700mg, about 700-800mg, about 800-900mg, about 900-1,000mg, about 1-2g, about 2-3g, about 3-4g, about 4-5g, about 5-6g, about 6-7 g, about 7-8g, about 8-9g, about 9-10g, about 10-20g, about 20-30g, about 30-40g, about 40-50g, about 50-60g, about 60-70g, about 70-80g, about 80-90g, about 90-100g, about 10 It can have any appropriate mass, such as 0-200g, approximately 200-300g, approximately 300-400g, approximately 400-500g, approximately 500-600g, approximately 600-700g, approximately 700-800g, approximately 800-900g, approximately 900-1,000g, approximately 10-100μg, approximately 100-1,000μg, approximately 1-10mg, approximately 10-100mg, approximately 100-1,000mg, approximately 1-10g, approximately 10-100g, or approximately 100-1,000g. The above range of approximately 1g or less, or approximately 100mg or less, may be of interest for drug delivery systems delivered onto or into the eyeball.

[0068] The sustained delivery component may be any appropriate percentage of the graft, such as approximately 1-99% by weight, approximately 1-10% by weight, approximately 10-20% by weight, approximately 20-30% by weight, approximately 30-40% by weight, approximately 40-50% by weight, approximately 50-60% by weight, approximately 60-70% by weight, approximately 70-80% by weight, approximately 80-90% by weight, approximately 90-99% by weight, approximately 1-30% by weight, approximately 30-65% by weight, approximately 65-99% by weight, approximately 1-50% by weight, or approximately 50-99% by weight.

[0069] The drug delivery system is available in doses of approximately 10 μg to 100 mg, 10 to 20 μg, 20 to 30 μg, 30 to 40 μg, 40 to 50 μg, 50 to 60 μg, 60 to 70 μg, 70 to 80 μg, 80 to 90 μg, 90 to 100 μg, 100 to 200 μg, 200 to 300 μg, 300 to 400 μg, 400 to 500 μg, 500 to 600 μg, 600 to 700 μg, 700 to 800 μg, 800 to 900 μg, and approximately 900-1,000 μg, approx. 1-2 mg, approx. 2-3 mg, approx. 3-4 mg, approx. 4-5 mg, approx. 5-6 mg, approx. 6-7 mg, approx. 7-8 mg, approx. 8-9 mg, approx. 9-10 mg, approx. 10-20 mg, approx. 20-30 mg, approx. 30-40 mg, approx. 40-50 mg, approx. 50-60 mg, approx. 60-70 mg, approx. 70-80 mg, approx. 80-90 mg, approx. 90-100 mg, approx. 100-200 mg, approx. 200-300 mg, approx. 300-400 mg, approx. 40 0~500mg, approx. 500~600mg, approx. 600~700mg, approx. 700~800mg, approx. 800~900mg, approx. 900~1,000mg, approx. 1~2g, approx. 2~3g, approx. 3~4g, approx. 4~5g, approx. 5~6g, approx. 6 ~7g, approximately 7~8g, approximately 8~9g, approximately 9~10g, approximately 10~20g, approximately 20~30g, approximately 30~40g, approximately 40~50g, approximately 50~60g, approximately 60~70g, approximately 70~80g, approximately 80~90g, approximately 90~100g, approx. Any appropriate size may be 100-200g, approximately 200-300g, approximately 300-400g, approximately 400-500g, approximately 500-600g, approximately 600-700g, approximately 700-800g, approximately 800-900g, approximately 900-1,000g, approximately 10-100μg, approximately 100-1,000μg, approximately 1-10mg, approximately 10-100mg, approximately 100-1,000mg, approximately 1-10g, approximately 10-100g, or approximately 100-1,000g. The above range of approximately 1g or less, or approximately 100mg or less, may be of interest to drug delivery systems delivered onto or into the eyeball.

[0070] Typical examples of non-biodegradable or non-biodegradable materials for grafts include silicone or PVA (Psivida, et al.) as a semipermeable membrane.

[0071] Other possible sustained-delivery components may be based on cell-based approaches such as encapsulated cell technology; and reservoir-type approaches (forsight4; Replenish).

[0072] Neurotrophic agents, FAS / FASL inhibitors, TNF-α / TNFR inhibitors, and / or mitochondrial peptides may or may not be covalently bound to the sustained delivery component.

[0073] In some embodiments, the neuronutrient is covalently bound to the sustained-delivery component. In some embodiments, the neuronutrient is not covalently bound to the sustained-delivery component.

[0074] In some embodiments, the FAS / FASL inhibitor is covalently bound to the sustained delivery component. In some embodiments, the FAS / FASL inhibitor is not covalently bound to the sustained delivery component.

[0075] In some embodiments, the TNF-α / TNFR inhibitor is covalently bound to the sustained delivery component. In some embodiments, the TNF-α / TNFR inhibitor is not covalently bound to the sustained delivery component.

[0076] In some embodiments, the mitochondrial peptide is covalently bonded to the sustained delivery component. In some embodiments, the mitochondrial peptide is not covalently bonded to the sustained delivery component.

[0077] In some embodiments, the oligonucleotide is covalently bonded to the sustained delivery component. In some embodiments, the oligonucleotide is not covalently bonded to the sustained delivery component.

[0078] For example, neuronutrient solutions are formula [ka] The compound represented by may be covalently bonded to the sustained delivery component, and Neu-H is a neuronutrient such as the neuronutrient described above.

[0079] Oligonucleotides are, [ka] The sustained delivery component may be covalently bonded to a compound represented by the formula, and Nuc-H is an oligonucleotide such as the aforementioned oligonucleotide.

[0080] FAS / FASL inhibitors are formulated as follows: [ka] The sustained delivery component may be covalently bonded to a compound represented by , and FAS-H is a FAS / FASL inhibitor such as the FAS / FASL inhibitors mentioned above.

[0081] TNF-α / TNFR inhibitors are formulated as follows: [ka] The sustained delivery component may be covalently bonded to a compound represented by , and TNF-H is a TNF-α / TNFR inhibitor such as the TNF-α / TNFR inhibitors mentioned above.

[0082] Mitochondrial peptides are, [ka] The sustained delivery component may be covalently bonded to a compound represented by , where Mit-H is a mitochondrial peptide such as the mitochondrial peptide mentioned above.

[0083] Chemokine inhibitors are formulated as follows: [ka] The compound represented by may be covalently bonded to the sustained delivery component, and CK-H is a chemokine inhibitor such as the chemokine inhibitors mentioned above.

[0084] Cysteine-aspartate protease is, [ka] The sustained delivery component may be covalently bonded to a compound represented by , and CAS-H is a cysteine-aspartate protease such as the cysteine-aspartate protease mentioned above.

[0085] With respect to any related structural representation of formulas C, 3, 4, II, 5, 6, or 7, R 1 These are independently H, or C such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl. 1ー6 It is alkyl.

[0086] With respect to any related structural representation of formulas C, 3, 4, II, 5, 6, or 7, R 2 These are independently H, or C such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl. 1ー6 It is alkyl.

[0087] Regarding the representation of any related structure of formulas C, 3, 4, II, 5, 6, or 7, or the following compounds, R 3 These are independently H, or C such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl. 1ー6 It is alkyl.

[0088] Examples of compounds of formula 3 are VGDGGLFEKKL-PEG-Si(OH)3 (where "VGDGGLFEKKL" is disclosed as Sequence ID No. 1) or VGDGGLFEKKL-PEG-SiOR 1 Ure 2 Ure 3 ("VGDGGLFEKKL" is disclosed as Sequence ID No. 1), and PEG is a polyethylene glycol chain (e.g., -(OCH2CH2) n - where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.). In the body, the ester bond can be hydrolyzed to release VGDGGLFEKKL (SEQ ID NO: 1).

[0089] Formula C, or SiOR of 3-5 1 Ure 2 Ure 3 The group can covalently bond with silica in silica-based drug delivery systems to form compounds represented, for example, by formula C1, 3D, 4D, or 5D, where D is SiOR of formula C, 3, 4, 5, 6, or 7. 1 Ure 2 Ure 3 It is a sustained-delivery component containing Si.

[0090] [ka]

[0091] The drug delivery system may optionally further contain antioxidants such as ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, potassium pyrosulfite, propyl gallate, sodium pyrosulfite, sodium thiosulfate, vitamin E, 3,4-dihydroxybenzoic acid, and cysteine.

[0092] For some therapies, drug delivery systems may be infused at reduced temperatures, such as approximately -7°C to 17°C, approximately -7°C to 0°C, approximately 0°C to 5°C, approximately 5°C to 10°C, and approximately 10°C to 17°C, to improve the performance of the drug delivery system. For example, this may provide greater sustained drug delivery, greater consistency in drug levels (concentration), and improved efficacy.

[0093] A drug delivery system comprising neurotrophic agents, FAS / FASL inhibitors, TNF-α / TNFR inhibitors, mitochondrial peptides, oligonucleotides, chemokine inhibitors, or cysteine-aspartate proteases, and any sustained-delivery components (hereinafter referred to as the “Subject Drug Delivery System”) can be administered to mammals such as humans by appropriate methods such as injection into a part of the body or surgical procedure, oral administration, or topical application to the eye or skin. In some embodiments, the Subject Drug Delivery System is injected into or implanted within the eye, including the anterior chamber, posterior chamber, subconjunctival space, or sub-Tenon's space. In some embodiments, the Subject Drug Delivery System may be injected subcutaneously or directly into the heart, brain, or tissues within or surrounding the cochlea, into vascular structures such as coronary or cerebral arteries, or into cerebrospinal fluid (CSF), or into a reservoir communicating with CSF or the vitreous humor.

[0094] In some embodiments, the subject drug delivery system may be injected directly into the heart, injected or implanted into an artery (coronary artery), or delivered to the site of myocardial infarction via a catheter.

[0095] In some embodiments, the drug delivery system of the subject may be injected directly into the brain, injected or implanted intraarterially (typically into the carotid, cerebral, or vertebral arteries), or delivered to the site of infarction (stroke) via a catheter.

[0096] The catheter used to deliver the subject drug delivery system may be combined with a device used to perform mechanical embolization / thrombectomy or stent placement.

[0097] The drug delivery system of the subject may be administered, for example, as a bolus after embolus removal / thrombectomy or stent placement, or by continuous injection into the area of ​​interest over a period of 0.1 minutes to 30 days, 0.1 to 10 minutes, 10 to 20 minutes, 20 to 40 minutes, 40 to 60 minutes, 1 to 2 hours, 2 to 3 hours, 3 to 4 hours, 4 to 5 hours, 5 to 6 hours, 6 to 8 hours, 8 to 10 hours, 10 to 12 hours, 12 to 18 hours, 18 to 24 hours, 1 to 2 days, 2 to 3 days, 3 to 4 days, 4 to 5 days, 5 to 6 days, 6 to 7 days, 1 to 2 weeks, 2 to 3 weeks, or approximately 3 to 4 weeks.

[0098] The drug delivery system of the subject can extend the time that the drug remains in the body. For example, the drug delivery system can deliver therapeutic concentrations of the drug for at least approximately 2 weeks, at least approximately 4 weeks, at least approximately 6 weeks, at least approximately 8 weeks, at least approximately 3 months, at least approximately 4 months, at least approximately 5 months, at least approximately 6 months, at least approximately 7 months, at least approximately 8 months, at least approximately 9 months, at least approximately 10 months, at least approximately 11 months, at least approximately 1 year, at least approximately 1.5 years, at least approximately 2 years, at least approximately 3 years, at least approximately 4 years, approximately 1 to 6 months, approximately 6 to 12 months, approximately 12 to 18 months, approximately 18 to 24 months, approximately 24 to 36 months, up to approximately 2 years, up to approximately 3 years, up to approximately 4 years, up to approximately 5 years, or up to approximately 10 years. The drug delivery system may be injected, implanted, or modified within any of the above timeframes.

[0099] In some embodiments, the drug delivery system for the subject is used for age-related macular degeneration, retinal artery occlusion, retinal vein occlusion, retinal detachment, central serous retinopathy, chorioretinopathy, diabetic retinopathy, macular telangiectasia, familial exudative vitreoretinopathy, retinopathy of prematurity, vitreomacular traction, macular hole / packer, ocular injury, pathological myopia, uveitis (creeping choroidopathy, sympathetic ophthalmitis, birdshot choroidopathy, acute multiple macular pigment epitheliopathy (AMPPE), Behçet's disease, sarcoidosis, and Vogt's disease. It may be administered to mammals such as humans to treat conditions or diseases affecting the choroid or retina, such as Koyanagi-Harada syndrome (VKH), oculocutaneous albinism, retinitis pigmentosa (RP), total choroidal atrophy, Leber congenital amaurosis (LCA), Usher syndrome, Stargardt disease, juvenile X-linked retinoschisis, Leber hereditary optic nerve atrophy, Best's disease, color blindness, cone-rod dystrophy, gynostosis, juvenile macular degeneration, Kearns-Sayre syndrome, or combinations thereof.

[0100] In some embodiments, the subject composition may be administered to mammals such as humans to treat conditions or diseases affecting the optic nerve, such as glaucoma (primary open-angle glaucoma (POAG), acute primary angle-closure glaucoma (APACG), chronic angle-closure glaucoma, pigmentary glaucoma, pseudoexfoliation glaucoma, normal-tension glaucoma, pediatric glaucoma, and secondary glaucoma), ischemic optic neuropathy, optic neuritis / neuromyelitis optica, Leber hereditary optic nerve atrophy, optic nerve atrophy, optic nerve edema, increased intracranial pressure (pseudobrain tumor), or combinations thereof.

[0101] In some embodiments, the subject drug delivery system may be administered to or implanted in mammals such as humans to treat ear disorders including Meniere's disease, sensorineural hearing loss including ototoxic hearing loss, ototoxic hearing loss, or hearing loss caused by ototoxicity, immunological hearing loss, hereditary / congenital hearing loss (including Usher, Alport, and Waadenburg), noise-related hearing loss, or hearing loss caused by noise, age-related hearing loss, traumatic hearing loss, vascular collapse-related hearing loss, or hearing loss caused by vascular collapse, infection-related hearing loss, or hearing loss caused by infection, etc., or combinations thereof.

[0102] In some embodiments, the drug delivery system of the subject is used for Alzheimer's disease / dementia, anoxia, stroke, Friedreich's ataxia, telangiectasia ataxia, Asperger's syndrome (autism), intracranial hypertension (pseudotumor), traumatic brain injury, concussion, diabetic nephropathy, dystonia, essential tremor, epilepsy, Riley-Day syndrome, ganglioside storage, giant cell arteritis, Guillain-Barré syndrome, Huntington's disease, Refsum disease, Kearns-Sayre syndrome, and It may be administered to or transplanted into mammals such as humans to treat central nervous system (CNS) disorders such as other mitochondrial myopathy including Leber optic neuropathy, amyotrophic lateral sclerosis, multiple system atrophy, myasthenia gravis, neurological complications of AIDS, neuromyelitis optica (Devic's disease), autoimmune encephalitis / myelitis, olivopontocerebellar atrophy, Parkinson's disease, peripheral neuropathy, Pompe disease, shaken baby syndrome, Tay-Sachs disease, Wallenberg syndrome, vasculitis, or combinations thereof.

[0103] Example 1: Solid-phase synthesis of peptide 6-L-MET12 characterized by amide bonds Using methods known in the art, peptide 6 is linked to the resin at its NH2 terminus, protected with a BOC group and a t-Bu ester group, and linked to the NH2 terminus-PEG at its carboxylic acid terminus, resulting in the resin-LK(Boc)-K(Boc)-E(tBu)-FLGGD(tBu)-GV-CO2(CH2-CH2-O) n-CH2-CH2-NH2 is provided. The properties of the starting materials and the order of the reactions may be changed to improve efficiency and selectivity, and all reactions are carried out using methods known in the art. MET12 is also protected. The free amine of the protected peptide 6 compound and the free acid of protected MET12 can be coupled by any suitable peptide coupling method known in the art. After the coupling reaction, the protected amide can be completely deprotected using TFA or other acid-catalyzed methods known in the art to release the peptide 6-L-MET12 amide derivative. As known in the art, different orthogonal protecting strategies may be employed as needed to optimize the efficiency of the entire procedure.

[0104] Example 2: Solid-phase synthesis of peptide 6-L-MET12 characterized by ester bonds Using methods known in the art, peptide 6 is linked to the resin at its NH2 terminus, protected with a CBz group over the free amine group and a benzyl group over the free acid group, and bonded to polyethylene glycol at its carboxylic acid terminus, forming the resin-LK(Cbz)-K(Cbz)-E(Bn)-FLGGD(Bn)-GV-CO2(CH2-CH2-O) n -CH2-CH2-OH is provided. To improve selectivity, the properties of the starting materials and the order of the reactions may be changed, and all reactions are carried out using methods known in the art. MET12 is also protected. The free alcohol terminus of the protected peptide 6 compound and the free acid of protected MET12 can be coupled by any suitable ester coupling method known in the art. After the coupling reaction, the protected ester can be completely deprotected using hydrogenation or other debenzylation methods known in the art to release the peptide 6-L-MET12 ester derivative. As known in the art, different orthogonal protecting strategies may be employed as needed to optimize the efficiency of the overall procedure.

[0105] The following embodiments are those that the inventor particularly anticipates.

[0106] Embodiment 1. A drug delivery system comprising neurotrophic agents, FAS / FASL inhibitors, TNF-α / TNFR inhibitors, mitochondrial peptides, chemokine inhibitors, or cysteine-aspartate proteases, and any sustained-delivery component.

[0107] Embodiment 2. A drug delivery system according to Embodiment 1, comprising a neuronutrient.

[0108] Embodiment 3. A drug delivery system according to Embodiment 1, comprising a FAS / FASL inhibitor.

[0109] Embodiment 4. A drug delivery system according to Embodiment 1, comprising a TNF-α / TNFR inhibitor.

[0110] Embodiment 5. A drug delivery system according to Embodiment 1, comprising a mitochondrial peptide.

[0111] Embodiment 6. A drug delivery system according to Embodiment 1, comprising both a neurotrophic agent and a FAS / FASL inhibitor.

[0112] Embodiment 7. The drug delivery system according to Embodiment 6, wherein the neurotrophic agent and the FAS / FASL inhibitor are covalently bonded to each other.

[0113] Embodiment 8. The drug delivery system according to Embodiment 7, wherein the neurotrophic agent and the FAS / FASL inhibitor are covalently bonded to each other via a binding group.

[0114] Embodiment 9. A drug delivery system according to Embodiment 1, comprising both a neurotrophic agent and a TNF-α / TNFR inhibitor.

[0115] Embodiment 10. The drug delivery system according to Embodiment 9, wherein the neurotrophic agent and the TNF-α / TNFR inhibitor are covalently bound to each other.

[0116] Embodiment 11. The drug delivery system according to Embodiment 10, wherein the neurotrophic agent and the TNF-α / TNFR inhibitor are covalently bonded to each other via a binding group.

[0117] Embodiment 12. A drug delivery system according to Embodiment 1, comprising both a neurotrophic agent and a mitochondrial peptide.

[0118] Embodiment 13. The drug delivery system according to Embodiment 12, wherein the neurotrophic agent and the mitochondrial peptide are covalently bonded to each other.

[0119] Embodiment 14. The drug delivery system according to Embodiment 13, wherein the neurotrophic agent and the mitochondrial peptide are covalently bonded to each other via a binding group.

[0120] Embodiment 15. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, wherein the neurotrophic agent contains CNTF peptide.

[0121] Embodiment 16. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the neuronutrient contains peptide 6.

[0122] Embodiment 17. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, wherein the neuronutrient contains peptide 21.

[0123] Embodiment 18. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the neuronutrient contains recombinant CNTF.

[0124] Embodiment 19. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein the neuronutrient contains BDNF.

[0125] Embodiment 20. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein the neuronutrient contains GDNF.

[0126] Embodiment 21. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, wherein the FAS / FASL inhibitor includes FLIP.

[0127] Embodiment 22. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, wherein the FAS / FASL inhibitor includes MET12.

[0128] Embodiment 23. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, wherein the FAS / FASL inhibitor includes ONL1204.

[0129] Embodiment 24. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, wherein the FAS / FASL inhibitor contains a FAS apoptosis inhibitor molecule.

[0130] Embodiment 25. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein the FAS / FASL inhibitor contains nucleolar protein 3.

[0131] Embodiment 26. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25, wherein the FAS / FASL inhibitor includes DcR1.

[0132] Embodiment 27. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, wherein the FAS / FASL inhibitor includes DcR2.

[0133] Embodiment 28. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27, wherein the FAS / FASL inhibitor includes DcR3.

[0134] Embodiment 29. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28, wherein the TNF-α / TNFR inhibitor includes etanercept.

[0135] Embodiment 30. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29, wherein the TNF-α / TNFR inhibitor includes infliximab.

[0136] Embodiment 31. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, wherein the TNF-α / TNFR inhibitor includes golimumab.

[0137] Embodiment 32. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31, wherein the TNF-α / TNFR inhibitor includes certolizumab.

[0138] Embodiment 33. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32, wherein the TNF-α / TNFR inhibitor includes adalimumab.

[0139] Embodiment 34. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, or 33, wherein the TNF-α / TNFR inhibitor contains R1antTNF.

[0140] Embodiment 35. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34, wherein the TNF-α / TNFR inhibitor includes DMS5540.

[0141] Embodiment 36. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35, wherein the TNF-α / TNFR inhibitor includes TROS.

[0142] Embodiment 37. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein the TNF-α / TNFR inhibitor includes aTROSAB.

[0143] Embodiment 38. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 37, wherein the mitochondrial peptide contains humanin.

[0144] Embodiment 39. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, or 38, wherein the mitochondrial peptide contains a humanin analog.

[0145] Embodiment 40. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, or 39, wherein the mitochondrial peptide contains s14G-humanin.

[0146] Embodiment 41. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein the mitochondrial peptide comprises MTP101.

[0147] Embodiment 42. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41, wherein the sustained delivery component is silica-based.

[0148] Embodiment 43. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42, wherein the sustained delivery component is porous.

[0149] Embodiment 44. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42, wherein the sustained delivery component is nonporous.

[0150] Embodiment 45. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, or 44, wherein the neuronutrient is covalently bound to the sustained delivery component.

[0151] Embodiment 46. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45, wherein the FAS / FASL inhibitor is covalently bound to the sustained delivery component.

[0152] Embodiment 47. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, or 46, wherein the TNF-α / TNFR inhibitor is covalently bound to the sustained delivery component.

[0153] Embodiment 48. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, or 47, wherein the mitochondrial peptide is covalently bonded to the sustained delivery component.

[0154] Embodiment 49. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 47, or 48, wherein the neuronutrient is not covalently bound to the sustained delivery component.

[0155] Embodiment 50. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 47, 48, or 49, wherein the FAS / FASL inhibitor is not covalently bound to the sustained delivery component.

[0156] Embodiment 51. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 49, or 50, wherein the TNF-α / TNFR inhibitor is not covalently bound to the sustained delivery component.

[0157] Embodiment 52. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 49, 50, 51, or 52, wherein the mitochondrial peptide is not covalently bound to the sustained delivery component.

[0158] Embodiment 53. The sustained delivery component is of the type described in U.S. Patent No. 9,949,922 by Jokinen et al., issued on April 24, 2018, and is part of the drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52.

[0159] Embodiment 54. The sustained delivery component is of the type described in U.S. Patent Application No. 20140057996 by Jokinen et al., published on February 27, 2014, and is part of the drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52.

[0160] Embodiment 55. The sustained delivery component is of the type described in U.S. Patent No. 9,603,801 by Barnett et al., issued on March 28, 2017, and is part of the drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52.

[0161] Embodiment 56. The sustained delivery component is of the type described in U.S. Patent No. 9,808,421 by Ashton et al., issued on November 7, 2017, and is part of the drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52.

[0162] Embodiment 57. The sustained delivery component is of the type described in U.S. Patent No. 9,333,173 by Ashton et al., issued on May 10, 2016, and is part of the drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52.

[0163] Embodiment 58. The sustained delivery component is of the type described in Ashton et al., U.S. Patent Publication No. 20140271764, published on September 28, 2014, and is part of the drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52.

[0164] Embodiment 59. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, or 58, further comprising oligonucleotides.

[0165] Embodiment 60. A drug delivery system containing oligonucleotides and sustained-release components.

[0166] Embodiment 61. The drug delivery system according to embodiment 59 or 60, wherein the oligonucleotide includes a small interfering RNA (siRNA).

[0167] Embodiment 62. A drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59, wherein the neuronutrient contains nerve growth factor (NGF).

[0168] Embodiment 63. A method for treating a medical condition including 1) a hereditary or age-related disorder or degeneration of the choroid, retina, or optic nerve, 2) an ear disorder, or 3) a neurological or CNS disorder, comprising administering a drug delivery system according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, or 62 to a mammal in need of treatment.

[0169] Embodiment 64. A drug delivery system or method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, or 63, wherein the FAS inhibitor includes bicyclol.

[0170] Embodiment 65. A drug delivery system or method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, or 63, wherein the chemokine inhibitor includes NR58.3-14-3.

[0171] (Note) (Note 1) A drug delivery system comprising a first pharmaceutically active ingredient (API) and a sustained delivery component, wherein the first API is a neurotrophic agent, a FAS / FASL inhibitor, a TNF-α / TNFR inhibitor, a mitochondrial peptide, a chemokine inhibitor, a cysteine-aspartate protease, or a combination thereof.

[0172] (Note 2) A drug delivery system further comprising a second API, wherein the first API is a neurotrophic agent and the second API is a FAS / FASL inhibitor, a TNF-α / TNFR inhibitor, a mitochondrial peptide, an oligonucleotide, a chemokine inhibitor, or a CASPASE, as described in Appendix 1.

[0173] (Note 3) A drug delivery system further comprising a second API, wherein the first API is a FAS / FASL inhibitor and the second API is a TNF-α / TNFR inhibitor, a mitochondrial peptide, an oligonucleotide, a chemokine inhibitor, or a CASPASE, as described in Appendix 1.

[0174] (Note 4) A drug delivery system according to Appendix 1, further comprising a second API, wherein the first API is a TNF-α / TNFR inhibitor and the second API is a mitochondrial peptide, oligonucleotide, chemokine inhibitor, or CASPASE.

[0175] (Note 5) A drug delivery system according to Appendix 1, further comprising a second API, wherein the first API is an oligonucleotide and the second API is a chemokine inhibitor or a CASPASE.

[0176] (Note 6) A drug delivery system according to Appendix 1, further comprising a second API, wherein the first API is a chemokine inhibitor and the second API is a caspase.

[0177] (Appendix 7) The drug delivery system according to Appendix 1, 2, 3, 4, 5, or 6, wherein the first API and the second API are not covalently bonded to each other.

[0178] (Appendix 8) The drug delivery system according to Appendix 1, 2, 3, 4, 5, or 6, wherein the first API is covalently bonded to the second API.

[0179] (Appendix 9) The drug delivery system according to Appendix 1, 2, 3, 4, 5, 6, 7, or 8, wherein the first API is covalently bonded to the sustained release component.

[0180] (Appendix 10) The drug delivery system according to Appendix 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein the second API is covalently bonded to the sustained release component.

[0181] (Appendix 11) The drug delivery system according to Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, having about 100 μg to about 1 mg of the first API.

[0182] (Appendix 12) The drug delivery system according to Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, having about 100 μg to about 1 mg of the second API.

[0183] (Appendix 13) The drug delivery system according to Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein the weight of the graft is about 300 μg to about 10 mg.

[0184] (Appendix 14) A method of treating a medical condition comprising administering to a mammal in need of treatment a drug delivery system as described in Supplementary Notes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, the medical condition including (1) a hereditary or age-related disorder or degeneration of the choroid, retina, or optic nerve, (2) an ear disorder, or (3) a neurological or CNS disorder.

[0185] (Supplementary Note 15) The method according to Supplementary Note 14, wherein the drug delivery system is injected into the eye of the mammal.

[0186] (Supplementary Note 16) The method according to Supplementary Note 14 or 15, wherein the mammal is a human.

[0187] (Supplementary Note 17) Use of a FAS / FASL inhibitor, a TNF-α / TNFR inhibitor, a mitochondrial peptide, a chemokine inhibitor, a cysteine-aspartic acid protease, or a combination thereof, in the manufacture of a drug delivery system for the treatment of (1) a hereditary or age-related disorder or degeneration of the choroid, retina, or optic nerve, (2) an ear disorder, or (3) a neurological or CNS disorder, wherein the drug delivery system further comprises a sustained release component.

[0188] (Supplementary Note 18) The use according to Supplementary Note 17, wherein the drug delivery system is injected into the eye of the mammal.

[0189] (Supplementary Note 19) The use according to Supplementary Note 17 or 18, wherein the mammal is a human.

[0190] (Supplementary Note 20) A kit comprising a drug delivery system as described in Supplementary Notes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 for the treatment of (1) a hereditary or age-related disorder or degeneration of the choroid, retina, or optic nerve, (2) an ear disorder, or (3) a neurological or CNS disorder, and a label with instructions for use of the drug delivery system.

[0191] (Note 21) The kit described in Appendix 20, wherein the drug delivery system is injected into the eye of a mammal.

[0192] (Note 22) The kit as described in Appendix 20 or 21, wherein the mammal is a human.

Claims

1. A drug delivery system comprising a first pharmaceutically active ingredient (API) and a polymer that provides sustained release of the first API, wherein the first API is a peptide comprising a portion of the ciliary neurotrophic factor (CNTF) sequence, and the drug delivery system is injected intraocularly into mammals and is not used for the treatment of neurological diseases or CNS disorders.

2. The drug delivery system according to claim 1, further comprising a second API, wherein the second API is an apoptosis signaling fragment inhibitor or an apoptosis signaling fragment ligand inhibitor (FAS / FASL inhibitor), a tumor necrosis factor-α inhibitor or a tumor necrosis factor-α receptor inhibitor (TNF-α / TNFR inhibitor), a mitochondrial peptide, an oligonucleotide, a chemokine inhibitor, or a caspase inhibitor.

3. The drug delivery system according to claim 2, wherein the first API and the second API are not covalently bonded to each other.

4. The drug delivery system according to claim 2, wherein the first API is covalently bonded to the second API.

5. The drug delivery system according to claim 1, 2, 3, or 4, wherein the first API is covalently bonded to the polymer.

6. The drug delivery system according to claim 2, 3, or 4, wherein the second API is covalently bonded to the polymer.

7. The drug delivery system according to claim 2, 3, 4, or 6, comprising the first API in an amount of about 100 μg to about 1 mg and the second API in an amount of about 100 μg to about 1 mg.

8. The drug delivery system according to claim 1, 2, 3, 4, 5, 6, or 7, wherein the weight is approximately 300 μg to approximately 10 mg.

9. The drug delivery system according to claim 2, wherein the second API is a compound comprising the peptide represented by Sequence ID No.

5.

10. The drug delivery system according to claim 2, wherein the second API is the peptide represented by Sequence ID No.

3.

11. The drug delivery system according to claim 2, wherein the second API is bicyclol.

12. The drug delivery system according to claim 2, wherein the second API is a compound comprising the peptide represented by Sequence ID No. 4.