Compositions derived from mesenchymal stromal cells and methods of use thereof

Abstract

Disclosed herein are compositions comprising a secretome obtained from the conditioned media of one or more p53-silenced mesenchymal stroma cells (MSCs), conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), or exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs). Also disclosed herein are methods of using those compositions.

Description

COMPOSITIONS DERIVED FROM MESENCHYMAL STROMAL CELLS AND METHODS OF USE THEREOFI. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claim priority to U.S. Provisional Application No. 63 / 648,595 filed 16 May 2024, which is incorporated by reference herein in its entirety.II. REFERENCE TO THE SEQUENCE LISTING

[0002] The Sequence Listing submitted 16 May 2025 as a text file named “024-031-Sen-PCT (GW143) - Sequence Listing”, created on 16 May 2025 and having a size of 4,096 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5).HI. BACKGROUND

[0003] Diabetes represents one of the most widespread metabolic diseases worldwide and hyperglycemia is the common outcome of the two main forms of this disorder: type 1 diabetes mellitus, characterized by autoimmune destruction of pancreatic P-cells, and type 2 diabetes mellitus (T2DM), which is characterized by insulin resistance and a poor efficacy of insulin to control glucose homeostasis. T2DM is often associated with an exacerbation of the obese condition leading to the so-called metabolic syndrome. In this context, the adipose tissue seems to be crucially involved in the production of inflammatory biomarkers, resulting from a crosstalk between immune cells, adipocytes, and macrophages that permeate it.

[0004] One of the major consequences of diabetes mellitus is peripheral vascular disease (PVD). PVD is the inadequate perfusion of blood in the peripheral arteries often triggered by atherosclerosis, one of the major consequences of diabetes mellitus. Every day, 230 patients undergo diabetes mellitus-related amputation due to PVD. In these patients, PVD most often occurs secondarily to total occlusion of major vessels in the limb such as the femoral or tibial artery. Therefore, it is important to improve blood flow and neovascularization to reduce amputation. Moreover, diabetic wounds represent a global clinical and economic challenge, characterized by prolonged healing durations, an increased risk of infection, and severe complications, including limb amputation. These chronic wounds impose a significant burden on healthcare systems due to frequent hospitalizations, the need for advanced wound care therapies, and extensive long-term patient management.

[0005] Thus, there remains an urgent need to stimulate endothelial cell regeneration. Consequently, the present disclosure provides compositions for and methods of treating subjects having diabetes and / or other diseases or disorders, which can be used alone or in combination with other treatments.IV. BRIEF DESCRIPTION OF THE FIGURES

[0006] FIG. 1A - FIG. IB show human EPCs 48 hrs. (2 days) after high glucose exposure by FACS Analysis. Within 48 hrs., there was significant apoptosis and death of EPCs in high glucose. This apoptotic death was associated with p53, p21, PUMA and Caspase-3 gene upregulation. The solid purple indicates the isotype control. The green line indicates normal glucose (100 mg %) while the red line indicates high glucose (360 mg %).

[0007] FIG. 2 shows EPCs in high glucose. From left to right, the left-most panel shows EPCs with no modification while the remaining panels show EPCs in high glucose post-p53 silencing at day 14 and day 28 (two right most panels). EPCs help form tubular capillary’ structures in Matrigel indicating retention of endothelial cell function not only morphologically but also functionally.

[0008] FIG. 3 shows the right hind limb ischemia model in a diabetic mouse. The ischemic side is indicated with an arrow. Two points (Day 4 or Day 11) following delivery of saline or EPCs are shown. At each time point, the top panel received saline, the middle panel received p53sh- Sham transduced EPCs, and bottom panel received p53sh-EPCs. The reperfusion is best noted in the lowest panel with perfusion, which appeared similar to the non-ischemic side.

[0009] FIG. 4A shows increased wound healing or endothelial cell regeneration in-vitro with addition of p53sh EPC-conditioned media. Here, endothelial cells were cultured in wound healing plate and conditioned media from null (Scramble) and p53sh-transduced EPCs were added in 1 : 20 ratio to the exosome free culture media. When conditioned media from p53sh-EPC was added to the culture media, increased wound healing was observed when compared with null and control media (n = 3). FIG. 4B shows increased wound healing or endothelial cell regeneration with addition of the exosomal portion of p53sh EPC-conditioned media (CM). Here, endothelial cells were cultured in wound healing plates and exosomes from conditioned media from null- transduced EPCs and p53sh-transduced EPCs were added to the exosome free culture media. FIG. 4C shows that when exosomes from p53sh-EPC w ere added to the culture media, increased wound healing was observed when compared with null and control media (n = 2).

[0010] FIG. 5A shows the results of a wound healing assay or an endothelial scratch test assay. Here, HUVEC cells treated with saline (untreated), treated with scramble or null- and treated with CM derived from p53sh human BM-MSCs (right panel). Picture taken post-staining of the scratch test. FIG. 5B shows viable HUVEC cell counts following exposure to p53 silenced BM-MSC derived CM (green), scramble transduced MSC-CM (red), and saline (control) (blue).

[0011] FIG. 6 shows a schematic for a wound healing assay.

[0012] FIG. 7A - FIG. 7B show7the comparison of two protocols for BM-MSC exosome production. FIG. 7A shows the exosome protocol developed at George Washington Universityfocused on ultracentrifugation while FIG. 7B shows the exosome protocol developed at Renosome based on tangential flow filtration.

[0013] FIG. 8 shows the evaluation of p53 siRNA efficacy in MSCs measured via a Lumit Assay. Here, two p53-targeted siRNAs achieved significant knockdown (KD) in MSCs (61-71% KD), while the scrambled negative control siRNA did not significantly alter p53 expression in MSCs. p53 siRNA S605 demonstrated better knockdown in both cell types.

[0014] FIG. 9A - FIG. 9B show the initial characterization of MSC-derived exosome using fNTA. Here, MSCs were transfected with scramble or p53 siRNA, and exosomes were isolated 96 hrs. later using tangential flow filtration and ExoQuick precipitation. The exosomes were fluorescently labeled and analyzed with a NanoSight instrument (fNTA) and allowed for real-time visualization and analysis of individual nanoparticles in solution. The size range of detected particles was consistent with the expected size range for exosomes (30 nm -150 nm). The concentration of exosomes was within the typical range reported for MSC-derived exosomes.

[0015] FIG. 10A shows that a refined wound assay demonstrated a clear differential of wound healing over time (0 hr. - 24 hrs.). In FIG. 10B, the wound healing was measured by calculating circular area of wound gap wherein a small area value indicates greater wound healing.V. BRIEF SUMMARY

[0016] Disclosed herein is a composition, comprising: a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs). Disclosed herein is a composition, comprising: conditioned media obtained from one or more p53- silenced bone marrow derived mesenchymal stromal cells (BM-MSCs). Disclosed herein is a composition, comprising: exosomes obtained from the conditioned media of one or more p53- silenced bone marrow derived mesenchymal stromal cells (BM-MSCs).

[0017] Disclosed herein is a composition, comprising: a secretome obtained from the conditioned media of one or more p53-silenced adipose derived mesenchymal stroma cells (AT-MSCs). Disclosed herein is a composition, comprising: conditioned media obtained from one or more p53- silenced adipose derived mesenchymal stromal cells (AT-MSCs). Disclosed herein is a composition, comprising: exosomes obtained from the conditioned media of one or more p53- silenced adipose derived mesenchymal stromal cells (AT-MSCs).

[0018] Disclosed herein is a composition, comprising: a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB- MSCs). Disclosed herein is a composition, comprising: conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs). Disclosed herein is a composition, comprising: exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs).

[0019] Disclosed herein is a composition, comprising: a secretome obtained from the conditioned media of one or more p53-silenced birth-associated tissue (BAT) derived mesenchymal stroma cells (BAT-MSCs). Disclosed herein is a composition, comprising: conditioned media obtained from one or more p53-silenced birth-associated tissue (BAT) derived mesenchymal stroma cells (BAT-MSCs). Disclosed herein is a composition, comprising: exosomes obtained from the conditioned media of one or more p53-silenced birth-associated tissue (BAT) derived mesenchymal stroma cells (BAT-MSCs).

[0020] Disclosed herein is a pharmaceutical formulation comprising a secretome obtained from the conditioned media of one or more p53-silenced mesenchymal stroma cells (MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising conditioned media obtained from one or more p53- silenced mesenchymal stromal cells (MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0021] Disclosed herein is a pharmaceutical formulation comprising a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM- MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0022] Disclosed herein is a pharmaceutical formulation comprising a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB- MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0023] Disclosed herein is a pharmaceutical formulation comprising a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT- MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0024] Disclosed herein is a pharmaceutical formulation comprising a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs; and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs; and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0025] Disclosed herein is a method of preparing a disclosed composition.

[0026] Disclosed herein is a method of preparing a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53- silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof.

[0027] Disclosed herein is a method of preparing a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof.

[0028] Disclosed herein is a method of preparing a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or morep53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof.

[0029] Disclosed herein is a method of preparing a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof.

[0030] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; transducing the BM-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced BM-MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; transducing the PB-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced PB-MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; transducing the AT-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced AT-MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT-MSCs in media; transducing the BAT-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced BAT-MSCs in media; and collecting the spent media.

[0031] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; transducing the BM-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced BM-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; transducing the PB-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced PB-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; transducing the AT-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced AT-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT- MSCs in media; transducing the BAT-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced BAT-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media.

[0032] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; transducing the BM-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced BM-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; transducing the PB-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced PB-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; transducing the AT-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced AT-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT-MSCs in media; transducing the BAT-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced BAT-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes.

[0033] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; transducing the BM-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced BM-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; transducing the PB-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced PB-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; transducing the AT-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced AT-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT-MSCs in media; transducing the BAT-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced BAT-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome.

[0034] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; silencing p53 in BM-MSCs; culturing the p53-silenced BM-MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; silencing p53 in PB-MSCs; culturing the p53- silenced PB-MSCs in media; and collecting the spent media. Disclosed herein is a method ofpreparing a composition, the method comprising culturing AT-MSCs in media; silencing p53 in AT-MSCs; culturing the p53-silenced AT-MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT- MSCs in media; silencing p53 in BAT-MSCs; culturing the p53-silenced BAT-MSCs in media; and collecting the spent media.

[0035] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; silencing p53 in BM-MSCs; culturing the p53-silenced BM-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing PB- MSCs in media; silencing p53 in PB-MSCs; culturing the p53-silenced PB-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing AT- MSCs in media; silencing p53 in AT-MSCs; culturing the p53-silenced AT-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT- MSCs in media; silencing p53 in BAT-MSCs; culturing the p53-silenced BAT-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media.

[0036] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; silencing p53 in BM-MSCs; culturing the p53-silenced BM-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; silencing p53 in PB-MSCs; culturing the p53- silenced PB-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; silencing p53 in AT-MSCs; culturing the p53-silenced AT-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT- MSCs in media; silencing p53 in BAT-MSCs; culturing the p53-silenced BAT-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes.

[0037] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; silencing p53 in BM-MSCs; culturing the p53-silenced BM-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media;silencing p53 in PB-MSCs; culturing the p53-silenced PB-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; silencing p53 in AT-MSCs; culturing the p53-silenced AT-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT-MSCs in media; silencing p53 in BAT- MSCs; culturing the p53-silenced BAT-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome.

[0038] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; using siRNA to silence p53 in BM-MSCs; culturing the p53-silenced BM- MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; using siRNA to silence p53 in PB-MSCs; culturing the p53-silenced PB-MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing AT- MSCs in media; using siRNA to silence p53 in AT-MSCs; culturing the p53-silenced AT-MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT-MSCs in media; using siRNA to silence p53 in BAT- MSCs; culturing the p53-silenced BAT-MSCs in media; and collecting the spent media.

[0039] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; using siRNA to silence p53 in BM-MSCs; culturing the p53-silenced BM- MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; using siRNA to silence p53 in PB-MSCs; culturing the p53-silenced PB- MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; using siRNA to silence p53 in AT-MSCs; culturing the p53-silenced AT- MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT-MSCs in media; using siRNA to silence p53 in BAT-MSCs; culturing the p53-silenced BAT-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media.

[0040] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; using siRNA to silence p53 in BM-MSCs; culturing the p53-silenced BM- MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes. Disclosed herein is a method of preparinga composition, the method comprising culturing PB-MSCs in media; using siRNA to silence p53 in PB-MSCs; culturing the p53-silenced PB-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing AT- MSCs in media; using siRNA to silence p53 in AT-MSCs; culturing the p53-silenced AT-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT-MSCs in media; using siRNA to silence p53 in BAT- MSCs; culturing the p53-silenced BAT-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes.

[0041] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; using siRNA to silence p53 in BM-MSCs; culturing the p53-silenced BM- MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing PB- MSCs in media; using siRNA to silence p53 in PB-MSCs; culturing the p53-silenced PB-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; using siRNA to silence p53 in AT-MSCs; culturing the p53-silenced AT-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT-MSCs in media; using siRNA to silence p53 in BAT-MSCs; culturing the p53-silenced BAT-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome.

[0042] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed composition or a disclosed pharmaceutical formulation.

[0043] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof.

[0044] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof.

[0045] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof.

[0046] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof.

[0047] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof.

[0048] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof.

[0049]

[0050] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of acomposition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof.

[0051] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs). (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof.

[0052] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof.

[0053] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof, wherein, following administration, one or more physiological changes is effected in the subject; one or more positive and / or favorable physiological changes is generated in the subject; wound healing is improved and / or enhanced in the subject; one or more diabetes-related symptoms or complications are treated in the subject; one or more diabetes-related vascular issues or diabetes-related vascular complications are treated in the subject; vascular regeneration is improved and / or enhanced and / or stimulated and / or promoted in one or more tissues and / or one or more organs in the subject; apoptosis of cells exposed to hyperglycemia is prevented; the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia is prevented; apoptosis of endothelial cells exposed to hyperglycemic conditions is prevented; the amountand / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia is prevented; endothelial regeneration is improved and / or enhanced and / or stimulated and / or promoted in the subject; systemic inflammation is diminished and / or decreased in the subject; renal function is improved and / or enhanced in the subject; one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation are restored in the subj ect; or any combination thereof.

[0054] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof, wherein, following administration, one or more physiological changes is effected in the subject; one or more positive and / or favorable physiological changes is generated in the subject; wound healing is improved and / or enhanced in the subject; one or more diabetes-related symptoms or complications are treated in the subject; one or more diabetes-related vascular issues or diabetes- related vascular complications are treated in the subject; vascular regeneration is improved and / or enhanced and / or stimulated and / or promoted in one or more tissues and / or one or more organs in the subject; apoptosis of cells exposed to hyperglycemia is prevented; the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia is prevented; apoptosis of endothelial cells exposed to hyperglycemic conditions is prevented; the amount and / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia is prevented; endothelial regeneration is improved and / or enhanced and / or stimulated and / or promoted in the subject; systemic inflammation is diminished and / or decreased in the subject; renal function is improved and / or enhanced in the subject; one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation are restored in the subject; or any combination thereof.

[0055] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof,wherein, following administration, one or more physiological changes is effected in the subject; one or more positive and / or favorable physiological changes is generated in the subject; wound healing is improved and / or enhanced in the subject; one or more diabetes-related symptoms or complications are treated in the subject; one or more diabetes-related vascular issues or diabetes- related vascular complications are treated in the subject; vascular regeneration is improved and / or enhanced and / or stimulated and / or promoted in one or more tissues and / or one or more organs in the subject; apoptosis of cells exposed to hyperglycemia is prevented; the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia is prevented; apoptosis of endothelial cells exposed to hyperglycemic conditions is prevented; the amount and / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia is prevented; endothelial regeneration is improved and / or enhanced and / or stimulated and / or promoted in the subject; systemic inflammation is diminished and / or decreased in the subject; renal function is improved and / or enhanced in the subject; one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation are restored in the subject; or any combination thereof.

[0056] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof, wherein, following administration, one or more physiological changes is effected in the subject; one or more positive and / or favorable physiological changes is generated in the subject; wound healing is improved and / or enhanced in the subject; one or more diabetes-related symptoms or complications are treated in the subject; one or more diabetes-related vascular issues or diabetes- related vascular complications are treated in the subject; vascular regeneration is improved and / or enhanced and / or stimulated and / or promoted in one or more tissues and / or one or more organs in the subject; apoptosis of cells exposed to hyperglycemia is prevented; the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia is prevented; apoptosis of endothelial cells exposed to hyperglycemic conditions is prevented; the amount and / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia is prevented; endothelial regeneration is improved and / or enhanced and / or stimulated and / or promoted in the subject; systemic inflammation is diminished and / or decreased in the subject; renal function is improved and / or enhanced in the subject; one or more aspects of cellular homeostasis and / or cellularfunctionality and / or metabolic dysregulation are restored in the subject; or any combination thereof.

[0057] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof, wherein, following administration, one or more physiological changes is effected in the subject; one or more positive and / or favorable physiological changes is generated in the subject; wound healing is improved and / or enhanced in the subject; one or more diabetes- related symptoms or complications are treated in the subject; one or more diabetes-related vascular issues or diabetes-related vascular complications are treated in the subject; vascular regeneration is improved and / or enhanced and / or stimulated and / or promoted in one or more tissues and / or one or more organs in the subject; apoptosis of cells exposed to hyperglycemia is prevented; the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia is prevented; apoptosis of endothelial cells exposed to hyperglycemic conditions is prevented; the amount and / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia is prevented; endothelial regeneration is improved and / or enhanced and / or stimulated and / or promoted in the subject; systemic inflammation is diminished and / or decreased in the subject; renal function is improved and / or enhanced in the subject; one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation are restored in the subj ect; or any combination thereof.VI. DETAILED DESCRIPTION

[0058] The present disclosure describes formulations, compounded compositions, kits, capsules, containers, and / or methods thereof. It is to be understood that the inventive aspects of which are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0059] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. Thepublications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.A. Definitions

[0060] Before the present compounds, compositions, articles, systems, devices, and / or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0061] This disclosure describes inventive concepts with reference to specific examples. However, the intent is to cover all modifications, equivalents, and alternatives of the inventive concepts that are consistent with this disclosure.

[0062] As used in the specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.

[0063] The phrase “consisting essentially of’ limits the scope of a claim to the recited components in a composition or the recited steps in a method as well as those that do not materially affect the basic and novel characteristic or characteristics of the claimed composition or claimed method. The phrase “consisting of’ excludes any component, step, or element that is not recited in the claim. The phrase “comprising” is synonymous with “including”, “containing”, or “characterized by”, and is inclusive or open-ended. “Comprising” does not exclude additional, unrecited components or steps.

[0064] In an aspect, when referring to any numerical value, the term “about” means a value falling within a range that is ± 10% of the stated value.

[0065] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit betweentwo particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0066] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0067] In an aspect, the terms “optional” or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. In an aspect, a disclosed method can optionally comprise one or more additional steps, such as, for example, repeating an administering step or altering an administering step.

[0068] In an aspect, the term “subject’7refers to the target of administration, e.g.. a human being. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc ), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g, mouse, rabbit, rat, guinea pig, fruit fly, etc.). Thus, the subject of the disclosed methods can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Alternatively, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex, and thus, adult and child subjects, as well as fetuses, whether male or female, are intended to be covered. In an aspect, a subject can be a human patient. In an aspect, a subject can have diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof. In an aspect, a subject can be at risk of developing diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof.

[0069] In an aspect, the term “diagnosed” means having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by one or more of the disclosed compositions (including a disclosed secretome, a disclosed conditioned media, a disclosed plurality of exosomes, or a pharmaceutical formulation) or by one or more of the disclosed methods. For example, “diagnosed with diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healingdisease or disorder, or any combination thereof’ means having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition that can be treated by one or more of the disclosed compositions and / or disclosed pharmaceutical formulations, or by one or more of the disclosed methods. In an aspect, an examination can be physical, can involve various tests (e.g., blood tests, genotyping, biopsies, etc.) and assays (e.g., enzvmatic assay), or a combination thereof.

[0070] A “patient” refers to a subject afflicted with diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD). a wound healing disease or disorder, or any combination thereof. In an aspect, a patient can refer to a subject that has been diagnosed with or is suspected of having diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof. In an aspect, a patient can refer to a subject that has been diagnosed with or is suspected of having diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof and is seeking treatment or receiving treatment for such a disease or disorder.

[0071] In an aspect, the phrase “identified to be in need of treatment for a disorder,” or the like, refers to selection of a subject based upon need for treatment of the disorder. For example, a subject can be identified as having a need for treatment of a disorder (e.g., such diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof) based upon an earlier diagnosis by a person of skill and thereafter subjected to treatment for the disorder (e.g., such as diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof). In an aspect, the identification can be performed by a person different from the person making the diagnosis. In an aspect, the administration can be performed by one who performed the diagnosis.

[0072] In an aspect, “inhibit,” “inhibiting”, and “inhibition” mean to diminish or decrease an activity, level, response, condition, severity, disease, or other biological parameter. This can include, but is not limited to, the complete ablation of the activity, level, response, condition, severity, disease, or other biological parameter. This can also include, for example, a 10% inhibition or reduction in the activity, level, response, condition, severity, disease, or otherbiological parameter as compared to the native or control level (e.g., a subject not having diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty7liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof). Thus, in an aspect, the inhibition or reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of reduction in between as compared to native or control levels. In an aspect, the inhibition or reduction can be 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90- 100% as compared to native or control levels. In an aspect, the inhibition or reduction can be 0- 25%, 25-50%, 50-75%, or 75-100% as compared to native or control levels.

[0073] The words “treat” or “treating” or ’‘treatment” include palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is. treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In an aspect, the terms cover any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the undesired physiological change, disease, pathological condition, or disorder from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the physiological change, disease, pathological condition, or disorder, z.e., arresting its development; or (iii) relieving the physiological change, disease, pathological condition, or disorder, z.e., causing regression of the disease. For example, in an aspect, treating diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof can reduce the severity of an established diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD). a wound healing disease or disorder, or any combination thereof in a subject by 1 %- 100% as compared to a control (such as, for example, an individual not having such a disease or disorder). In an aspect, treating can refer to a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%. 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity7of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty7liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof. For example, treating diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheralvascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof can reduce one or more symptoms of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof in a subject by 1 %-l 00% as compared to a control (such as, for example, an individual not having diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD). a wound healing disease or disorder, or any combination thereof). In an aspect, treating can refer to 1%, 2%. 3%, 4%. 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% reduction of one or more symptoms of an established diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof. It is understood that treatment does not necessarily refer to a cure or complete ablation or eradication of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney7disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof. However, in an aspect, treatment can refer to a cure or complete ablation or eradication of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty' liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof.

[0074] In an aspect, the term “prevent” or “preventing” or “prevention” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially byadvance action. It is understood that where reduce, inhibit, or prevent are used herein, unless specifically indicated otherwise, the use of the other tw o w ords is also expressly disclosed. In an aspect, preventing diabetes, a diabetes-related complication, hyperglycemia, diabetic kidneydisease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof is intended. The words “prevent” and “preventing” and “prevention” also refer to prophylactic or preventative measures for protecting or precluding a subject (e.g., an individual) not having a given diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty- liver disease (NAFLD), a wound healing disease or disorder, or any' combination thereof related complication from progressing to that complication.

[0075] In an aspect, the terms “administering’’ and “administration” refer to any method of providing one or more of the disclosed compositions (comprising a disclosed secretome, a disclosed conditioned media, a disclosed exosome or plurality' of disclosed exosomes), disclosed pharmaceutical formulations, or a combination thereof to a subject.

[0076] In an aspect, a therapeutically effective amount of disclosed vector can be delivered intravenously and can comprise a range of about 1 x IO10vg / kg to about 2 x 1014vg / kg.

[0077] In an aspect, the skilled person can determine an efficacious dose, an efficacious schedule, and an efficacious route of administration for one or more of the disclosed compositions disclosed pharmaceutical formulations, or a combination thereof so as to treat or prevent diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof. In an aspect, the skilled person can also alter, change, or modify an aspect of an administering step to improve efficacy of one or more of the disclosed compositions, disclosed pharmaceutical formulations, or a combination thereof.

[0078] In an aspect, “modifying the method” can comprise modifying or changing one or more features or aspects of one or more steps of a disclosed method. For example, in an aspect, a method can be altered by changing the amount of one or more of the disclosed compositions, disclosed pharmaceutical formulations, or a combination thereof administered to a subject, or by changing the frequency of administration of one or more of the disclosed compositions, disclosed pharmaceutical formulations, or a combination thereof to a subject, or by changing the duration of time one or more of the disclosed compositions, disclosed pharmaceutical formulations, or a combination are administered to a subject.

[0079] In an aspect, “concurrently” means (1) simultaneously in time, or (2) at different times during the course of a common treatment schedule.

[0080] In an aspect, the term “contacting” refers to bringing one or more of the disclosed compositions (comprising a disclosed secretome, a disclosed conditioned media, a disclosed exosome or plurality of disclosed exosomes), disclosed isolated nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof together with a target area or intended target area in such a manner that the one or more of the disclosed compositions (comprising a disclosed secretome, a disclosed conditioned media, a disclosed exosome or plurality of disclosed exosomes), disclosed isolated nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof exert an effect on the intended target or targeted area either directly or indirectly. A target area or intended target area can be one or more of a subject's organs (e.g., lungs, heart, liver, muscle, kidney, brain, etc.). In anaspect, a target area or intended target area can be any cell or any organ affected by diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty7liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof.

[0081] In an aspect, ‘"determining” can refer to measuring or ascertaining the presence and severity of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty7liver disease (NAFLD). a wound healing disease or disorder, or any combination thereof. Methods and techniques used to determine the presence and / or severity of diabetes, a diabetes- related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof are typically known to the medical arts. For example, the art is familiar with the ways to identify and / or diagnose the presence, severity, or both of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney7disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty7liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof.

[0082] In an aspect, “effective amount” and “amount effective” can refer to an amount that is sufficient to achieve the desired result such as, for example, the treatment and / or prevention of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty7liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof. In an aspect, the terms “effective amount” and “amount effective” can refer to an amount that is sufficient to achieve the desired an effect on an undesired condition (e.g.. diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty7liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof). For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms but is generally insufficient to cause adverse side effects. In an aspect, “therapeutically effective amount” means an amount of a disclosed composition (comprising a disclosed secretome, a disclosed conditioned media, a disclosed exosome or plurality of disclosed exosomes) or a disclosed pharmaceutical formulation; that (i) treats the particular disease, condition (such as diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty7liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof), (ii) attenuates, ameliorates, or eliminates one or more symptoms of theparticular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein (e.g., diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof). The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the disclosed compositions (comprising a disclosed secretome, a disclosed conditioned media, a disclosed exosome or plurality of disclosed exosomes). disclosed isolated nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations employed; the disclosed methods employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the disclosed compositions (comprising a disclosed secretome, a disclosed conditioned media, a disclosed exosome or plurality of disclosed exosomes), disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations employed; the duration of the treatment; drugs used in combination or coincidental with the disclosed compositions (comprising a disclosed secretome, a disclosed conditioned media, a disclosed exosome or plurality of disclosed exosomes), disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations employed, and other like factors well-known in the medical arts. For example, it is well within the skill of the art to start doses of the disclosed compositions (comprising a disclosed secretome, a disclosed conditioned media, a disclosed exosome or plurality of disclosed exosomes), disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, then the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, a single dose of the disclosed compositions (comprising a disclosed secretome, a disclosed conditioned media, a disclosed exosome or plurality of disclosed exosomes). disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulation can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition, such as, for example, diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease,nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof.

[0083] In an aspect, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. In an aspect, a pharmaceutical carrier employed can be a solid, liquid, or gas. In an aspect, examples of solid carriers can include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. In an aspect, examples of liquid carriers can include sugar syrup, peanut oil, olive oil, and water. In an aspect, examples of gaseous carriers can include carbon dioxide and nitrogen. In preparing a disclosed composition for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques. Proper fluidity7can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0084] In an aspect, the term “excipient7’ refers to an inert substance which is commonly used as a diluent, vehicle, preservative, binder, or stabilizing agent, and includes, but is not limited to, proteins (e.g., serum albumin, etc.), amino acids (e.g., aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc.), fatty acids and phospholipids (e.g., alky l sulfonates, caprylate, etc.), surfactants (e.g.. SDS, polysorbate, nonionic surfactant, etc ), saccharides (e.g., sucrose, maltose, trehalose, etc.) and polyols (e.g., mannitol, sorbitol, etc.). See, also, for reference. Remington’s Pharmaceutical Sciences, (1990) Mack Publishing Co., Easton, Pa., which is hereby incorporated by reference in its entirety7.

[0085] In an aspect, “RNA therapeutics” can refer to the use of oligonucleotides to target RNA. RNA therapeutics can offer the promise of uniquely targeting the precise nucleic acids involved in a particular disease with greater specificity7, improved potency, and decreased toxicity. This could be particularly powerful for genetic diseases where it is most advantageous to aim for the RNA as opposed to the protein. In an aspect, a therapeutic RNA can comprise one or more expression sequences. As known to the art, expression sequences can comprise an RNAi, shRNA, mRNA, non-coding RNA (ncRNA), an antisense such as an antisense RNA, miRNA, morpholino oligonucleotide, peptide-nucleic acid (PNA) or ssDNA (with natural, and modified nucleotides, including but not limited to, LNA, BNA, 2’-O-Me-RNA, 2’-MEO-RNA, 2’-F-RNA), or analog or conjugate thereof. In an aspect, a disclosed therapeutic RNA can comprise one or more long non-coding RNA (IncRNA). such as, for example, a long intergenic non-coding RNA (lincRNA), pre-transcript, pre-miRNA, pre-mRNA, competing endogenous RNA (ceRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), pseudo-gene, rRNA, or tRNA. In an aspect, ncRNA can be piwi-interacting RNA (piRNA), primary miRNA (pri-miRNA), or premature miRNA (pre-miRNA). In an aspect, a disclosed therapeutic RNA or a RNA therapeutic can comprise antisense oligonucleotides (ASOs) that inhibit mRNA translation, oligonucleotides that function via RNA interference (RNAi) pathway, RNA molecules that behave like enzymes (ribozymes), RNA oligonucleotides that bind to proteins and other cellular molecules, and ASOs that bind to mRNA and form a structure that is recognized by RNase H resulting in cleavage of the mRNA target. Generally speaking, as known to the art, RNAi operates sequence specifically and post-transcriptionally by activating ribonucleases which, along with other enzymes and complexes, coordinately degrade the RNA after the original RNA target has been cut into smaller pieces while antisense oligonucleotides bind to their target nucleic acid via Watson-Crick basepairing, and inhibit or alter gene expression via steric hindrance, splicing alterations, initiation of target degradation, or other events.

[0086] In an aspect, “operably linked’' means that expression of a gene or a transgene is under the control of a promoter with which it is spatially connected. A promoter can be positioned 5’ (upstream) or 3’ (downstream) of a gene under its control. The distance between the promoter and a gene can be approximately the same as the distance between that promoter and the gene it controls in the gene from which the promoter is derived. As is known in the art, variation in this distance can be accommodated without loss of promoter function.

[0087] In an aspect, an “enhancer” such as a transcription or transcriptional enhancer refers to regulatory DNA segment that is typically found in multicellular eukaryotes. An enhancer can strongly stimulate (“enhance”) the transcription of a linked transcription unit, i.e., it acts in cis. An enhancer can activate transcription over very long distances of many thousand base pairs, and from a position upstream or downstream of the site of transcription initiation. An enhancer can have a modular structure by being composed of multiple binding sites for transcriptional activator proteins. Many enhancers control gene expression in a cell type-specific fashion. Several remote enhancers can control the expression of a singular gene while a singular enhance can stimulate the transcription of one or more genes.

[0088] In an aspect, “expression cassette” or “transgene cassette” can refer to a distinct component of vector DNA comprising a transgene and one or more regulatory sequences to be expressed by a transfected cell. Generally, an expression cassette or transgene cassette can comprise a promoter sequence, an open reading frame (i.e., the transgene), and a 3’ untranslated region (e.g., in eukaryotes a polyadenylation site).

[0089] In an aspect, “promoter” or “promoters” are known to the art. Depending on the level and tissue-specific expression desired, a variety of promoter elements can be used. A promoter can be tissue-specific or ubiquitous and can be constitutive or inducible, depending on the pattern of the gene expression desired. A promoter can be native (endogenous) or foreign (exogenous) and can be a natural or a synthetic sequence. By foreign or exogenous, it is intended that the transcriptional initiation region is not found in the wild-type host into which the transcriptional initiation region is introduced.

[0090] “Tissue-specific promoters” are known to the art and include, but are not limited to, neuron-specific promoters, muscle-specific promoters, liver-specific promoters, skeletal musclespecific promoters, and heart-specific promoters.

[0091] In an aspect, an “inducible promoter” refers to a promoter that can be regulated by positive or negative control. Factors that can regulate an inducible promoter include, but are not limitedto, chemical agents (e.g., the metallothionein promoter or a hormone inducible promoter), temperature, and light.

[0092] In an aspect, a disclosed promoter can be a promoter / enhancer. In an aspect, the term promoter / enhancer can refer to a segment of DNA that contains nucleotide sequences capable of providing both promoter and enhancer functions.

[0093] '‘Sequence identity” and “sequence similarity ” can be determined by alignment of two peptide or two nucleotide sequences using global or local alignment algorithms. Sequences may then be referred to as “substantially identical” or “essentially similar” when they are optimally aligned. For example, sequence similarity or identity can be determined by searching against databases such as FASTA, BLAST, etc., but hits should be retrieved and aligned pairwise to compare sequence identity. Two proteins or two protein domains, or two nucleic acid sequences can have “substantial sequence identity” if the percentage sequence identity is at least 70%, 75%, 80%, 85%. 90%, 95%, 98%, 99% or more, preferably 90%, 95%, 98%, 99% or more. Such sequences are also referred to as “variants” herein, e.g., other vanants of glycogen branching enzymes and amylases. It should be understood that sequence with substantial sequence identity do not necessarily have the same length and may differ in length. For example, sequences that have the same nucleotide sequence but of which one has additional nucleotides on the 3’- and / or 5 '-side are 100% identical.

[0094] In an aspect, “immune tolerance,” “immunological tolerance,” and “immunotolerance” refers to a state of unresponsiveness or blunted response of the immune system to substances (e.g., a disclosed polypeptide, a disclosed isolated nucleic acid molecule, a disclosed vector, a disclosed transgene product, a disclosed pharmaceutical formulation, a disclosed therapeutic agent, etc.) that have the capacity to elicit an immune response in a subject. Immune tolerance is induced by prior exposure to a specific antigen. Immune tolerance can be determined in a subject by measuring antibodies against a particular antigen or by liver-restricted transgene expression with an AAV vector. Low or absent antibody titers over time is an indicator of immune tolerance. For example, in some embodiments, immune tolerance can be established by having IgG antibody titers of less than or equal to about 12,000, 11,500, 1 1,000, 10,500, 10,000, 9,500, 9,000, 8,500, 8,000, 7,500, 7,000, 6,500, or 6,000 within following gene therapy (such as the administration of the transgene encoding, for example, a lysosomal enzy me.

[0095] In an aspect, “immune modulator” refers to an agent that is capable of adjusting a given immune response to a desired level (e.g. as in immunopotentiation, immunosuppression, or induction of immunologic tolerance). Examples of immune modulators include but are not limited to, a disclosed immune modulator can comprise aspirin, azathioprine, belimumab, betamethasone dipropionate, betamethasone valerate, bortezomib, bredinin, cyazathioprine, cyclophosphamide,cyclosporine, deoxyspergualin, didemnin B, fluocinolone acetonide, folinic acid, ibuprofen, IL6 inhibitors (such as sarilumab) indomethacin, inebilizumab, intravenous gamma globulin (IVIG), methotrexate, methylprednisolone, my cophenolate mofetil, naproxen, prednisolone, prednisone, prednisolone indomethacin, rapamycin, rituximab, sirolimus, sulindac, synthetic vaccine particles containing rapamycin (SVP-Rapamycin or mTOR), thalidomide, tocilizumab, tolmetin, triamcinolone acetonide, anti-CD3 antibodies, anti-CD4 antibodies, anti-CD19 antibodies, anti- CD20 antibodies, anti-CD22 antibodies, anti-CD40 antibodies, anti-FcRN antibodies, anti-IL6 antibodies, anti-IGFIR antibodies, an IL2 mutein, a BTK inhibitor, or a combination thereof. In an aspect, a disclosed immune modulator can comprise one or more Treg (regulatory T cells) infusions (e.g., antigen specific Treg cells to AAV). In an aspect, a disclosed immune modulator can be bortezomib or SVP-Rapamycin. In an aspect, a disclosed immune modulator can be Tacrolimus. In an aspect, an immune modulator can be administered by any suitable route of administration including, but not limited to, in utero. intra-CSF. intrathecally, intravenously, subcutaneously, transdermally, intradermally, intramuscularly, orally, transcutaneously, intraperitoneally (IP), or intravaginally. In an aspect, a disclosed immune modulator can be administered using a combination of routes. Administration can also include hepatic intra-arterial administration or administration through the hepatic portal vein (HPV). Administration of an immune modulator can be continuous or intermittent, and administration can comprise a combination of one or more routes.

[0096] In an aspect, the term “immunotolerant” refers to unresponsiveness to an antigen (e.g., a vector, a therapeutic protein, a transgene product, etc.). An immunotolerant promoter can reduce, ameliorate, or prevent transgene-induced immune responses that can be associated with gene therapy. Assays known in the art to measure immune responses, such as immunohistochemical detection of cytotoxic T cell responses, can be used to determine whether one or more promoters can confer immunotolerant properties.

[0097] In an aspect, the term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and / or warnings concerning the use of such therapeutic products.

[0098] In an aspect, the term “in combination” in the context of the administration of other therapies (e.g.. other agents) includes the use of more than one therapy (e.g., drug therapy). Administration “in combination with” one or more further therapeutic agents includes simultaneous (e.g., concurrent) and consecutive administration in any order. The use of the term “in combination” does not restrict the order in which therapies are administered to a subject. By way of non-limiting example, a first therapy (e.g., a disclosed composition comprising a disclosedsecretome, a disclosed conditioned media, a disclosed exosome or plurality of disclosed exosomes, a disclosed polypeptide, a disclosed isolated nucleic acid molecule, a disclosed vector, a disclosed pharmaceutical formulation, or a combination thereof) can be administered prior to (e.g., 1 minute. 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours. 8 hours. 12 hours, 24 hours, 48 hours. 72 hours, 96 hours, 1 week. 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks), concurrently, or after (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks. 6 weeks. 7 weeks. 8 weeks. 9 weeks. 10 weeks, 11 weeks, or 12 weeks or longer) the administration of a second therapy (e.g., agent) to a subject having or diagnosed with diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof.

[0099] Disclosed are the components to be used to prepare the disclosed compositions (comprising a disclosed secretome, a disclosed conditioned media, a disclosed exosome or plurality of disclosed exosomes), disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations as well as the disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C- D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additionalsteps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.B. Compositions1. Media, Secretomes, and Exosomes

[0100] Disclosed herein is a composition, comprising: a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs). Disclosed herein is a composition, comprising: conditioned media obtained from one or more p53- silenced bone marrow derived mesenchymal stromal cells (BM-MSCs). Disclosed herein is a composition, comprising: exosomes obtained from the conditioned media of one or more p53- silenced bone marrow derived mesenchymal stromal cells (BM-MSCs).

[0101] Disclosed herein is a composition, comprising: a secretome obtained from the conditioned media of one or more p53-silenced adipose derived mesenchymal stroma cells (AT-MSCs). Disclosed herein is a composition, comprising: conditioned media obtained from one or more p53- silenced adipose derived mesenchymal stromal cells (AT-MSCs). Disclosed herein is a composition, comprising: exosomes obtained from the conditioned media of one or more p53- silenced adipose derived mesenchymal stromal cells (AT-MSCs).

[0102] Disclosed herein is a composition, comprising: a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB- MSCs). Disclosed herein is a composition, comprising: conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs). Disclosed herein is a composition, comprising: exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs).

[0103] Disclosed herein is a composition, comprising: a secretome obtained from the conditioned media of one or more p53-silenced birth-associated tissue (BAT) derived mesenchymal stroma cells (BAT-MSCs). Disclosed herein is a composition, comprising: conditioned media obtained from one or more p53-silenced birth-associated tissue (BAT) derived mesenchymal stroma cells (BAT-MSCs). Disclosed herein is a composition, comprising: exosomes obtained from the conditioned media of one or more p53-silenced birth-associated tissue (BAT) derived mesenchymal stroma cells (BAT-MSCs). Birth-associated tissue (BAT) derived MSCs can include MSCs derived from amniotic fluid (AF-MSCs), human amnion membrane (HAM-MSCs), chorion membrane (CM-MSCs), chorion villi (CV-MSCs), decidua (D-MSCs), placenta (PL- MSCs), cord blood (CB-MSCs), Wharton’s jelly (WJ-MSCs), umbilical cord (UC-MSCs), and any combination thereof.

[0104] As know n to the art, TP53 (Tumor Protein P53) is a protein coding gene. Gene Ontology7(GO) annotations related to this gene include DNA-binding transcription factor activity andprotein heterodimerization activity. This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. For more information, see HGNC 11998; NCBI Gene 7157: Ensembl ENSG00000141510; OMIM 191170; and UniProtKB / Swiss-Prot P04637.

[0105] In an aspect, BM-MSCs can be defined by cell surface markers. In an aspect, BM-MSCs can be positive for cell surface expression of CD 13, CD44, CD73 (SH3), CD90, CD105 (SH2), CD166, STRO-1, or any combination thereof. In an aspect, BM-MSCs can be negative for cell surface expression of CD 14, CD34, CD45, or any combination thereof.

[0106] In an aspect, AT-MSCs can be positive for cell surface expression of CD9, CD13, CD29, CD44, CD54, CD73 (SH3), CD90, CD105 (SH2), CD106, CD146, CD166, HLA I, STRO-1, or any combination thereof. In an aspect, AT-MSCs can be negative for cell surface expression of CDl lb, CD14, CD19, CD31. CD34. CD45, CD79a. CD133. CD144. HLA-DR, or any combination thereof.

[0107] In an aspect, PB-MSCs can be positive for cell surface expression of CD44, CD54, CD90, CD105 (SH2), CD166, or any combination thereof. In an aspect, PB-MSCs can be negative for cell surface expression of CD14. CD34, CD45, CD31, or any combination thereof.

[0108] In an aspect, a disclosed composition can be concentrated. In an aspect, a disclosed secretome can be concentrated. In an aspect, a disclosed conditioned media can be concentrated. In an aspect, disclosed exosomes can be concentrated.

[0109] In an aspect, a disclosed composition can be cell-free. In an aspect, a disclosed secretome can be cell-free. In an aspect, a disclosed conditioned media can be cell-free. In an aspect, disclosed exosome can be cell-free.

[0110] In an aspect, secretome can refer to proteins secreted by a cell, a tissue, or an organism. In an aspect, secretome can refer to proteins secreted by a population of disclosed MSCs, BM- MSCs, PB-MSCs, AT-MSCs, BAT-MSCs, or any combination thereof.

[0111] In an aspect, MSCs can be genetically engineered and / or genetically modified. For example, in an aspect, a population of disclosed BM-MSCs can be genetically engineered and / or genetically modified. In an aspect, a population of disclosed PB-MSCs can be genetically engineered and / or genetically modified. In an aspect, a population of disclosed AT-MSCs can be genetically engineered and / or genetically modified. In an aspect, a population of disclosed BATs- MSCs can be genetically engineered and / or genetically modified. In an aspect, a disclosed genetic modification can be temporary' or can be permanent.

[0112] In an aspect disclosed p53-silenced BM-MSCs can overexpress superoxide dismutase (SOD2) and / or catalase (CAT). In an aspect, disclosed p53-silenced PB-MSCs can overexpress superoxide dismutase (SOD2) and / or catalase (CAT). In an aspect, disclosed p53-silenced AT- MSCs can overexpress superoxide dismutase (SOD2) and / or catalase (CAT). In an aspect, disclosed p53-silenced BAT-MSCs can overexpress superoxide dismutase (SOD2) and / or catalase (CAT).

[0113] In an aspect, a disclosed secretome can orchestrate the subtle and complex processes of embry onic development, can maintain the function of individual organs, and can coordinate organ activity through inter-organ communication. In an aspect, spent media can be the cell culture media that is formed by cell growth and remains after culturing of cells.

[0114] In an aspect of a disclosed composition, p53 silencing can be achieved by one or more methods known in the art. For example, in an aspect, a disclosed method for silencing p53 can comprise p53 gene knockout, RNA interference (RNAi), p53 gene mutation, epigenetic modifications (e.g., DNA methylation and histone modifications), small molecule inhibition, MDM2 interaction (protein that binds to p53 and promotes its degradation, effectively reducing p53 levels), viral proteins (e.g., ElB-55k and E4-ORF3, which can interact with p53 and disrupt its function, either by promoting p53 degradation or by interfering with p53's ability to bind to DNA), or any combination thereof. In an aspect. RNA interference (RNAi) can comprise using small interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) to target and suppress the expression of p53.

[0115] In an aspect, p53 silencing can occur via shRNA delivered via adenoviral vector. In an aspect, p53 silencing can occur via siRNA delivered with a lipid-based transfection reagent (such as, for example. RNAiMAX (Thermo Fisher Scientific)). In an aspect. siRNA delivered via a lipid-based transfection reagent eliminates the need to quantify viral clearance.

[0116] In an aspect, p53 silencing can occur using one or more functional inhibitors. In an aspect, “an inhibitor of p53 function” can be any substance capable of inhibiting either (i) the function of the p53 protein and / or (ii) the expression of the p53 gene. For example, in an aspect, an inhibitor of p53 function can act directly on the p53 protein to inhibit the function thereof and can act directly on the p53 gene to inhibit the expression thereof. Moreover, in an aspect, an inhibitor of p53 function can also act on one or more substances that act on a factor involved in p53 signal transduction to result in inhibition of the function of the p53 protein or the expression of the p53 gene. Examples of chemical inhibitors of p53 are known to the art. In an aspect, a chemical inhibitor of p53 includes, but is not limited to, a p53 inhibitor typified by pifithrin (PFT)-a and - P, which are disclosed in WO 00 / 44364, PFT-g disclosed in Storm et al. (Nat. Chem. Biol. 2, 474 (2006)), analogue thereof and salts thereof (for example, acid addition salts such as hydrochloridesand hydrobromides, and the like), and the like. Of these, PFT-a and analogues thereof [2-(2- Imino-4,5,6,7-tetrahydrobenzothiazol-3-yl)-l-p-tolylethanone, HBr (product name: Pifithrin-a) and l-(4-Nitrophenyl)-2-(4,5,6,7-tetrahydro-2-imino-3(2H)-benzothiazolyl)ethanone, HBr (product name: Pifithrin-a, p-Nitro)], PFT-J3 and analogues thereof [2-(4- Methylphenyl)imidazo[2,l-b]-5.6.7.8-tetrahydrobenzothiazole, HBr (product name: Pifithrin-a, Cyclic) and 2-(4-Nitrophenyl)imidazo[2,l-b]-5,6,7,8-tetrahydrobenzothiazole (product name: Pifithrin-a, p-Nitro, Cyclic)], and PFT-p. [Phenylacetylenylsulfonamide (product name: Pifithrin- p)] are commercially available from Merck.

[0117] In an aspect, disclosed BM-MSCs can be cultured in ordinary conditions. In an aspect, disclosed BM-MSCs can be cultured in hyperglycemic conditions. In an aspect, disclosed BM- MSCs can be cultured in xeno-free conditions or media. In an aspect, disclosed AT-MSCs can be cultured in ordinary' conditions. In an aspect, disclosed AT-MSCs can be cultured in hyperglycemic conditions. In an aspect, disclosed AT-MSCs can be cultured in xeno-free conditions or media. In an aspect, disclosed PB-MSCs can be cultured in ordinary conditions. In an aspect, disclosed PB-MSCs can be cultured in hyperglycemic conditions. In an aspect, disclosed PB-MSCs can be cultured in xeno-free conditions or media. In an aspect, disclosed BAT-MSCs can be cultured in ordinary conditions. In an aspect, disclosed BAT-MSCs can be cultured in hyperglycemic conditions. In an aspect, disclosed BAT-MSCs can be cultured in xeno- free conditions or media. In an aspect, disclosed MSCs can be cultured in exosome-free media.

[0118] In an aspect, exosome can be obtained and / or isolated from disclosed MSCs by one or more methods known to those skilled in the art. For example, in an aspect, exosome can be obtained using either protocol described in FIG. 7. In an aspect, Table 9 provides details of the protocols disclosed in FIG. 7. In an aspect, exosomes obtained from a disclosed population of MSCs can be subjected to an analysis. In an aspect, exosomes obtained from a disclosed population of p53-silenced MSCs can be subjected to an analysis. In an aspect, exosomes obtained from a disclosed population of MSCs can be characterized by one or more genes having modulated expression. In an aspect, exosomes obtained from a disclosed population of p53-silenced MSCs can be characterized by one or more genes having modulated expression.

[0119] In an aspect, modulated expression can be an increased expression when compared to a control or reference value. In an aspect, modulated expression can be a decreased expression when compared to a control or reference value. In an aspect, modulated expression of one or more genes in p53-silenced MSCs can be an increased expression when compared to a control or reference value or when compared to value obtained from a sham treated or scramble treated group. In an aspect, modulated expression can be a decreased expression when compared to a control or reference value or when compared to value obtained from a sham treated or scrambletreated group. In an aspect, a disclosed increase in expression level one or more genes (including one or more genes of interest) in p53-silenced MSCs can comprise at least a 1-fold, at least a 2- fold, at least a 3-fold, at least a 4-fold, at least a 5-fold, at least a 6-fold, at least a 7-fold, at least a 8-fold, at least a 9-fold, or at least a 10-fold increase over the value obtained from sham-treated MSCs, scramble-treated MSCs, or control MSCs. In an aspect, a disclosed increase in expression level one or more genes (including one or more genes of interest) in p53-silenced MSCs can comprise at least a 10-fold, at least a 20-fold, at least a 30-fold, at least a 40-fold, at least a 50- fold, at least a 60-fold, at least a 70-fold, at least a 80-fold, at least a 90-fold, or at least a 100-fold increase over the value obtained from sham-treated MSCs, scramble-treated MSCs, or control MSCs. In an aspect, a disclosed decrease in expression level one or more genes (including one or more genes of interest) in p53-silenced MSCs can comprise at least a 1-fold, at least a 2-fold, at least a 3-fold, at least a 4-fold, at least a 5-fold, at least a 6-fold, at least a 7-fold, at least a 8-fold, at least a 9-fold, or at least a 10-fold decrease over the value obtained from sham-treated MSCs, scramble-treated MSCs, or control MSCs. In an aspect, a disclosed decrease in expression level one or more genes (including one or more genes of interest) in p53-silenced MSCs can comprise at least a 10-fold, at least a 20-fold, at least a 30-fold, at least a 40-fold, at least a 50-fold, at least a 60-fold, at least a 70-fold, at least a 80-fold, at least a 90-fold, or at least a 100-fold decrease over the value obtained from sham-treated MSCs. scramble-treated MSCs, or control MSCs.

[0120] In an aspect, exosomes obtained from p53-silenced MSCs (including, for example, BM- MSCs) can have increased expression of SERPINB3, ARG1, KITLG, SERPINB12, TXNRD3, SFRP1, SERPINA12, MRAS, or any combination thereof. In an aspect, exosomes obtained from p53-silenced MSCs (including, for example. BM-MSCs) can have increased expression of one or more genes identified in Table 1.Table 1 - Identifying Information for Selected Genes of Interest

[0121] In an aspect, exosomes obtained from p53-silenced MSCs (including, for example, BM- MSCs) can have increased expression of one or more genes identified in Table 4 (infra). In an aspect, exosomes obtained from p53-silenced MSCs (including, for example, BM-MSCs) can have increased expression of one or more genes identified in Table 4 (infra).

[0122] In an aspect, exosomes obtained from p53-silenced MSCs (including, for example, BM- MSCs) can have decreased expression of one or more genes identified in Table 6 (infra). In an aspect, exosomes obtained from p53-silenced MSCs (including, for example, BM-MSCs) can have decreased expression of one or more genes identified in Table 6 (infra).

[0123] In an aspect, when administered to a subject in need thereof, a disclosed composition can effect one or more physiological changes. In an aspect, a disclosed composition can effect and / or can generate one or more positive and / or favorable physiological changes in a subject. In anaspect, when administered to a subject in need thereof, a disclosed composition can improve and / or enhance wound healing in the subj ect. In an aspect, when administered to a subj ect in need thereof, a disclosed composition can treat one or more diabetes-related symptoms or complications in the subject. In an aspect, when administered to a subject in need thereof, a disclosed composition can treat one or more diabetes-related vascular issues or diabetes-related vascular complications in the subj ect. In an aspect, when administered to a subj ect in need thereof, a disclosed composition can improve and / or enhance and / or stimulate and / or promote vascular regeneration in one or more tissues and / or one or more organs. In an aspect, when administered to a subject in need thereof, a disclosed composition can prevent apoptosis of cells exposed to hyperglycemia. In an aspect, when administered to a subject in need thereof, a disclosed composition can prevent the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia. In an aspect, when administered to a subject in need thereof, a disclosed composition can prevent apoptosis of endothelial cells exposed to hyperglycemia. In an aspect, when administered to a subject in need thereof, a disclosed composition can prevent the amount and / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia.

[0124] In an aspect, when administered to a subject in need thereof, a disclosed composition can improve and / or enhance and / or stimulate and / or promote endothelial regeneration in the subject. In an aspect, when administered to a subject in need thereof, a disclosed composition can diminish and / or decrease systemic inflammation in the subject. In an aspect, when administered to a subject in need thereof, a disclosed composition can improve and / or enhance renal function in the subject. In an aspect, when administered to a subject in need thereof, a disclosed composition can restore one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation in the subject.

[0125] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow- derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs). (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow- derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can effect one or more physiological changes.

[0126] In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs),or (iv) any combination thereof can effect and / or can generate one or more positive and / or favorable physiological changes in a subject.

[0127] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can improve and / or enhance wound healing in the subject.

[0128] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can treat one or more diabetes-related symptoms or complications in the subject.

[0129] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can treat one or more diabetes-related vascular issues or diabetes-related vascular complications in the subject.

[0130] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs). (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can improve and / or enhance and / or stimulate and / or promote vascular regeneration in one or more tissues and / or one or more organs.

[0131] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii)exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can prevent apoptosis of cells exposed to hyperglycemia. In an aspect, when administered to a subject in need thereof, a disclosed composition can prevent the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia.

[0132] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can prevent apoptosis of endothelial cells exposed to hyperglycemia. In an aspect, when administered to a subject in need thereof, a disclosed composition can prevent the amount and / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia.

[0133] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can improve and / or enhance and / or stimulate and / or promote endothelial regeneration in the subject.

[0134] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs). or (iv) any combination thereof can diminish and / or decrease systemic inflammation in the subject.

[0135] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can improve and / or enhance renal function in the subject.

[0136] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can restore one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation in the subj ect.

[0137] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof can effect one or more physiological changes.

[0138] In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53 -silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB- MSCs), or (iv) any combination thereof can effect and / or can generate one or more positive and / or favorable physiological changes in a subject.

[0139] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof can improve and / or enhance wound healing in the subject.

[0140] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral bloodderived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof can treat one or more diabetes-related symptoms or complications in the subject.

[0141] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof can treat one or more diabetes-related vascular issues or diabetes-related vascular complications in the subject.

[0142] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof improve and / or enhance and / or stimulate and / or promote vascular regeneration in one or more tissues and / or one or more organs.

[0143] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs). or (iv) any combination thereof can prevent apoptosis of cells exposed to hyperglycemia. In an aspect, when administered to a subject in need thereof, a disclosed composition can prevent the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia.

[0144] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof can prevent apoptosis of endothelial cells exposed to hyperglycemia. In an aspect, when administered to a subject in need thereof, a disclosed composition can prevent the amount and / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia.

[0145] In an aspect when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof can improve and / or enhance and / or stimulate and / or promote endothelial regeneration in the subject.

[0146] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof can diminish and / or decrease systemic inflammation in the subject.

[0147] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof can improve and / or enhance renal function in the subject.

[0148] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs). or (iv) any combination thereof can restore one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation in the subject.

[0149] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derivedmesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can effect one or more physiological changes.

[0150] In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can effect and / or can generate one or more positive and / or favorable physiological changes in a subject.

[0151] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs). (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can improve and / or enhance wound healing in the subject.

[0152] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can treat one or more diabetes-related symptoms or complications in the subject.

[0153] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs). (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can treat one or more diabetes-related vascular issues or diabetes-related vascular complications in the subject.

[0154] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derivedmesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof improve and / or enhance and / or stimulate and / or promote vascular regeneration in one or more tissues and / or one or more organs.

[0155] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can prevent apoptosis of cells exposed to hyperglycemia. In an aspect, when administered to a subject in need thereof, a disclosed composition can prevent the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia.

[0156] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can prevent apoptosis of endothelial cells exposed to hyperglycemia. In an aspect, when administered to a subject in need thereof, a disclosed composition can prevent the amount and / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia.

[0157] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can improve and / or enhance and / or stimulate and / or promote endothelial regeneration in the subject.

[0158] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can diminish and / or decrease systemic inflammation in the subject.

[0159] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs). (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can improve and / or enhance renal function in the subject.

[0160] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can restore one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation in the subj ect.

[0161] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can effect one or more physiological changes.

[0162] In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can effect and / or can generate one or more positive and / or favorable physiological changes in a subject.

[0163] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silencedbirth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can improve and / or enhance wound healing in the subject.

[0164] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (li) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can treat one or more diabetes-related symptoms or complications in the subject.

[0165] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can treat one or more diabetes-related vascular issues or diabetes-related vascular complications in the subject.

[0166] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof improve and / or enhance and / or stimulate and / or promote vascular regeneration in one or more tissues and / or one or more organs.

[0167] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can prevent apoptosis of cells exposed to hyperglycemia. In an aspect, when administered to a subject in need thereof, a disclosed composition can prevent the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia.

[0168] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (hi) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can prevent apoptosis of endothelial cells exposed to hyperglycemia. In an aspect, when administered to a subject in need thereof, a disclosed composition can prevent the amount and / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia.

[0169] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (hi) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can improve and / or enhance and / or stimulate and / or promote endothelial regeneration in the subject.

[0170] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (hi) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can diminish and / or decrease systemic inflammation in the subject.

[0171] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can improve and / or enhance renal function in the subject.

[0172] In an aspect, when administered to a subject in need thereof, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells(BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can restore one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation in the subject.

[0173] In an aspect, wherein restoring one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation in the subject comprises altering the expression of one or more genes related to mitochondrial biogenesis, one or more genes related to apoptosis, one or more genes related to vascular regeneration, one or more genes related to inflammation, one or more podocyte-specific genes, one or more antioxidant genes, or any combination thereof.

[0174] In an aspect, a disclosed gene related to mitochondrial biogenesis can comprise TFAM, ATP5B, NRF1, SDHB, NDUFA1, PGC1A, PRDM16, UCP1, CEBP-A, PPARG, or any combination thereof. In an aspect, a disclosed gene related to apoptosis can comprise p53, p21, BCL2, CASP3, CASP9, or any combination thereof. In an aspect, a disclosed gene related to vascular regeneration can comprise VEGF-A. PECAM1. eNOS, KDR. or any combination thereof. In an aspect, a disclosed podocyte-specific gene can comprise NPHS1, SYNPO / O2, WT1, or any combination thereof. In an aspect, a disclosed antioxidant gene can comprise SOD1, SOD2, SOD3, GPX1, GPX3, CAT, or any combination thereof. In an aspect, a disclosed gene related to inflammation comprise PTGS2, IL6, TNFa. NFKB, or any combination thereof.

[0175] In an aspect, a disclosed composition can be used in a method of treating a subject having diabetes. In an aspect, a disclosed composition can be used in a method of treating a subject having a diabetes-related complication or diabetes-related system. In an aspect, a disclosed composition can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed composition can be used in a method of treating a subject having diabetic ulcers or diabetic wounds. In an aspect, a disclosed composition can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed composition can be used in a method of treating a subject having nonalcoholic fatty liver disease (NAFLD). In an aspect, a disclosed composition can be used in a method of treating a subject having hyperglycemia. In an aspect, a disclosed composition can be used in a method of treating a subject having a chronic kidney disease. In an aspect, a disclosed composition can be used in a method of treating a subject having a wound healing disease or disorder. In an aspect, a disclosed composition can be used in a method of treating a subject having a peripheral vascular disease. In an aspect, a disclosed composition can be used in a method of treating a subject having cardiovascular disease.

[0176] In an aspect, a disclosed composition can be used in a method of treating a subject having diabetes. In an aspect, a disclosed composition can be used in a method of treating a subject having a diabetes-related complication or diabetes-related system. In an aspect, a disclosedcomposition can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed composition can be used in a method of treating a subject having diabetic ulcers or diabetic wounds. In an aspect, a disclosed composition can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed composition can be used in a method of treating a subject having nonalcoholic fatty liver disease (NAFLD).

[0177] In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs). (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having diabetes. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having a diabetes-related complication or diabetes-related system. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53- silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs). or (iv) any combination thereof can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53- silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having diabetic ulcers or diabetic wounds. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can be used in a methodof treating a subject having diabetic kidney disease. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having nonalcoholic fatty liver disease (NAFLD).

[0178] In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having hyperglycemia. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having chronic kidney disease.

[0179] In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs). (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having a wound healing disease or disorder.

[0180] In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs). (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof can be used in a method of treating a subj ect having peripheral vascular disease and / or cardiovascular disease.

[0181] In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB- MSCs), or (iv) any combination thereof can be used in a method of treating a subject having diabetes. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53 -silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB- MSCs), or (iv) any combination thereof can be used in a method of treating a subject having a diabetes-related complication or diabetes-related system. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs). or (iv) any combination thereof can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having diabetic ulcers or diabetic wounds. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53 -silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media ofone or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having nonalcoholic fatty liver disease (NAFLD).

[0182] In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB- MSCs), or (iv) any combination thereof can be used in a method of treating a subject having hyperglycemia. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB- MSCs), or (iv) any combination thereof can be used in a method of treating a subject having chronic kidney disease. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs). (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having wound healing disease or disorder. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having peripheral vascular disease and / or cardiovascular disease.

[0183] In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having diabetes. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditionedmedia of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having a diabetes-related complication or diabetes-related system. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having diabetic ulcers or diabetic wounds. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs). or (iv) any combination thereof can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs). (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having nonalcoholic fatty liver disease (NAFLD). In an aspect, a disclosed comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can be used in a methodof treating a subject having hyperglycemia. In an aspect a disclosed comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53- silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having chronic kidney disease. In an aspect, a disclosed comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs). (ii) conditioned media obtained from one or more p53- silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having wound healing disease or disorder. In an aspect, a disclosed comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having peripheral vascular disease and / or cardiovascular disease.

[0184] In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs). (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can be used in a method of treating a subj ect having diabetes. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53- silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having a diabetes-related complication or diabetes-related system. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT- MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissuederived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53- silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having diabetic ulcers or diabetic wounds. In an aspect, a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having nonalcoholic fatty liver disease (NAFLD).

[0185] In an aspect, a disclosed comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT- MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs). (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having hyperglycemia. In an aspect, a disclosed comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can be used in a method of treating asubject having chronic kidney disease. In an aspect a disclosed comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53- silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having wound healing disease or disorder. In an aspect, a disclosed comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof can be used in a method of treating a subject having peripheral vascular disease and / or cardiovascular disease.

[0186] In an aspect, a disclosed composition can be incorporated into a cell-free therapy. In an aspect, a disclosed composition comprising a disclosed secretome can be incorporated into a cell- free therapy. In an aspect, a disclosed composition comprising a disclosed conditioned media can be incorporated into a cell-free therapy. In an aspect, a disclosed composition comprising disclosed exosomes can be incorporated into a cell-free therapy. In an aspect, a disclosed cell- free therapy can confer advantages and / or benefits (e.g., reduced cost, improved or easier handling, and reduced immunogenicity). In an aspect, a disclosed composition can be incorporated into a pharmaceutical formulation. In an aspect, a disclosed composition comprising a disclosed secretome can be incorporated into a pharmaceutical formulation. In an aspect, a disclosed composition comprising a disclosed conditioned media can be incorporated into a pharmaceutical formulation. In an aspect, a disclosed composition comprising disclosed exosomes can be incorporated into a pharmaceutical formulation. In an aspect, a disclosed pharmaceutical formulation can confer advantages and / or benefits (e.g., reduced cost, improved or easier handling, and reduced immunogenicity).

[0187] Disclosed herein are exosomes retrieved from the spent media of cultured p53-silenced MSCs. Disclosed herein are exosomes retrieved from the spent media of cultured p53-silenced BM-MSCs. Disclosed herein are exosomes retrieved from the spent media of cultured p53- silenced PB-MSCs. Disclosed herein are exosomes retrieved from the spent media of cultured p53-silenced AT-MSCs. Disclosed herein are exosomes retrieved from the spent media of cultured p53-silenced BAT-MSCs.2. Vectors

[0188] Disclosed herein is a vector comprising a disclosed nucleic acid molecule. Disclosed herein is a vector comprising a disclosed p53-silencing shRNA.

[0189] In an aspect, a disclosed vector can be a viral vector or a non-viral vector. In an aspect, a disclosed non-viral vector can be a polymer-based vector, a peptide-based vector, a lipid nanoparticle, a solid lipid nanoparticle, or a cationic lipid-based vector. In an aspect, a disclosed viral vector can be an adenovirus vector, an AAV vector, a herpes simplex virus vector, a retrovirus vector, a lentivirus vector, and alphavirus vector, a flavivirus vector, a rhabdovirus vector, a measles virus vector, a Newcastle disease viral vector, a poxvirus vector, or a picomavirus vector.

[0190] In an aspect, a disclosed promoter can be tissue-specific or ubiquitous and can be constitutive or inducible, depending on the pattern of the expression desired. A promoter can be native or foreign and can be a natural or a synthetic sequence. By foreign, it is intended that the transcriptional initiation region is not found in the wild-type host into which the transcriptional initiation region is introduced. In an aspect, a disclosed promoter can be a promoter / enhancer. In an aspect, a disclosed promoter for the disclosed nucleic acid molecule can be an endogenous promoter. In an aspect, a disclosed endogenous promoter can be an endogenous promoter / enhancer. In an aspect, a disclosed endogenous promoter or a disclosed endogenous promoter / enhancer can generally be obtained from anon-coding region upstream of a transcription initiation site of a gene of interest. In an aspect, a disclosed endogenous promoter or a disclosed endogenous promoter / enhancer can be used for constitutive and efficient expression of a disclosed gene. In an aspect, a disclosed promoter for the one or more disclosed guide RNA sequences can be a CMV promoter or a CMV promoter / enhancer. CMV promoters and CMV promoters / enhancers are well known to the art.

[0191] In an aspect, a disclosed vector can comprise the sequence for one or more regulatory' elements. In an aspect, a disclosed regulatory element can comprise promoters, enhancers, internal ribosomal entry sites (IRES), and other expression control elements (e.g., transcription termination signals, such as polyadenylation signals and poly-U sequences). Regulatory elements can include those that direct constitutive expression of a nucleotide sequence in many ty pes of host cells and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). In an aspect, a disclosed regulatory’ element can comprise Woodchuck Hepatitis Virus (WHV) Posttranscriptional Regulator Element (WPRE), triplex from MALAT1, the PRE of Hepatitis B virus (HPRE), an iron response element, or any combination thereof. For example, a disclosed regulatory’ element can comprise a promoteroperably linked to a disclosed nucleic acid molecule, wherein the promoter drives the expression of a disclosed p53-silencing element.

[0192] In an aspect, a disclosed vector can be used to transduce a population of MSCs with a p53- silencing element (e g., shRNA). In an aspect, a disclosed vector can be used to transduce a population of BM-MSCs with a p53-silencing element (e.g., shRNA). In an aspect, a disclosed vector can be used to transduce a population of PB-MSCs with a p53-silencing element (e.g., shRNA). In an aspect, a disclosed vector can be used to transduce a population of AT-MSCs with a p53-silencing element (e g., shRNA). In an aspect, a disclosed vector can be used to transduce a population of BAT-MSCs with a p53-silencing element (e.g., shRNA).

[0193] In an aspect, a disclosed vector can ameliorate and / or mitigate the negative and / or deleterious effect that diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD). a wound healing disease or disorder, or any combination thereof has on a subject.3. Pharmaceutical Formulations

[0194] Disclosed herein is a pharmaceutical formulation comprising a secret ome obtained from the conditioned media of one or more p53-silenced mesenchymal stroma cells (MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising conditioned media obtained from one or more p53- silenced mesenchymal stromal cells (MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0195] Disclosed herein is a pharmaceutical formulation comprising a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM- MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs); and one or more pharmaceutically acceptable earners, excipients, and / or diluents.

[0196] Disclosed herein is a pharmaceutical formulation comprising a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / ordiluents. Disclosed herein is a pharmaceutical formulation comprising conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB- MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0197] Disclosed herein is a pharmaceutical formulation comprising a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT- MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation compnsing exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0198] Disclosed herein is a pharmaceutical formulation comprising a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs); and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation comprising conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs; and one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Disclosed herein is a pharmaceutical formulation compnsing exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs; and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0199] In an aspect, a disclosed pharmaceutical formulation can be used in a disclosed method of treating a subject. In an aspect, a disclosed pharmaceutical formulation can be used in a method of treating a subject having diabetes. In an aspect, a disclosed pharmaceutical formulation can be used in a method of treating a subject having a diabetes-related complication or diabetes-related system. In an aspect, a disclosed pharmaceutical formulation can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed pharmaceutical formulation can be used in a method of treating a subject having diabetic ulcers or diabetic wounds. In an aspect, a disclosed pharmaceutical formulation can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed pharmaceutical formulation can be usedin a method of treating a subject having nonalcoholic fatty liver disease (NAFLD). In an aspect, a disclosed pharmaceutical formulation can be used in a method of treating a subject having hyperglycemia. In an aspect, a disclosed pharmaceutical formulation can be used in a method of treating a subject having a chronic kidney disease. In an aspect, a disclosed pharmaceutical formulation can be used in a method of treating a subject having a wound healing disease or disorder. In an aspect, a disclosed pharmaceutical formulation can be used in a method of treating a subject having a peripheral vascular disease. In an aspect, a disclosed pharmaceutical formulation can be used in a method of treating a subject having cardiovascular disease. In an aspect, when administered to a subject in need thereof, a disclosed pharmaceutical formulation can effect one or more physiological changes. In an aspect, a disclosed pharmaceutical formulation can effect and / or can generate one or more positive and / or favorable physiological changes in a subject. In an aspect, when administered to a subject in need thereof, a disclosed pharmaceutical formulation can improve and / or enhance wound healing in the subject. In an aspect, when administered to a subject in need thereof, a disclosed pharmaceutical formulation can treat one or more diabetes-related symptoms or complications in the subject. In an aspect, when administered to a subject in need thereof, a disclosed pharmaceutical formulation can treat one or more diabetes-related vascular issues or diabetes-related vascular complications in the subject. In an aspect, when administered to a subject in need thereof, a disclosed pharmaceutical formulation can improve and / or enhance and / or stimulate and / or promote vascular regeneration in one or more tissues and / or one or more organs. In an aspect, when administered to a subject in need thereof, a disclosed pharmaceutical formulation can prevent apoptosis of cells exposed to hyperglycemia. In an aspect, when administered to a subject in need thereof, a disclosed pharmaceutical formulation can prevent the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia. In an aspect, when administered to a subject in need thereof, a disclosed pharmaceutical formulation can prevent apoptosis of endothelial cells exposed to hyperglycemia. In an aspect, when administered to a subject in need thereof, a disclosed pharmaceutical formulation can prevent the amount and / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia. In an aspect, when administered to a subject in need thereof, a disclosed pharmaceutical formulation can improve and / or enhance and / or stimulate and / or promote endothelial regeneration in the subject. In an aspect, when administered to a subject in need thereof, a disclosed pharmaceutical formulation can diminish and / or decrease systemic inflammation in the subject. In an aspect, when administered to a subject in need thereof, a disclosed pharmaceutical formulation can improve and / or enhance renal function in the subject. In an aspect, when administered to a subject in need thereof, a disclosed pharmaceuticalformulation can restore one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation in the subject.

[0200] In an aspect, a disclosed pharmaceutical formulation can comprise (i) one or more active agents, (ii) biologically active agents, (iii) one or more pharmaceutically active agents, (iv) one or more immune-based therapeutic agents, (v) one or more clinically approved agents, or (vi) a combination thereof. In an aspect, a disclosed composition can comprise one or more proteasome inhibitors. In an aspect, a disclosed composition can comprise one or more immunosuppressives or immunosuppressive agents. In an aspect, an immunosuppressive agent can be anti-thymocyte globulin (ATG), cyclosporine (CSP), mycophenolate mofetil (MMF), or a combination thereof. In an aspect, a disclosed formulation can comprise an anaplerotic agent (such as, for example, C7 compounds like triheptanoin or MCT).

[0201] In an aspect, a disclosed formulation can comprise an RNA therapeutic. In an aspect, a disclosed RNA therapeutic can comprise RNA-mediated interference (RNAi) and / or antisense oligonucleotides (ASO). A disclosed RNA therapeutic can comprise therapy delivered via LNPs. In an aspect, a disclosed pharmaceutical formulation can comprise an enzyme or enzyme precursor for enzyme replacement therapy (ERT).

[0202] Disclosed herein is a pharmaceutical formulation comprising a disclosed vector. Vectors are discussed supra.4. Cells

[0203] Disclosed herein are cells comprising a disclosed nucleic acid molecule, a disclosed vector, and / or a disclosed plasmid. Disclosed herein are cells contacted with one or more disclosed polypeptides, one or more disclosed nucleic acid molecule, one or more disclosed vectors, and / or one or more disclosed plasmids. Cells are known to the art.

[0204] Disclosed herein are MSCs characterized by p53-silencing. Disclosed herein are BM- MSCs characterized by p53-silencing. Disclosed herein are PB-MSCs characterized by p53- silencing. Disclosed herein are AT-MSCs characterized by p53-silencing. Disclosed herein are BAT-MSCs characterized by p53-silencing.

[0205] Disclosed herein are p53-silenced MSCs. Disclosed herein are p53-silenced BM-MSCs.

[0206] Disclosed herein are p53-silenced PB-MSCs. Disclosed herein are p53-silenced AT- MSCs. Disclosed herein are p53-silenced BAT-MSCs. Disclosed herein are cultured p53- silenced MSCs. Disclosed herein are cultured p53-silenced BM-MSCs. Disclosed herein are cultured p53-silenced PB-MSCs. Disclosed herein are cultured p53-silenced AT-MSCs. Disclosed herein are cultured p53-silenced BAT-MSCs.

[0207] Disclosed herein are cultured p53-silenced MSCs that generate spent media during the culturing process. Disclosed herein are cultured p53-silenced BM-MSCs that generate spentmedia during the culturing process. Disclosed herein are cultured p53-silenced PB-MSCs that generate spent media during the culturing process. Disclosed herein are cultured p53-silenced AT-MSCs that generate spent media during the culturing process. Disclosed herein are cultured p53-silenced BAT-MSCs that generate spent media during the culturing process.5. Animals

[0208] Disclosed herein are animals treated with a disclosed secretome, a disclosed conditioned media, a disclosed plurality of exosomes or a disclosed population of exosomes, a disclosed pharmaceutical formulation, a disclosed vector, and / or a disclosed plasmid. Disclosed herein are animals treated with one or more disclosed secretomes, one or more disclosed conditioned media, one or more disclosed exosomes, one or more disclosed pharmaceutical formulations, one or more disclosed vectors, and / or one or more disclosed plasmids. In an aspect, a disclosed animal can be used to validate the efficacy of a disclosed secretome, a disclosed conditioned media, a disclosed plurality of exosomes or a disclosed population of exosomes, a disclosed pharmaceutical formulation, a disclosed vector, and / or a disclosed plasmid. In an aspect, a disclosed animal can be used to validate the efficacy of one or more disclosed secretomes, one or more disclosed conditioned media, one or more disclosed exosomes, one or more disclosed pharmaceutical formulations, one or more disclosed vectors, and / or one or more disclosed plasmids.6. Kits

[0209] Disclosed herein is a kit comprising a disclosed secretome, a disclosed conditioned media, a disclosed plurality of exosomes or a disclosed population of exosomes, a disclosed pharmaceutical formulation, a disclosed vector, and / or a disclosed plasmid. Disclosed herein is a kit comprising one or more disclosed secretomes, one or more disclosed conditioned media, one or more disclosed exosomes, one or more disclosed pharmaceutical formulations, one or more disclosed vectors, and / or any combination thereof. Disclosed herein is a kit comprising a disclosed secretome, a disclosed conditioned media, a disclosed plurality of exosomes or a disclosed population of exosomes, a disclosed pharmaceutical formulation, a disclosed vector, and / or a disclosed plasmid; and one or more agents. Disclosed herein is a kit comprising one or more disclosed secretomes, one or more disclosed conditioned media, one or more disclosed exosomes, one or more disclosed pharmaceutical formulations, one or more disclosed vectors, and / or one or more disclosed plasmids; and one or more agents. In an aspect, a disclosed kit can comprise a label or package insert with instructions for use.

[0210] “Agents’’ and “Therapeutic Agents” are known to the art and are described supra. In an aspect, the one or more agents can treat, prevent, inhibit, and / or ameliorate one or more comorbidities in a subject. In an aspect, a disclosed kit can comprise (i) one or more active agents, (ii) biologically active agents, (iii) one or more pharmaceutically active agents, (iv) one or moreimmune-based therapeutic agents, (v) one or more clinically approved agents, or (vi) a combination thereof. In an aspect, a disclosed kit can be used in a method of treating a subject having diabetes. In an aspect, a disclosed kit can be used in a method of treating a subject having a diabetes-related complication or diabetes-related system. In an aspect, a disclosed kit can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed kit can be used in a method of treating a subject having diabetic ulcers or diabetic wounds. In an aspect, a disclosed kit can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed kit can be used in a method of treating a subj ect having nonalcoholic fatty liver disease (NAFLD). In an aspect, a disclosed kit can be used in a method of treating a subject having hyperglycemia. In an aspect, a disclosed kit can be used in a method of treating a subject having a chronic kidney disease. In an aspect, a disclosed kit can be used in a method of treating a subject having a wound healing disease or disorder. In an aspect, a disclosed kit can be used in a method of treating a subject having a peripheral vascular disease. In an aspect, a disclosed kit can be used in a method of treating a subject having cardiovascular disease. In an aspect, a disclosed kit can effect one or more physiological changes. In an aspect, a disclosed kit can effect and / or can generate one or more positive and / or favorable physiological changes in a subject. In an aspect, a disclosed kit can improve and / or enhance wound healing in the subject. In an aspect, a disclosed kit can treat one or more diabetes-related symptoms or complications in the subject. In an aspect, a disclosed kit can treat one or more diabetes-related vascular issues or diabetes- related vascular complications in the subject. In an aspect, a disclosed kit can improve and / or enhance and / or stimulate and / or promote vascular regeneration in one or more tissues and / or one or more organs. In an aspect, a disclosed kit can prevent apoptosis of cells exposed to hyperglycemia.

[0211] In an aspect, a disclosed kit can prevent the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia. In an aspect, a disclosed kit can prevent apoptosis of endothelial cells exposed to hyperglycemia. In an aspect, a disclosed kit can prevent the amount and / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia. In an aspect, a disclosed kit can improve and / or enhance and / or stimulate and / or promote endothelial regeneration in the subject. In an aspect, a disclosed kit can diminish and / or decrease systemic inflammation in the subject. In an aspect, a disclosed kit can improve and / or enhance renal function in the subject. In an aspect, a disclosed kit can restore one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation in the subject.

[0212] In an aspect, a disclosed kit can comprise at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose (such as, for example, generating a disclosed secretome, a disclosed conditioned media, a disclosed exosome or adisclosed plurality of exosomes, or any combination thereof)- Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0213] In an aspect, a kit for use in a disclosed method can comprise one or more containers holding disclosed cells (such as BM-MSCs, PB-MSCs, AT-MSCs, BAT-MSCs, or any combination thereof), disclosed siRNAs, disclosed shRNAs. disclosed p53-silencing agents, disclosed flasks or wells, disclosed medias, disclosed vectors, or any combination thereof,

[0214] In an aspect, suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The containers can be formed from a variety of materials such as glass or plastic. The container can hold a disclosed polypeptide, a disclosed isolated nucleic acid molecule, a disclosed vector, a disclosed pharmaceutical formulation, or a combination thereof, and can have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).

[0215] The label or package insert can indicate that a disclosed polypeptide, a disclosed isolated nucleic acid molecule, a disclosed vector, a disclosed pharmaceutical formulation, a disclosed RNA therapeutic, or a combination thereof can be used for treating, preventing, inhibiting, and / or ameliorating complications and / or symptoms associated with diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof. A disclosed kit can comprise additional components necessary for administration such as, for example, other buffers, diluents, filters, needles, and syringes.C. Methods

[0216] Disclosed herein are methods using one or more disclosed compositions.1. Methods of Preparing a Disclosed Composition

[0217] Disclosed herein is a method of preparing a disclosed composition.

[0218] Disclosed herein is a method of preparing a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53- silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof.

[0219] Disclosed herein is a method of preparing a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof.

[0220] Disclosed herein is a method of preparing a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof.

[0221] Disclosed herein is a method of preparing a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof.

[0222] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; transducing the BM-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced BM-MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; transducing the PB-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced PB-MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; transducing the AT-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced AT-MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT-MSCs in media; transducing the BAT-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced BAT-MSCs in media; and collecting the spent media.

[0223] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; transducing the BM-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced BM-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; transducing the PB-MSCs with a viral vectorcomprising a p53 shRNA; culturing the transduced PB-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; transducing the AT-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced AT-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT- MSCs in media; transducing the BAT-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced BAT-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media.

[0224] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; transducing the BM-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced BM-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; transducing the PB-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced PB-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purify ing the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; transducing the AT-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced AT-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purify ing the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT-MSCs in media; transducing the BAT-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced BAT-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes.

[0225] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; transducing the BM-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced BM-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; transducing the PB-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced PB-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; transducing the AT-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced AT-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosedherein is a method of preparing a composition, the method comprising culturing BAT-MSCs in media; transducing the BAT-MSCs with a viral vector comprising a p53 shRNA; culturing the transduced BAT-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome.

[0226] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; silencing p53 in BM-MSCs; culturing the p53-silenced BM-MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; silencing p53 in PB-MSCs; culturing the p53- silenced PB-MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; silencing p53 in AT-MSCs; culturing the p53-silenced AT-MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT- MSCs in media; silencing p53 in BAT-MSCs; culturing the p53-silenced BAT-MSCs in media; and collecting the spent media.

[0227] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; silencing p53 in BM-MSCs; culturing the p53-silenced BM-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing PB- MSCs in media; silencing p53 in PB-MSCs; culturing the p53-silenced PB-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing AT- MSCs in media; silencing p53 in AT-MSCs; culturing the p53-silenced AT-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT- MSCs in media; silencing p53 in BAT-MSCs; culturing the p53-silenced BAT-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media.

[0228] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; silencing p53 in BM-MSCs; culturing the p53-silenced BM-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; silencing p53 in PB-MSCs; culturing the p53- silenced PB-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; silencing p53 in AT-MSCs; culturing the p53-silenced AT-MSCs in media; collecting the spent media; isolatingexosomes from the spent media; and concentrating and / or purifying the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT- MSCs in media; silencing p53 in BAT-MSCs; culturing the p53-silenced BAT-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes.

[0229] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; silencing p53 in BM-MSCs; culturing the p53-silenced BM-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; silencing p53 in PB-MSCs; culturing the p53-silenced PB-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; silencing p53 in AT-MSCs; culturing the p53-silenced AT-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT-MSCs in media; silencing p53 in BAT- MSCs; culturing the p53-silenced BAT-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome.

[0230] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; using siRNA to silence p53 in BM-MSCs; culturing the p53-silenced BM- MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; using siRNA to silence p53 in PB-MSCs; culturing the p53-silenced PB-MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing AT- MSCs in media; using siRNA to silence p53 in AT-MSCs; culturing the p53-silenced AT-MSCs in media; and collecting the spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT-MSCs in media; using siRNA to silence p53 in BAT- MSCs; culturing the p53-silenced BAT-MSCs in media; and collecting the spent media.

[0231] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; using siRNA to silence p53 in BM-MSCs; culturing the p53-silenced BM- MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; using siRNA to silence p53 in PB-MSCs; culturing the p53-silenced PB- MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; using siRNA to silence p53 in AT-MSCs; culturing the p53-silenced AT-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT-MSCs in media; using siRNA to silence p53 in BAT-MSCs; culturing the p53-silenced BAT-MSCs in media; collecting the spent media; and concentrating and / or purifying the collected spent media.

[0232] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; using siRNA to silence p53 in BM-MSCs; culturing the p53-silenced BM- MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing PB-MSCs in media; using siRNA to silence p53 in PB-MSCs; culturing the p53-silenced PB-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing AT- MSCs in media; using siRNA to silence p53 in AT-MSCs; culturing the p53-silenced AT-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT-MSCs in media; using siRNA to silence p53 in BAT- MSCs; culturing the p53-silenced BAT-MSCs in media; collecting the spent media; isolating exosomes from the spent media; and concentrating and / or purifying the isolated exosomes.

[0233] Disclosed herein is a method of preparing a composition, the method comprising culturing BM-MSCs in media; using siRNA to silence p53 in BM-MSCs; culturing the p53-silenced BM- MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing PB- MSCs in media; using siRNA to silence p53 in PB-MSCs; culturing the p53-silenced PB-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing AT-MSCs in media; using siRNA to silence p53 in AT-MSCs; culturing the p53-silenced AT-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome. Disclosed herein is a method of preparing a composition, the method comprising culturing BAT-MSCs in media; using siRNA to silence p53 in BAT-MSCs; culturing the p53-silenced BAT-MSCs in media; collecting the spent media; and concentrating and / or purifying the secretome.

[0234] In an aspect of a disclosed method, purifying a disclosed composition can comprise any method or technique known to the skilled person. For example, purification techniques and reagents are identified in Table 9 and in FIG. 7A and FIG. 7B.

[0235] In an aspect, a disclosed method can further comprise defining and / or characterizing the identity or nature of the MSCs. In an aspect of a disclosed method, BM-MSCs can be defined and / or characterized by cell surface markers. In an aspect, BM-MSCs can be positive for cell surface expression of CD 13, CD44, CD73 (SH3), CD90, CD 105 (SH2), CD 166, STRO-1, or any combination thereof. In an aspect, BM-MSCs can be negative for cell surface expression of CD14, CD34, CD45, or any combination thereof. In an aspect, AT-MSCs can be positive for cell surface expression of CD9, CD13, CD29, CD44, CD54, CD73 (SH3), CD90, CD105 (SH2), CD106, CD146, CD166, HLA I, STRO-1, or any combination thereof. In an aspect, AT-MSCs can be negative for cell surface expression of CDl lb, CD14, CD19, CD31, CD34, CD45, CD79a, CD133, CD144, HLA-DR, or any combination thereof. In an aspect, PB-MSCs can be positive for cell surface expression of CD44, CD54, CD90, CD 105 (SH2), CD 166, or any combination thereof. In an aspect, PB-MSCs can be negative for cell surface expression of CD14, CD34, CD45, CD31, or any combination thereof.

[0236] In an aspect, a disclosed media can be Fetal Bovine Serum (FBS), Human Serum Albumin (HSA), axeno-free media, or any serum-free media. In an aspect of a disclosed method, culturing the transduced BM-MSCs, PB-MSCs, AT-MSCs, or BAT-MSCs can comprise using an exosome- free FBS, a xeno-free media, an exosome-free HAS, or a serum-free, exosome-free media. In an aspect of a disclosed method, culturing the transduced BM-MSCs. PB-MSCs, AT-MSCs, or BAT- MSCs can comprise using an exosome-free FBS, an exosome-free HAS, a xeno-free media, or a serum-free, exosome-free media.

[0237] In an aspect of a disclosed method, culturing the transduced BM-MSCs, PB-MSCs, AT- MSCs, or BAT-MSCs can comprise about 24 hours to about 144 hours. In an aspect of a disclosed method, culturing the transduced BM-MSCs, PB-MSCs, AT-MSCs, or BAT-MSCs can comprise about 110 hours to about 130 hours. In an aspect of a disclosed method, culturing the transduced BM-MSCs, PB-MSCs, AT-MSCs, or BAT-MSCs can comprise adding fresh media one or more times during culturing.

[0238] In an aspect of a disclosed method, during the culturing of the transduced BM-MSCs. PB- MSCs, AT-MSCs, or BAT-MSCs, collecting the spent media can occur at about 6 hours, at about 12 hours, at about 18 hours, at about 24 hours, at about 36 hours, at about 48 hours, at about 60 hours, at about 72 hours, at about 84 hours, at about 96 hours, at about 108 hours, at about 120 hours, at about 132 hours, at about 144 hours, or more than at least 144 hours, or any combination thereof.

[0239] In an aspect of a disclosed method, culturing p53-silenced BM-MSCs, PB-MSCs, AT- MSCs, or BAT-MSCs can comprise using an exosome-free FBS, a xeno-free media, an exosome- free HAS, or a serum-free, exosome-free media. In an aspect of a disclosed method, culturingp53-silenced BM-MSCs, PB-MSCs, AT-MSCs, or BAT-MSCs can comprise using an exosome- free FBS, an exosome-free HAS, a xeno-free media, or a serum-free, exosome-free media. In an aspect of a disclosed method, culturing p53-silenced BM-MSCs, PB-MSCs, AT-MSCs, or BAT- MSCs can comprise about 24 hours to about 144 hours. In an aspect of a disclosed method, culturing p53-silenced BM-MSCs. PB-MSCs. AT-MSCs. or BAT-MSCs can comprise about 110 hours to about 130 hours.

[0240] In an aspect of a disclosed method, culturing p53-silenced BM-MSCs, PB-MSCs, AT- MSCs, or BAT-MSCs can comprise adding fresh media one or more times during culturing. In an aspect of a disclosed method, adding fresh media during the culturing of p53-silenced BM- MSCs, PB-MSCs, AT-MSCs, or BAT-MSCs can occur at about 6 hours, at about 12 hours, at about 18 hours, at about 24 hours, at about 36 hours, at about 48 hours, at about 60 hours, at about 72 hours, at about 84 hours, at about 96 hours, at about 108 hours, at about 120 hours, at about 132 hours, at about 144 hours, or more than at least 144 hours, or any combination thereof.

[0241] In an aspect, a disclosed method can further comprise concentrating the collected spent media. In an aspect, a disclosed method can further comprise concentrating the collected spent media to obtain a condition media. In an aspect, the disclosed collected spent media can be concentrated by at least 1-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, or more than 25-fold. In an aspect of a disclosed method, concentrating the collected spent media can comprise using a concentrator having a 5 kDa, a 10 kDa, a 15 kDa, or a 20 kDa cut off. In an aspect, a skilled person can identify an appropriate cut off for concentration. In an aspect, a disclosed method can further comprise dividing the spent media into an exosomal fraction and a non-exosomal fraction. In an aspect, an exosome or a plurality of exosomes can be characterized by size and / or the presence of one or more surface markers. In an aspect, a disclosed surface marker can comprise CD81, CD63, Alix, or any combination thereof.

[0242] In an aspect, exosomes can comprise small extracellular vesicles (sEVs), large extracellular vesicles (sEVs), microvesicles, small ectosomes, apoptotic bodies, or any combination thereof. In an aspect, exosomes can be isolated using any method or technique known to the art. For example, U.S. Patent App. Publication No. 2022 / 0118452, which is incorporated by reference in its entirety for teaching the isolating one or more subpopulations of the extracellular vesicles, can also be incorporated by reference for its teaching of methods / techniques to sort exosomes subpopulations based on size and surface markers, which can, in an aspect, be applied here as well.

[0243] In an aspect, nanoparticle tracking analysis (NTA) is a widely used technique to visualize and characterize EVs, providing various information from a single technique, such as size, sizedistribution, concentration, surface biomarkers, etc. In an aspect, NTA tracks the Brownian motion of nanoparticles in a solution using a laser beam, which uses a high-sensitivity camera to capture the scattered light from nanoparticles in real-time. By analyzing trajectories of nanoparticles frame by frame within a certain period, the diffusion coefficient of each particle is calculated from its motion, and the hydrodynamic diameter is subsequently calculated using the Stokes-Einstein equation. Currently, there are two modes of NTA based on detecting signals either from the scattered lights from EVs or fluorescent emission of fluorescence-labeled EVs. NTA instruments currently have four choices of lasers (e.g., 405, 488, 532, or 642 nm).

[0244] In an aspect, along with the appropriate filters, a wide range of fluorescent tags can be used to facilitate fluorescence measurements of EVs. The light-scattering mode NTA has the same working principle as dynamic light scattering (DLS), both of which track the Brownian motion of the objects by detecting the scattered lights. DLS is another commonly used technique to characterize EVs in solution. DLS only provides information on EV size and size distribution by analyzing the scattered light intensities. However, NTA generates a number-based size and size distribution by visualization. Compared to NTA, DLS does not offer information related to concentration or numbers because it analyzes all particles in solution simultaneously. In addition, DLS has challenges in analyzing poly disperse samples, where scattered lights from larger obj ects dominant over the smaller ones. One benefit of DLS over NTA is the upper detection threshold of around 6 pm versus 1 pm for NTA. In general, the size obtained from DLS is slightly larger than that from NTA because of the intrinsic heterogeneity of EVs and the domination of scattered light by larger-sized objects.

[0245] Consequently, the fluorescent mode of NTA (fNTA) was developed, which detects fluorescently labeled EVs (see, e.g., FIG. 9A - FIG. 9B showing data for MSC-derived exosomes). Switching from scattering to fluorescence mode, a long-pass filter is normally used to block the excitation wavelength. The fluorescent mode of NTA not only provides more accurate size and concentration information but also allows for the confirmation of EV types. When EV samples are analyzed in both light scattering and fluorescent modes, the percentage of EVs with labeled specific protein markers can be obtained in the solution. With the capability of multiple labeling, biomarker-positive or negative EVs allow the establishment of EV profiling as a supporting method for EV quantification.

[0246] In summary. NTA provides real-time EV analysis in solution, yielding accurate information regarding EV size, size distribution, and phenotypes. If EV samples are properly prepared and NTA instrument parameters are well calibrated, NTA quantification is highly valuable for EV studies, such as the evaluation of isolation methods, dynamic studies of EV production and release, and EV detection based on surface markers. The selection of light-scattering mode vs. fluorescent mode depends on the study needs and the information to be obtained. In an aspect, a disclosed method can use a Multifunctional Exosome Sorter (MFES), which can dissect the whole exosome population into subpopulations based on size and surface markers.

[0247] In an aspect, a disclosed method of preparing a disclosed composition can further comprise purifying the collected spent media. In an aspect, a disclosed method of preparing a disclosed composition can further comprise purifying the isolated exosomes. In an aspect, a disclosed method of preparing a disclosed composition can further comprise purifying the secretome. In an aspect, a disclosed method of preparing a disclosed composition can further comprise characterizing the purified spent media. In an aspect, a disclosed method of preparing a disclosed composition can further comprise characterizing the isolated exosomes. In an aspect, a disclosed method of preparing a disclosed composition can further comprise characterizing the secretome.

[0248] In an aspect, a disclosed method can comprise using Protocol 1 or Protocol 2 as listed in Table 9. In an aspect, a disclosed method can comprise using the protocol described in FIG. 7A. In an aspect, a disclosed method can comprise using the protocol described in FIG. 7B. In an aspect, p53 can be silenced using one or more techniques or methods known to the skilled person. In an aspect, p53 in BM-MSCs, PB-MSCs, AT-MSCs, and / or BAT-MSCs can be silenced using one or more techniques or methods known to the skilled person. In an aspect, p53 in BM-MSCs, PB-MSCs, AT-MSCs, and / or BAT-MSCs can be silenced using shRNA. In an aspect, a disclosed shRNA targeting p53 can comprise any known commercially available shRNA targeting p53. In an aspect, p53 in BM-MSCs, PB-MSCs, AT-MSCs, and / or BAT-MSCs can be silenced using siRNA. In an aspect, a disclosed siRNA targeting p53 can comprise any known commercially available siRNA targeting p53 or derivations thereof. For example, siRNA targeted p53 can be purchased from Thermo-Fisher as s529268, s529269, s529270, s536422, s536423, s536424, s605, s606, or s607 (Thermo-Fisher Cat. #s 4302420 and 4390824). In an aspect, a disclosed siRNA targeting p53 can comprise the sequence set forth in SEQ ID NO:01 or SEQ ID NO:02, or a fragment thereof.

[0249] In an aspect, a disclosed siRNA can be encapsulated in lipid nanoparticles. In an aspect, lipid nanoparticles or LNPs can deliver siRNA targeting p53. In an aspect, lipid nanoparticles or LNPs can deliver nucleic acid (e.g., DNA or RNA), protein (e.g., RNA-guided DNA binding agent), or nucleic acid together with protein. LNPs can comprise biodegradable, ionizable lipids. For example, LNPs can comprise (9Z,12Z)-3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3- (diethylamino)propoxy)carbonyl)oxy)methyl)propyl octadeca-9, 12-di enoate, also called 3-((4,4- bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl (9Z,12Z)-octadeca-9,12-dienoate) or another ionizable lipid. In an aspect, the term cationic andionizable in the context of LNP lipids can be used interchangeably, e.g., wherein ionizable lipids are cationic depending on the pH.

[0250] In an aspect, a disclosed adenoviral vector can express at least one transcript of interest for a length of time that approximates the time it takes a MSC to differentiate into its mature endothelial cell. In an aspect, a disclosed adenoviral vector can express at least one transcript of interest for at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, or more than 6 weeks.

[0251] In an aspect, a disclosed p53 siRNA can comprise the oligonucleotide comprising SEQ ID NO:01 or SEQ ID NO:02. In an aspect, a disclosed p53 siRNA can comprise the oligonucleotide comprising SEQ ID NO:01 or a fragment thereof or SEQ ID NO:02 or a fragment thereof.Table 2 - Sequences of siRNA Targeting p53

[0252] In an aspect, a disclosed vector that does not integrate into the chromosomal DNA of bone marrow derived mesenchymal stromal cell can be used to express p53-specific siRNA in a BM- MSC. In an aspect, a disclosed MSC (BM-MSC, PB-MSC, AT-MSC, or BAT-MSC) can be genetically modified to transiently reduce p53 expression completely. In an aspect, a disclosed MSC (BM-MSC, PB-MSC, AT-MSC, or BAT-MSC) can be genetically modified to transiently reduce p53 expression from about 5% to about 75% from the amount of p53 expressed in the cell before genetic modification. In an aspect, a disclosed MSC (BM-MSC, PB-MSC, AT-MSC, or BAT-MSC) may be genetically modified to transiently reduce p53 expression to about 5%, about 10%, about 25%, about 50%, or about 75% from the amount of p53 expressed in the cell before genetic modification. In an aspect, a disclosed MSC (BM-MSC, PB-MSC, AT-MSC, or BAT- MSC) can be genetically modified to transiently reduce p53 expression to about 30% to about 50% from the amount of p53 expressed in the cell before genetic modification. In an aspect, a disclosed MSC (BM-MSC, PB-MSC, AT-MSC, or BAT-MSC) can be genetically modified to transiently reduce p53 expression to about 30%, about 33%, about 36%, about 40%, about 45%, or about 50% from the amount of p53 expressed in the cell before genetic modification.

[0253] In an aspect, p53 can be silenced using one or more functional inhibitors. In an aspect, in addition to (or in lieu of) using a disclosed nuclear reprogramming substance, a functional inhibitor of p53 can be brought into contact with a disclosed starting cell. In an aspect, “an inhibitor of p53 function” can be any substance capable of inhibiting either (i) the function of thep53 protein and / or (ii) the expression of the p53 gene. For example, in an aspect, an inhibitor of p53 function can act directly on the p53 protein to inhibit the function thereof and can act directly on the p53 gene to inhibit the expression thereof. Moreover, in an aspect, an inhibitor of p53 function can also act on one or more substances that act on a factor involved in p53 signal transduction to result in inhibition of the function of the p53 protein or the expression of the p53 gene.

[0254] In an aspect, a disclosed functional inhibitor of p53 can be a substance that inhibits the expression of the p53 gene, and can more preferably be an expression vector that encodes an siRNA or shRNA against p53. Examples of substances that inhibit the function of the p53 protein include, but are not limited to, a chemical inhibitor of p53, a dominant negative mutant of p53 or a nucleic acid that encodes the same, an anti-p53 antagonist antibody or a nucleic acid that encodes the same, a decoy nucleic acid comprising a consensus sequence of a p53-responsive element, or a substance that inhibits the p53 pathway, and can more preferably be a chemical inhibitor of p53, a dominant negative mutant of p53 or a nucleic acid that encodes the same, or a p53 pathway inhibitor. Examples of chemical inhibitors of p53 are know n to the art. In an aspect, a chemical inhibitor of p53 includes, but is not limited to, a p53 inhibitor typified by pifithrin (PFT)-a and PFT-P, which are disclosed in WO 00 / 44364, PFT-p disclosed in Storm et al. (Nat. Chem. Biol. 2, 474 (2006)), analogue thereof and salts thereof (for example, acid addition salts such as hydrochlorides and hydrobromides, and the like), and the like. Of these, PFT-a and analogues thereof [2-(2-Imino-4,5,6,7-tetrahydrobenzothiazol-3-yl)-l-p-tolylethanone, HBr (product name: Pifithrin-a) and l-(4-Nitrophenyl)-2-(4,5,6,7-tetrahydro-2-imino-3(2H)- benzothiazolyl)ethanone, HBr (product name: Pifithrin-a, p-Nitro)]. PFT-P and analogues thereof [2-(4-Methylphenyl)imidazo[2,l-b]-5.6.7.8-tetrahydrobenzothiazole. HBr (product name: Pifithrin-a, Cyclic) and 2-(4-Nitrophenyl)imidazo[2,l-b]-5,6,7,8-tetrahydrobenzothiazole (product name: Pifithrin-a, p-Nitro, Cyclic)], and PFT-p. [ Phenylacetylenylsulfonamide (product name: Pifithrin-p)] are commercially available from Merck.

[0255] In an aspect, contact of a chemical inhibitor of p53 with MSCs can be performed by dissolving the inhibitor at an appropriate concentration in an aqueous or non-aqueous solvent, adding the solution of the inhibitor to a medium suitable for cultivation of MSCs isolated from a human or mouse (for example, minimal essential medium (MEM), Dulbecco's modified Eagle medium (DMEM). RPMI1640 medium, 199 medium, F12 medium and the like supplemented with about 5 to 20% fetal bovine serum) so that the inhibitor concentration falls in a range that fully inhibits the p53 function and does not cause cytotoxicity, and then culturing the cells for a given period. The inhibitor concentration can vary depending on the kind of inhibitor used and can be chosen as appropriate over the range of about 0.1 nM to about 100 nM. In an aspect, theduration of contact is not particularly limited, as far as it is sufficient to achieve nuclear reprogramming of the cells; usually, the inhibitor can be allowed to co-present in the medium until a positive colony emerges.

[0256] In an aspect, exosome secretion can be enhanced by modulating environmental factors such as adjusting pH levels, altering oxygen levels to induce hypoxic conditions, applying physical stimulation through shear stress, or using lipopolysaccharide stimulation to activate inflammatory pathways and promote exosome release. In an aspect, methods and techniques to increase or enhance exosome stimulation are known to those in the art. In an aspect, adjusting pH levels can increase or enhance exosome secretion (see, e.g., Ullah M, et al. (2020) J Cell Physiol. 235(11 ): 8845-8859, which is incorporated by reference in its entirety for the teachings concerning the effect of acidic pH on MSC exosome secretion). In an aspect, altering oxygen levels to induce hypoxic conditions can increase or enhance exosome secretion (see, e.g., Patel DB, et al. (2017) Bioeng Transl Med. 2(2): 170-179, which is incorporated by reference in its entirety for the teachings concerning the effect of altering oxygen levels on MSC exosome secretion). In an aspect, applying physical stimulation can increase or enhance exosome secretion (see, e.g., Wang X, et al. (2015) Sci Rep. 5: 1372, which is incorporated by reference in its entirety for the teachings concerning the effect of physical stimulation on MSC exosome secretion). In an aspect, using lipopolysaccharide stimulation can increase or enhance exosome secretion (see, e.g., Ti D, et al. (2015) J Transl Med. 13:308, which is incorporated by reference in its entirety’ for the teachings concerns the effect of liposaccharide stimulation on MSC exosome secretion).

[0257] In an aspect, p53 can be silenced using any method or technique known to the art. For example, U.S. Patent App. Publication No. 2021 / 0139910, which is incorporated by reference in its entirety for teaching the switching of epithelial cells switched to bone marrow derived mesenchymal stromal cells, can also be incorporated by reference for its teaching of methods / techniques to silence p53, which can, in an aspect, be applied here as well.

[0258] In an aspect, a disclosed MSC can be genetically modified to transiently reduce p53 expression. In an aspect, a disclosed genetically modified MSC can comprise p53 specific siRNA or p53-specific shRNA. In an aspect, a disclosed p53 specific siRNA or p53-specific shRNA can be provided by an adenoviral vector. In an aspect, for example, U.S. Patent App. Publication No. 2015 / 0140662, which is incorporated by reference in its entirety for teaching the switching of somatic cells switched to bone marrow derived MSCs, can also be incorporated by reference for its teaching of methods / techniques to silence p53, which can, in an aspect, be applied here as well.

[0259] In an aspect, a disclosed method can be optimized to generate a higher yield of exosomes. In an aspect, a disclosed method can be optimized to generate and / or purity’ a higher yield of exosomes. In an aspect, exosome secretion can be enhanced by modulating environmental factorssuch as adjusting pH levels, altering oxygen levels to induce hypoxic conditions, applying physical stimulation through shear stress, or utilizing lipopolysaccharide stimulation to activate inflammatory pathways and promote exosome release.

[0260] In an aspect, a disclosed method can further comprise subjecting the exosomal fraction to a proteomic analysis and / or a genomic analysis. In an aspect of a disclosed method, no additional growth factors and / or transcription factors are used. In an aspect, a disclosed media does not comprise growth factors and / or transcription factors. In an aspect, a disclosed method can further comprise measuring the expression of one or more genes related to mitochondrial biogenesis, one or more genes related to apoptosis, one or more genes related to vascular regeneration, one or more genes related to inflammation, one or more podocyte-specific genes, one or more antioxidant genes, or any combination thereof. In an aspect, a disclosed gene related to mitochondrial biogenesis can comprise TFAM, ATP5B, NRF1, SDHB, NDUFA1, PGC1A, PRDM16, UCP1, CEBP-A, PPARG, or any combination thereof. In an aspect, a disclosed gene related to apoptosis can comprise p53. p21, BCL2, CASP3, CASP9. or any combination thereof. In an aspect, a disclosed gene related to vascular regeneration can comprise VEGF-A, PEC AMI, eNOS, KDR, or any combination thereof. In an aspect, a disclosed podocyte-specific gene can comprise NPHS1, SYNPO / O2, WT1, or any combination thereof. In an aspect, a disclosed antioxidant gene can comprise SOD1, SOD2, SOD3, GPX1, GPX3, CAT, or any combination thereof. In an aspect, a disclosed gene related to inflammation comprise PTGS2, IL6, TNFa, NFKB, or any combination thereof.

[0261] In an aspect, exosomes obtained from p53-silenced MSCs (including, for example, BM- MSCs) can have increased expression of SERPINB3, ARG1, KITLG. SERPINB12, TXNRD3, SFRP1, SERPINA12, MRAS. or any combination thereof. In an aspect, exosomes obtained from p53-silenced MSCs (including, for example, BM-MSCs) can have increased expression of one or more genes identified in Table 1 (supra). In an aspect, exosomes obtained from p53-silenced MSCs (including, for example, BM-MSCs) can have increased expression of one or more genes identified in Table 5A (infra). In an aspect, exosomes obtained from p53-silenced MSCs (including, for example, BM-MSCs) can have increased expression of one or more genes identified in Table 5B (infra). In an aspect, exosomes obtained from p53-silenced MSCs (including, for example, BM-MSCs) can have decreased expression of one or more genes identified in Table 7A (infra). In an aspect, exosomes obtained from p53-silenced MSCs (including, for example, BM-MSCs) can have decreased expression of one or more genes identified in Table 7B (infra).

[0262] Disclosed herein is a composition made by a disclosed method. Disclosed herein is a composition comprising a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs) made by a disclosed method. Disclosed herein is a composition comprising a conditioned media obtained from one or more p53-silenced bone marrow7derived mesenchymal stromal cells (BM-MSCs) made by a disclosed method. Disclosed herein is a composition comprising a plurality of exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs) made by a disclosed method. Disclosed herein is a method of treating a subject, the method comprising administering to a subject having a disease or disorder a therapeutically effective amount of a composition comprising a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs). Disclosed herein is a method of treating a subject, the method comprising administering to a subject having a disease or disorder a therapeutically effective amount of a composition comprising a conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs). Disclosed herein is a method of treating a subject, the method comprising administering to a subject having a disease or disorder a therapeutically effective amount of a composition comprising a conditioned media obtained from one or more p53-silenced bone marrow^ derived mesenchymal stromal cells (BM-MSCs).

[0263] In an aspect of a disclosed method, the subject's disease or disorder can comprise hyperglycemia or diabetes, a chronic kidney disease, a wound healing disease or disorder, nonalcoholic fatty liver disease (NAFLD), peripheral vascular disease and / or cardiovascular disease, or any combination thereof.

[0264] In an aspect of a disclosed method, following the administering step, the progression of the subject's disease ordisorder can be slowed and / or diminished. In an aspect, a disclosed subject can have improved wound healing. In an aspect, a disclosed subject can have decreased macrophage activation and tissue infiltration. In an aspect, a disclosed subject can have a reduced urinary7protein: creatinine ratio when compared to the pre-administering step urinary7protein: creatinine ratio. In an aspect, a disclosed subject can have an improved renal blood flow and / or improved renal function when compared to the pre-administering step renal blood flow and / or renal function. In an aspect, a disclosed subject can have decreased proteinuria, improved blood pressure, improved clearance of urine protein, inulin, para amino Hippurate (PAH), plasma albumin, and creatinine, improved glomerular filtration rate (GFR), or any combination thereof when compared to the pre-administering step level or rate.

[0265] In an aspect, a disclosed method can further comprise monitoring the progression of the subject’s disease or disorder. In an aspect, monitoring the progression of the subject’s disease or disorder can comprise performing a gene expression analysis of genes related to mitochondrialbiogenesis, genes related to apoptosis, genes related to vascular regeneration, genes related to inflammation, podocyte-specific genes, antioxidant genes, or any combination thereof.

[0266] In an aspect, the disclosed genes related to mitochondrial biogenesis can comprise TFAM, ATP5B, NRF1, SDHB, NDUFA1, PGC1A, PRDM16, UCP1, CEBP-A, PPARG, or any combination thereof. In an aspect, the disclosed genes related to apoptosis can comprise p53, p2I, BCL2, CASP3, CASP9, or any combination thereof. In an aspect, the disclosed genes related to vascular regeneration can comprise VEGF-A, PECAM1, eNOS, KDR, or any combination thereof. In an aspect, the disclosed podocyte-specific genes can comprise NPHS1, SYNPO / O2, WT1, or any combination thereof. In an aspect, the disclosed antioxidant genes can comprise SOD1, SOD2, SOD3, GPX1, GPX3, CAT, any combination thereof. In an aspect, the disclosed genes related to inflammation can comprise PTGS2, IL6, TNFa, NFKB, or any combination thereof. In an aspect, a disclosed method can analyze gene expression of any combination of genes disclosed herein.2. Methods of Using a Disclosed Composition

[0267] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed composition or a disclosed pharmaceutical formulation.

[0268] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof.

[0269] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof.

[0270] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned mediaobtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof.

[0271] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof.

[0272] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof.

[0273] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof.

[0274] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof.

[0275] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs). (ii) conditioned mediaobtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof.

[0276] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) any combination thereof.

[0277] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof, wherein, following administration, one or more physiological changes is effected in the subject; one or more positive and / or favorable physiological changes is generated in the subject; wound healing is improved and / or enhanced in the subject; one or more diabetes-related symptoms or complications are treated in the subject; one or more diabetes-related vascular issues or diabetes-related vascular complications are treated in the subject; vascular regeneration is improved and / or enhanced and / or stimulated and / or promoted in one or more tissues and / or one or more organs in the subject; apoptosis of cells exposed to hyperglycemia is prevented; the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia is prevented; apoptosis of endothelial cells exposed to hyperglycemic conditions is prevented; the amount and / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia is prevented; endothelial regeneration is improved and / or enhanced and / or stimulated and / or promoted in the subject; systemic inflammation is diminished and / or decreased in the subject; renal function is improved and / or enhanced in the subject; one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation are restored in the subject; or any combination thereof.

[0278] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stroma cells (BM-MSCs), (ii) conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs), or (iv) any combination thereof, wherein, following administration, one or more physiological changes is effected in the subject; one or more positive and / or favorable physiological changes is generated in the subject; wound healing is improved and / or enhanced in the subject; one or more diabetes-related symptoms or complications are treated in the subject; one or more diabetes-related vascular issues or diabetes- related vascular complications are treated in the subject; vascular regeneration is improved and / or enhanced and / or stimulated and / or promoted in one or more tissues and / or one or more organs in the subject; apoptosis of cells exposed to hyperglycemia is prevented; the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia is prevented; apoptosis of endothelial cells exposed to hyperglycemic conditions is prevented; the amount and / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia is prevented; endothelial regeneration is improved and / or enhanced and / or stimulated and / or promoted in the subject; systemic inflammation is diminished and / or decreased in the subject; renal function is improved and / or enhanced in the subject; one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation are restored in the subject; or any combination thereof.

[0279] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced penpheral blood derived mesenchymal stroma cells (PB-MSCs), (ii) conditioned media obtained from one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced peripheral blood derived mesenchymal stroma cells (PB-MSCs), or (iv) any combination thereof, wherein, following administration, one or more physiological changes is effected in the subject; one or more positive and / or favorable physiological changes is generated in the subject; wound healing is improved and / or enhanced in the subject; one or more diabetes-related symptoms or complications are treated in the subject; one or more diabetes-related vascular issues or diabetes- related vascular complications are treated in the subject; vascular regeneration is improved and / or enhanced and / or stimulated and / or promoted in one or more tissues and / or one or more organs in the subject; apoptosis of cells exposed to hyperglycemia is prevented; the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia is prevented; apoptosis of endothelial cells exposed to hyperglycemic conditions is prevented; the amount and / or degreeand / or spread of apoptosis of endothelial cells exposed to hyperglycemia is prevented; endothelial regeneration is improved and / or enhanced and / or stimulated and / or promoted in the subject; systemic inflammation is diminished and / or decreased in the subject; renal function is improved and / or enhanced in the subject; one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation are restored in the subject; or any combination thereof.

[0280] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), (ii) conditioned media obtained from one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT- MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced adipose tissue derived mesenchymal stroma cells (AT-MSCs), or (iv) any combination thereof, wherein, following administration, one or more physiological changes is effected in the subject; one or more positive and / or favorable physiological changes is generated in the subject; wound healing is improved and / or enhanced in the subject; one or more diabetes-related symptoms or complications are treated in the subject; one or more diabetes-related vascular issues or diabetes- related vascular complications are treated in the subject; vascular regeneration is improved and / or enhanced and / or stimulated and / or promoted in one or more tissues and / or one or more organs in the subject; apoptosis of cells exposed to hyperglycemia is prevented; the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia is prevented; apoptosis of endothelial cells exposed to hyperglycemic conditions is prevented; the amount and / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia is prevented; endothelial regeneration is improved and / or enhanced and / or stimulated and / or promoted in the subject; systemic inflammation is diminished and / or decreased in the subject; renal function is improved and / or enhanced in the subject; one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation are restored in the subject; or any combination thereof.

[0281] Disclosed herein is a method of treating and / or preventing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (ii) conditioned media obtained from one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced birth associated tissue derived mesenchymal stroma cells (BAT-MSCs), or (iv) anycombination thereof, wherein, following administration, one or more physiological changes is effected in the subject; one or more positive and / or favorable physiological changes is generated in the subject; wound healing is improved and / or enhanced in the subject; one or more diabetes- related symptoms or complications are treated in the subject; one or more diabetes-related vascular issues or diabetes-related vascular complications are treated in the subject; vascular regeneration is improved and / or enhanced and / or stimulated and / or promoted in one or more tissues and / or one or more organs in the subject; apoptosis of cells exposed to hyperglycemia is prevented; the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia is prevented; apoptosis of endothelial cells exposed to hyperglycemic conditions is prevented; the amount and / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia is prevented; endothelial regeneration is improved and / or enhanced and / or stimulated and / or promoted in the subject; systemic inflammation is diminished and / or decreased in the subject; renal function is improved and / or enhanced in the subject; one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation are restored in the subj ect; or any combination thereof.

[0282] In an aspect, a disclosed composition or a disclosed pharmaceutical formulation can be used in a method of treating a subject having diabetes. In an aspect, a disclosed composition or a disclosed pharmaceutical formulation can be used in a method of treating a subject having a diabetes-related complication or diabetes-related system. In an aspect, a disclosed composition or a disclosed pharmaceutical formulation can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed composition or a disclosed pharmaceutical formulation can be used in a method of treating a subject having diabetic ulcers or diabetic wounds. In an aspect, a disclosed composition or a disclosed pharmaceutical formulation can be used in a method of treating a subject having diabetic kidney disease. In an aspect, a disclosed composition or a disclosed pharmaceutical formulation can be used in a method of treating a subject having nonalcoholic fatty liver disease (NAFLD). In an aspect, a disclosed composition or a disclosed pharmaceutical formulation can be used in a method of treating a subject having hyperglycemia. In an aspect, a disclosed composition or a disclosed pharmaceutical formulation can be used in a method of treating a subject having a chronic kidney disease. In an aspect, a disclosed composition or a disclosed pharmaceutical formulation can be used in a method of treating a subject having a wound healing disease or disorder. In an aspect, a disclosed composition or a disclosed pharmaceutical formulation can be used in a method of treating a subject having a peripheral vascular disease. In an aspect, a disclosed composition or a disclosed pharmaceutical formulation can be used in a method of treating a subject having cardiovascular disease.

[0283] In an aspect of a disclosed method, a subject can have diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty7liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof. In an aspect, a subject can be at risk of developing diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney7disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof.

[0284] In an aspect, regular interval of administration of a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof or a disclosed pharmaceutical formulation can comprise bimonthly, monthly, triweekly, biweekly, weekly, twice weekly, daily, or at variable intervals. In an aspect, administration of a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof to a subject can comprise intravenous injection, intramuscular injection, intracoronary7injection, intracerebroventricular injection, intracistema magna injection, intracerebral injection, intrathecal injection, or any combination thereof. In an aspect, administration of a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof to a subject can comprise local administration to one or more tissues or organs in the subject (e.g.. the subject’s heart, kidneys, liver, extremities). In an aspect, administration of a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof to a subject can comprise administration directly to a wound in the subject.

[0285] In an aspect, a subject can be an adult, a child, or an infant. In an aspect, a subject can be treatment-naive.

[0286] In an aspect, administration of a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs). or (iv) any combination thereof to a subject can restoring the subject’s wound healing ability. In an aspect, restoration of the subject’s wound healing ability can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of restoration when compared to a pre-existing level such as, for example, a pre-treatment level. In an aspect, the amount of restoration can be 10-20%, 20-30%, 30-40%, 40-50%. 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% more than a pre-existing level such as, for example, a pre-treatment level. In an aspect, restoration can be measured against a control level (e.g., a level in a subject not having have diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty’ liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof). In an aspect, restoration can be a partial or incomplete restoration. In an aspect, restoration can be complete or near complete restoration such that the level of expression, activity’ and / or functionality is similar to that of a wild-type or control level.

[0287] In an aspect, a disclosed method of administering a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs). (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof can restore one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation. In an aspect, restoring one or more aspects of cellular homeostasis and / or cellular functionality can comprise one or more of the following: (i) correcting cell starvation in one or more cell types (such as, for example, liver cells and muscle cells); (ii) normalizing aspects of the autophagy pathway (such as, for example, correcting, preventing, reducing, and / or ameliorating autophagy); (iii) improving, enhancing, restoring, and / or preserving mitochondrial functionality and / or structural integrity; (iv) improving, enhancing, restoring, and / or preserving organelle functionality and / or structural integrity; (v) preventing, slowing, and / or lessening diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof; (vi) correcting kidney enzyme and / or liver enzy me and / or cardiac enzy me dysregulation; (vii) reversing, inhibiting, preventing, stabilizing, and / or slowing the rate of progression of the multi-systemic manifestations of diabetes,a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof; (viii) reversing, inhibiting, preventing, stabilizing, and / or slowing the rate of progression of diabetes, a diabetes -related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof, or (ix) any combination thereof. In an aspect, restoring one or more aspects of cellular homeostasis can comprise improving, enhancing, restoring, and / or preserving one or more aspects of cellular structural and / or functional integrity.

[0288] In an aspect of a disclosed method, techniques to monitor, measure, and / or assess the restoring one or more aspects of cellular homeostasis and / or cellular functionality can comprise qualitative (or subjective) means as well as quantitative (or objective) means. These means are known to the skilled person. For example, hyperglycemia can be sporadically and / or continuously measured and monitored. Methods and techniques for measuring and monitoring hypoglycemia are know n to the skilled person and include, but not limited to, by continuous glucose monitoring (CGM) methods and capillary blood glucose sticks. In an aspect, a disclosed method can comprise measuring the level or amount of one or more biomarkers (e.g., glucose, ALT, creatinine, glycogen, hepatocellular vacuolation, etc.), one or more indicators of the subject’s metabolomic health, or any combination thereof. In an aspect, a disclosed method can comprise measuring the level or amount of one or more markers of cardiac function, one or more markers of kidney function, one or more markers of liver function, one or more indicators of any physiological system, or any combination thereof.

[0289] In an aspect, a disclosed method can comprise administering to the subject one or more additional therapeutic agents. In an aspect, a disclosed therapeutic agent can comprise enzyme replacement therapy, gene therapy, mRNA therapy, small molecule therapy, substrate reduction therapy, or any combination thereof.

[0290] In an aspect, a disclosed method can comprise validating the efficacy of the administered composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof. In an aspect, validating the efficacy of the administered composition or pharmaceutical formulation can comprise administering to the subject a disclosed polypeptide, measuring the activity or expression of one or more biomarkers related to cellular function; and comparing the resulting activity or expression level of the one or more biomarkers to a control level, wherein theadministered composition or pharmaceutical formulation is effective when the activity or expression level of the one or more biomarkers following treatment is modulated compared to the control level. In an aspect, modulated can comprise increasing the activity or expression level of the one or more biomarkers. In an aspect, modulated can comprise increasing the activity or expression level of the one or more biomarkers. In an aspect, modulated can comprise decreasing the activity or expression level of the one or more biomarkers.

[0291] In an aspect, a disclosed method can comprise measuring one or more biomarkers prior to the administering of a disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced mesenchymal stroma cells (MSCs). (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof.

[0292] In an aspect, a disclosed method can comprise measuring one or more biomarkers during the administering of one or more disclosed compositions comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof. In an aspect, a disclosed method can comprise measuring one or more biomarkers after the administering of one or more disclosed composition comprising (i) a secretome obtained from the conditioned media of one or more p53- silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof.

[0293] Thus, in an aspect, the increase or decrease in expression and / or activity' level postadministration can be a 10%. 20%. 30%. 40%. 50%. 60%, 70%, 80%, 90%, 100%, or any amount of reduction in between as compared to native or control levels (e.g., pre-administration level). In an aspect, the increase or decrease in expression and / or activity' level post-administration can be 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% as compared to a native or control level (e.g., pre-administration level). In an aspect, the inhibition or reduction can be 0-25%, 25-50%, 50-75%, or 75-100% as compared to native or control levels (e.g., pre- administration level). In an aspect, a native or control level can be a pre-disease or pre-disorder level or pre-treatment level).

[0294] In an aspect, measuring the expression of one or more disclosed biomarkers can comprise measuring the protein concentration of the transgene and / or the reporter gene or measuring themRNA level of transgene and / or the reporter gene. For example, in an aspect, measuring the protein concentration of transgene and / or the reporter gene comprises a protein chip analysis, an immunoassay, a ligand binding assay, a MALDI-TOF (Matrix Assisted Laser Desorption / Ionization Time of Flight Mass Spectrometry ) analysis, a SELDI-TOF (Sulface Enhanced Laser Desorption / Ionization Time of Flight Mass Spectrometry) analysis, a radioimmunoassay, a radioimmunodiffusion assay, an octeroni immunodiffusion method, rocket immunoelectrophoresis, tissue immunostaining, a complement fixation assay, 2D by electrophoretic analysis, liquid chromatography -Mass Spectrometry' (LC-MS), liquid chromatography-Mass Spectrometry / Mass Spectrometry (LC-MS / MS). Western blotting, ELISA (enzyme linked immunosorbent assay), or any combination thereof. Similarly, in an aspect, measuring the mRNA level of a disclosed lysosomal enzyme and / or the reporter gene comprises a reverse transcription polymerase reaction (RT-PCR), a competitive reverse transcription polymerase reaction (Competitive RT-PCR), a real-time reverse transcription polymerization, an enzyme reaction (Real-time RT-PCR), an RNase protection assay (RPA), Northern blotting, a DNA chip, or any combination thereof.

[0295] In an aspect, a disclosed method can further comprise monitoring the subject for adverse effects. In an aspect, in the absence of adverse effects, the method can further comprise continuing to treat the subject. In an aspect, in the presence of adverse effects, the method can further comprise modifying the treating step. Methods of monitoring a subject’s well-being can include both subj ective and objective criteria. Such methods are known to the skilled person. In an aspect, a disclosed method can further comprise repeating a monitoring step.

[0296] In an aspect, a disclosed method of treating and / or preventing disease progression of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidneydisease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof can further comprise administering one or more immune modulators. In an aspect, a disclosed immune modulator can be methotrexate, rituximab, intravenous gamma globulin, or bortezomib, or a combination thereof. In an aspect, a disclosed immune modulator can be bortezomib or SVP-Rapamycin. In an aspect, a disclosed immune modulator can be Tacrolimus. In an aspect, a disclosed immune modulator such as methotrexate can be administered at a transient low to high dose. In an aspect, a disclosed immune modulator can be administered at a dose of about 0.1 mg / kg body weight to about 0.6 mg / kg body weight. In an aspect, a disclosed immune modulator can be administered at a dose of about 0.4 mg / kg body w eight. In an aspect, a disclosed immune modulator can be administered at about a daily dose of 0.4 mg / kg body weight for 3 to 5 or greater cycles, with up to three days per cycle. In an aspect, a disclosed immune modulator can be administered at about a daily doseof 0.4 mg / kg body weight for a minimum of 3 cycles, with three days per cycle. In an aspect, a person skilled in the art can determine the appropriate number of cycles. In an aspect, a disclosed immune modulator can be administered as many times as necessary' to achieve a desired clinical effect.

[0297] In an aspect, a disclosed immune modulator can be administered orally about one hour before a disclosed composition or a disclosed pharmaceutical formulation. In an aspect, a disclosed immune modulator can be administered subcutaneously about 15 minutes before a disclosed composition or a disclosed pharmaceutical formulation. In an aspect, a disclosed immune modulator can be administered concurrently with a disclosed composition or a disclosed pharmaceutical formulation. In an aspect, a disclosed immune modulator can be administered orally about one hour or a few days before a disclosed composition or a disclosed pharmaceutical formulation. In an aspect, a disclosed immune modulator can be administered subcutaneously about 15 minutes before or a few days before a disclosed composition or a disclosed pharmaceutical formulation. In an aspect, a disclosed immune modulator can be administered concurrently with a disclosed composition or a disclosed pharmaceutical formulation.

[0298] In an aspect, a disclosed method of treating and / or preventing disease progression of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof can further comprise administering one or more proteasome inhibitors (e.g., bortezomib, carfilzomib, marizomib, ixazomib, and oprozomib). In an aspect, a proteasome inhibitor can be an agent that acts on plasma cells (e.g., daratumumab). In an aspect, an agent that acts on a plasma cell can be melphalan hydrochloride, melphalan, pamidronate disodium, carmustine. carfilzomib, carmustine, cyclophosphamide, daratumumab, doxorubicin hydrochloride liposome, doxorubicin hydrochloride liposome, elotuzumab, melphalan hydrochloride, panobinostat, ixazomib citrate, carfilzomib, lenalidomide, melphalan, melphalan hydrochloride, plerixafor, ixazomib citrate, pamidronate disodium, panobinostat. plerixafor. pomalidomide, pomalidomide, lenalidomide, selinexor, thalidomide, thalidomide, bortezomib, selinexor, zoledronic acid, or zoledronic acid.

[0299] In an aspect, a disclosed method can further comprise administering one or more proteasome inhibitors or agents that act on plasma cells prior to administering a disclosed composition or a disclosed pharmaceutical formulation. In an aspect, a disclosed method can comprise administering one or more proteasome inhibitors or one or more agents that act on plasma cells concurrently with administering a disclosed composition or a disclosed pharmaceutical formulation. In an aspect, a disclosed method can comprise administering one or more proteasome inhibitors or one or more agents that act on plasma cells subsequent toadministering a disclosed composition or a disclosed pharmaceutical formulation. In an aspect, a disclosed method can further comprise administering one or more proteasome inhibitors more than 1 time. In an aspect, a disclosed method can comprise administering one or more proteasome inhibitors repeatedly over time.

[0300] In an aspect, a disclosed method of treating and / or preventing disease progression of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty7liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof can further comprise administering one or more immunosuppressive agents. In an aspect, an immunosuppressive agent can be, but is not limited to, azathioprine, methotrexate, sirolimus, anti-thymocyte globulin (ATG), cyclosporine (CSP), mycophenolate mofetil (MMF), steroids, or a combination thereof. In an aspect, a disclosed method can comprise administering one or more immunosuppressive agents more than 1 time. In an aspect, a disclosed method can comprise administering one or more one or more immunosuppressive agents repeatedly over time. In an aspect, a disclosed method can comprise administering a compound that targets or alters antigen presentation or humoral or cell mediated or innate immune responses.

[0301] In an aspect, a disclosed method can further comprise administering a compound that exerts a therapeutic effect against B cells and / or a compound that targets or alters antigen presentation or humoral or cell mediated immune response. In an aspect, a disclosed compound can be rituximab, methotrexate, intravenous gamma globulin, anti CD4 antibody, anti CD2, an anti-FcRN antibody, a BTK inhibitor, an anti-IGFIR antibody, a CD19 antibody (e.g., inebilizumab), an anti-IL6 antibody (e g., tocilizumab), an antibody to CD40. an IL2 mutein. or a combination thereof. Also disclosed herein are Treg infusions that can be administered as a way to help with immune tolerance (e g., antigen specific Treg cells to AAV).

[0302] In an aspect, a disclosed method of treating and / or preventing disease progression of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof can further comprise repeating a disclosed administering step such as, for example, repeating the administering of a disclosed composition or a disclosed pharmaceutical formulation, a disclosed therapeutic agent, a disclosed immune modulator, a disclosed proteasome inhibitor, a disclosed immunosuppressive agent, a disclosed compound that exerts a therapeutic effect against B cells and / or a disclosed compound that targets or alters antigen presentation or humoral or cell mediated immune response.

[0303] In an aspect of a disclosed method, monitoring the progression of the subject’s disease or disorder can comprise measuring the subject’s proteinuria, urinary creatinine, plasma creatinine,urinary volume, or any combination thereof. In an aspect, a disclosed method can further comprise repeating the administering step one or more times. In an aspect, a disclosed method can further comprise monitoring the subject for adverse effects. In an aspect, in the absence of adverse effects, the method can further comprise continuing to treat the subject. In an aspect, in the presence of adverse effects, the method can further comprise modifying one or more steps of the method. In an aspect, modifying one or more steps of a disclosed method can comprise modifying the administering step. In an aspect, a disclosed method can further comprise administering to the subject one or more additional therapeutic agents.

[0304] In an aspect, a disclosed method of treating and / or preventing disease progression of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof can further comprise administering a [32 agonist. For example, in an aspect, a disclosed method can comprise administering a [32 agonist to increase the expression of one or more receptors for a lysosomal enzyme. In an aspect, [32 agonists include but are not limited to albuterol, clenbuterol, formoterol, indacaterol, olodaterol, salmeterol, vilanterol, and any combination thereof, growth hormones (e.g., human growth hormone), autocrine glycoprotein (e.g., Follistatin), or any combination thereof (see, e.g., U.S. Patent No. 8,679,478 for a discussion of appropriate [32 agonists, which patent is incorporated by reference it its entirety for these teachings).

[0305] In an aspect, a disclosed method of treating and / or preventing disease progression of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD). a wound healing disease or disorder, or any combination thereof can further comprise administering to a subject or patient one or more fibrates. In an aspect, a disclosed fibrate can comprise bezafibrate, fenofibrate, ciprofibrate, gemfibrozil, clofibrate, an analog thereof, or a combination thereof. In an aspect, a disclosed method can comprise repeating the administering of one or more fibrates one or more times. In an aspect, a therapeutically effective amount of one or more fibrates can comprise at least about 20 mg / day to at least 500 mg / day. In an aspect, a therapeutically effective amount of one or more fibrates can comprise at least about 20 mg / day, at least about 20 mg / day, about 30 mg / day, about 40 mg / day, at least about 50 mg / day, at least about 60 mg / day, at least about 70 mg / day, at least about 80 mg / day, at least about 90 mg / day. at least about 100 mg / day, at least about 120 mg / day, at least about 140 mg / day, at least about 160 mg / day, at least about 180 mg / day, at least about 200 mg / day, at least about 220 mg / day, at least about 240 mg / day, at least about 260 mg / day, at least about 280 mg / day, at least about 300 mg / day, at least about 320 mg / day, at least about 340 mg / day, at least about 360 mg / day. at least about 380mg / day, at least about 400 mg / day, at least about 420 mg / day, at least about 440 mg / day, at least about 460 mg / day, at least about 480 mg / day, or at least about 500 mg / day.

[0306] In an aspect, a disclosed method of treating and / or preventing disease progression of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof can further comprise modifying one or more of the disclosed steps. For example, modifying one or more steps of a disclosed method can comprise modifying or changing one or more features or aspects of one or more steps of a disclosed method. For example, in an aspect, a method can be altered by changing the amount of a disclosed composition or a disclosed pharmaceutical formulation thereof administered to a subject, or by changing the frequency of administration of a disclosed composition or a disclosed pharmaceutical formulation to a subject, or by changing the duration of time a disclosed composition or a disclosed pharmaceutical formulation is administered to a subject. In an aspect, one or more a disclosed composition or a disclosed pharmaceutical formulation can be administered concurrently or sequentially.

[0307] In an aspect, a disclosed method can further comprise diagnosing a subject with diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof using one or more known methods to the skilled person, such as, for example, genotyping. In an aspect, a disclosed composition or a disclosed pharmaceutical formulation does not elicit an immune response. In an aspect, a disclosed method can improve and / or extend the survivability of the subject, can improve a subject's quality of life, can increase and / or prolong a subject’s life span, or any combination thereof.

[0308] In an aspect, a disclosed method can comprise (1) generating one or more disclosed compositions comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof; (2) purifying one or more disclosed compositions comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof; (3) formulating one or more disclosed compositions comprising (i) a secretome obtained from the conditioned media of one ormore p53-silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53-silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof; (4) packaging one or more disclosed compositions comprising (i) a secretome obtained from the conditioned media of one or more p53-silenced mesenchymal stroma cells (MSCs), (ii) conditioned media obtained from one or more p53-silenced mesenchymal stromal cells (MSCs), (iii) exosomes obtained from the conditioned media of one or more p53- silenced mesenchymal stromal cells (MSCs), or (iv) any combination thereof, or (5) any combination thereof.

[0309] In an aspect, an improvement in one or more symptoms of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty7liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof can be subjective and / or objective. In an aspect, an improvement in one or more symptoms of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty7liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof can improve a subject's motor skills. In an aspect, an improvement in one or more symptoms of diabetes, a diabetes-related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty7liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof can improve a subject’s quality of life. In an aspect, a disclosed method can ameliorate and / or mitigate the negative and / or deleterious effect that have diabetes, a diabetes- related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof has on one or more organs in a subject including, for example, the brain, the spleen, the heart, the kidneys, the liver, the bones, the muscle, the lungs, or any combination thereof.VII. EXAMPLES

[0310] Diabetes mellitus (DM) (and its vascular complications) is the most common cause of cardiovascular complications such as diabetic kidney disease (DKD). Chronic kidney disease (CKD) in diabetes is a major cause of mortality and morbidity7. Appropriate treatment of CKD is important with an ever-increasing number of subjects with diabetes. Though both diabetes and CKD independently cause significant cardiovascular mortality and morbidity7, stem cell mediated therapy that has been successful in non-diabetic states have not been successful in diabetic states.Cell free therapy, which would be even more advantageous than cell -based therapy in CKD is also largely under-developed.

[0311] Hematopoietic cells with progenitor cell biomarkers (such as CD34 positive hematopoietic progenitor cells) target regions that need repair post-ischemic injury and help new vessel formation and tissue regeneration. For stem cells to survive in a pro-apoptotic hyperglycemic environment, however, genetic modifications to the progenitor cells are required to prevent apoptosis. Such modifications made to the CD34+ve hematopoietic progenitor cells by transiently silencing p53 (p53sh) prevented premature apoptosis without long term side-effect of unbridled cell proliferation, post-p53 silencing in presence of a pro-apoptotic condition such as hyperglycemia. Such modifications are designed to be effective only for 2-3 weeks (duration of the silencing vector effectiveness).

[0312] As detailed below, the present disclosure provides a cell free therapy option such as p53sh- MSCs conditioned media (CM), particularly the exosomal portion, is an attractive therapeutic option in DKD mouse model. The Examples that follow are illustrative of specific embodiments of the invention, and various uses thereof. They set forth for explanatory purposes only and are not to be taken as limiting the invention.Example 1 Determination of Whether p53sh MSC Derived Conditioned Media Improved Renal Function

[0313] Several experimental findings drove the experiments detailed herein Example 1. Progenitor or stem cells such as hematopoietic stem cells (HSCs) and mesenchymal stromal cells (MSCs) have significant regenerative paracrine properties that exist in their secretome. While these cells have the unique property' of homing-in to sites that need repair and regeneration, a hyperglycemic milieu impairs homing-in and migration properties of CD34+ve hematopoietic stem cells denoted as endothelial progenitor cells (EPCs). Furthermore, hyperglycemia leads to apoptotic death of progenitor cells, which altogether may have led to less-than-optimal results of stem and progenitor cell therapeutics in cardiovascular diseases due to poor survival of progenitor cells in a hostile hyperglycemic environment. To this end, data showed that mouse and human EPCs had a poor survival rate in a moderately high glucose level (20 mM = 360 mg%) (FIG. 1).

[0314] But, as apoptotic death of EPCs in hyperglycemia is mediated by up-regulation of apoptotic genes, such as p53 and its downstream cascade of proteins at a cellular level, the silencing of p53 prevented apoptosis of EPCs under hyperglycemia conditions. Furthermore, p53 silenced EPCs avoided apoptosis and progressed toward mature endothelial cells (cobble stone appearance) at day 28 (FIG. 2). Thus, these genetically modified EPCs (p53-silenced) were used to treat post femoral artery occluded ischemic hind-limb in diabetic Peripheral Vascular Disease (PVD) model. Upon transplantation, these p53-silenced EPCs contributed to collateral vesselformation and reperfusion in a femoral artery occlusion model (see, e.g., FIG. 3). The data demonstrate that p53-silenced EPCs were more efficient in assisting revascularization, secondary to paracrine properties.

[0315] Then, whether p53-silenced EPCs helped to treat diabetic peripheral vascular disease (PVD) was examined in the STZ-induced TIDM mouse models. In streptozotocin-induced type 1 diabetic CKD model, mice that received p53-silenced (p53sh) EPC under kidney capsule showed improved or reduced urine protein: creatinine ratio in the urine. Importantly, the renal blood flow increased in the p53sh EPC transplanted kidney compared to null EPC-transplanted kidney when examined 28 days post-cell transplantation and examined using Visual-sonics ultrasound. When p53sh-EPCs were transplanted, the comparison was made to Ad-Scramble transduced EPCs. The conditioned media experiments also demonstrated that p53sh-EPC conditioned media (unfractionated) had significantly better endothelial proliferation effect (in scratch-test assay) when compared with null EPC and saline (FIG. 4A). Moreover, exosomal components of p53sh-EPCs showed more proliferation capability in a scratch test when compared to non-exosomal compartment (FIG. 4B). p53 silenced BM-MSC had similar scratch test results when compared to controls (FIG. 5A). The post-scratch test viable HUVEC cell counts (when exposed to different conditioned media) in presence of hyperglycemia were also counted (FIG. 5B)

[0316] Now, turning to the inquiry of whether p53sh BM-MSC derived CM improved renal function in diabetic kidney disease mouse model and prevented macrophage activation and tissue infiltration. Wild-type (WT) hyperglycemic C57bl6 mice are used as a model for diabetes. Three groups of STZ-induced non-obese type 1 DM are used as shown in Table 3.Table 3 - Experimental Groups

[0317] To match viral construct backbones to reduce chances of off target effects, all viral constructs were obtained from Vector BioLabs. Therapy is delivered only after ascertaining that each mouse has reached a steady state of 250 mg % of blood glucose.

[0318] The method used to obtain CM from transduced MSCs is set forth below.

[0319] Ad-human-P53 (TP53)-shRNA (Vector Biolabs) was used to silence p53 and Ad- scrambled-null-shRNA was used as control. Adenovirus was expanded and tittered by usingHEK-293 cells (Lonza). FIG. 8 shows the evaluation of p53 siRNA efficacy in MSCs measured via a p53 protein Lumit Assay. Here, two p53-targeted siRNAs achieved significant knockdown (KD) in MSCs (61 % - 71 % KD), while the scrambled negative control siRNA did not significantly alter p53 expression in MSCs. p53 siRNA S605 demonstrated better knockdown in both cell types and is used in all additional studies.

[0320] To collect condition media, BM-MSCs or adipose MSCs were transduced with Ad- mp53sh or Ad-null. Transduction cells were grown in FBS free media for 24 hours to 48 hours and then, the supernatant media was collected and was concentrated 20-fold to obtain the concentrated conditioned media (CM).

[0321] Human endothelial cells (hUVEC) were cultured in wound healing plate followed by the manufacturer instruction for 24 hours. Then, 50 pL of CM were obtained from either null, p53sh, and non-transduced cells (control) were added into the respective wells. After 48 hours, cells were stained with a stain provided by the manufacturer and picture was taken under microscope. The number of cells per square area were calculated by Image J software and the viable cell numbers from each well were counted in Nexcelom cell counter.

[0322] A dilution series is run to identify the optimal dilution of CM. Then, 50 pL - 150 pL of concentrated CM-exosomal portion or saline are delivered under the kidney capsule similar to Kundu N, et al. (2021) J Am Heart Assoc. 10(7):e019365. Additionally and / or alternatively, 50 pL - 150 pL of concentrated CM-exosomal portion or saline are delivered directly to the kidney. The mouse BM-MSCs are commercially obtained and transduced by p53sh construct or appropriate sham viral-construct. 3-5 days post-transduction, CM without additional growth factor is obtained. Another method of exosomal delivery includes intrarenal injection.

[0323] Several measurements determinative of the outcome are obtained. Samples and / or estimates are collected from mice every 2 weeks for 1 month or 4 months. The animals are monitored and measured frequently until expiration. For example, samples are collected from the mice in each group w eekly or biweekly for 1 month or for 4 months.

[0324] Measurements include, but not limited to. FITC-inulin clearance for GFR, urine protein and creatinine, plasma albumin and creatinine, and any combination thereof. Blood pressure and clearance of para amino-hippurate (PAH) clearance for renal plasma flow are measured. The data show that transplanting p53sh EPC-CM (conditioned media) decreases proteinuria, normalizes blood pressure (by femoral arterial cannulation in anesthetized mice, as well as by radiotelemetry in conscious mice), and improves FITC-inulin and PAH clearances when compared to little or no decrease in proteinuria, little or no normalizations of blood pressure, and little to no improvement in FITC-inulin and PAH clearance following delivery' of null EPC or MSC or saline. Blood pressure and heart rate of the animals are obtained at the beginning and at the end of theexperiment, as well as multiple times between the beginning and the end of the experiment. BP is expected to reduce with increasing renal perfusion, which is estimated to be around the 3-month time point.

[0325] Proteinuria and estimation of urinary creatinine, plasma creatinine, and urine volume are measured. The Metabolic Cages for mice are used to study: daily food and water intake, urinary protein excretion, and renal function (including sodium, potassium, water excretion, GFR and metabolic rates (BMR) studies). This chamber is specifically designed to separate urine from feces for analysis. Urine protein and creatinine and serum creatinine is measured by Randox RX Monza chemical analyzer. In urine, urine exosome-based proteins (Wilms Tumor, Nephrin and Podocalcyxin) is examined to evaluate the effects of conditioned media therapy on podocytes. This is a more sensitive assay when compared to urine protein estimation.

[0326] Imaging is used to estimate angiogenesis. For instance, VisualSonics ultrasound (in vivo imaging) is done in live animals about every 2 weeks to measure perfusion / vascularization (Visualsonics Vevo 3100). Laser Doppler Perfusion Imager (LDPI) is used to measure renal blood flow (and to validate the PAH clearance and vice versa). Following EPC transplantation, Laser Doppler measurements are taken immediately prior to sacrifice of the animals at 1 -month or 4- months post-EPC transplantation.

[0327] Several samples or estimates are collected when the animals are sacrificed at 4 weeks post- EPC transplant. First, targeted gene expression analyses from kidney sections are performed. Whether gene expression differs between the treatment group and control group is examined. For example, p53 silencing can increase expression of genes associated with mitochondrial biogenesis and can improve impaired renal damage and apoptosis. Determination of the expression of several genes is performed, including: (i) genes associated with mitochondrial biogenesis; (ii) genes associated with apoptosis; (iii) genes associated with vascular-regeneration; (iv) podocytes- specific genes (including those associated with renal function); (v) antioxidant genes; (vii) inflammation related genes; and (viii) any combination thereof. Genes associated with mitochondrial biogenesis can include TFAM, ATP5B, NRF1, SDHB. NDUFA1, PGC1A, PRDM16, UCP1, CEBP-A, PPARG, and any combination thereof. Genes associated with apoptosis can include p53, p21, Bcl2, caspase 3, caspase 9, and any combination thereof. Genes associated with vascular-regeneration can include VEGF-A. PECAM1, eNOS, KDR, and any combination thereof. Genes associated with podocytes (and associated with renal function) can include nephrin, synaptopodin, WT1 (Wilm’s Tumor-1), and any combination thereof. Antioxidant genes that reduce reactive oxygen species (ROS) can include SOD1, SOD2, SOD3, GPX1, GPX3, CAT, and any combination thereof. Genes associated with inflammation can include cyclo-oxygenase-2, IL-6, TNFa, NFkB, and any combination thereof. mRNA (qRT-PCR)expression as well as protein expression (western blot) is quantified. Serum inflammatory markers are quantified by ELISA. As soluble markers of EC dysfunction correlate with chronic renal failure, IL-6, TNFa, and hs-CRP are measured from stored plasma obtained at sacrifice. Levels of IL-6, TNFa, and hs-CRP are expected to be lower in the mice that received p53sh EPC-derived conditioned media when compared to the null and controls.

[0328] Second, histology is performed. Kidney sections are used to observe improvement in podocyte and glomerular structure by using H&E staining and immunofluorescent and electron microscopy. Collagen deposition is assessed by Picrosirius red staining, hnmunohistochemistry is performed to study PECAM1 (CD31) capillary density, which is a marker of renal perfusion.

[0329] Third, glycemic indices associated metabolic studies are performed.: Glucose and insulin tolerance tests as described before (Shi Y, et al. (2024) Small. e2309276) are performed every 2 weeks and weights of the mice are obtained weekly.

[0330] Fourth, conditioned media is analyzed. The p53sh-BMMSC-CM is analyzed by proteomics and genomics to identify proteins responsible for improvement in renal function. Whether proteins identified from extracellular vesicles (EV) such as exosomes and non-EV material from the supernatant media obtained from the cells are effective in endothelial proliferation and angiogenesis. CM is obtained from several groups including (i) p53sh-BM- MSC; (ii) Null mEPCs: (iii) non-transduced BM-MSC; and (iv) saline (control). Whole or unfractionated supernatant is obtained and divided into (i) into exosomal material by ultracentrifugation at 100,000 g to obtain particles at size of 30 nm to 120 nm, and (ii) then all extra-cellular vesicles (EV) are removed and non-EV material (harvested from supernatant) from p53sh-MSC, Null-MSC, and saline (control) are analyzed. Micro-vesicles (120 nM - 1000 nM) are excluded from analysis. Apoptotic bodies (more than 1000 nM) are excluded for analysis

[0331] For exosome studies, the Fetal Bovine Serum (FBS) used in cell culture is exosome depleted FBS (Thermo Fisher Scientific A2720801). The supernatant of p53sh-EPC, Null-EPC, and MSC groups is collected once daily from day 7 to day 10 for exosome isolation. Exosome isolation is performed. Exosome isolation (ultracentrifugation method at 100.000 g), purification, storage and characterization are performed as previously described (Kundu N, et al. (2017) J Am HeartAssoc. 6(4):e005146; Kundu N, et al. (2021) J AmHeart Assoc. 10(7):e019365). Exosomes (30 nm - 120 nm) are characterized by exosomal surface marker proteins such as CD 81, CD 63 and Alix. Exosome mass spectrometry analysis of the cell-derived exosomes (50 pg protein) in PBS (duplicates in each group) are sent to the GW Bio-informatics Core.

[0332] Fifth, endothelial proliferation estimation tests are performed. Exosomal, non-exosomal material, and non-fractionated conditioned media are subjected to endothelial proliferation estimation tests. Here, human aortic ECs or Human umbilical vein ECs (both primary) areobtained from Cell Biologies. First, a cell proliferation assay using CytoSelect™ 24-Well Wound Healing Assay from Cell Biolabs (catalog number: CBA-120) is performed (see, for example, FIG. 5 and FIG. 6). A tube formation or an angiogenesis assay (Cell Biolabs, catalog number: CBA-200) using mouse primary kidney ECs on ECM gel with different additives, such as supernatant, or exosomes or non-exosomal material is performed.

[0333] Sixth, the proteomics of the conditioned media are evaluated. As the functionality of the different fractions of conditioned media is established, relevant fractions are subjected to a proteomic analysis and functional proteins are identified. The exosomal component is subjected to a proteomic analysis and functional proteins are identified. These data are compared to the results generated with endothelial proliferation assays.

[0334] FIG. 7A - FIG. 7B show the comparison of two protocols for xeno-free BM-MSC exosome production. FIG. 7A shows the exosome protocol developed at George Washington University while FIG. 7B shows the exosome protocol developed at Renosome.

[0335] FIG. 9A - FIG. 9B show the initial characterization of MSC-derived exosome using fNTA. Here, MSCs were transfected with scramble or p53 siRNA, and exosomes were isolated 96 hrs. later using tangential flow filtration and ExoQuick precipitation. The exosomes were fluorescently labeled and analyzed with a NanoSight instrument (fNTA) and allowed for real-time visualization and analysis of individual nanoparticles in solution. The size range of detected particles was consistent with the expected size range for exosomes (30 nm -150 nm). The concentration of exosomes was within the typical range reported for MSC-derived exosomes.

[0336] For in vitro studies, p53sh-MSC CM is expected to (1) increase the numbers of antiinflammatory’ macrophages based on cell surface marker profiling and gen...

Claims

1. VIII. CLAIMSWhat is claimed is:

1. A method of preparing a composition, the method comprising: silencing p53 in a population of mesenchymal stromal cells (MSCs); culturing the p53-silenced MSCs in media; and collecting the spent media.

2. The method of Claim 1, wherein the p53-silenced MSCs are bone-derived MSCs (BM-MSCs), adipose tissue-derived MSCs (AT-MSCs), peripheral blood-derived MSCs (PB-MSCs), or birth-associated tissue MSCs (BAT-MSCs).

3. The method of Claim 1 or Claim 2, wherein silencing p53 comprises transducing the MSCs with a viral vector comprising a p53 shRNA.

4. The method of Claim 1 or Claim 2, wherein silencing p53 comprises transfecting the MSCs with a p53 siRNA.

5. The method of any one of Claims 1 - 4, wherein culturing the p53-silenced MSCs comprises hyperglycemic conditions.

6. The method of Claim 1, wherein the culture media comprises Fetal Bovine Serum (FBS),Human Serum Albumin (HSA), serum-free media, or xeno-free media.

7. The method of any one of Claims 1 - 6, wherein culturing the p53-silenced MSCs comprises about 24 hours to about 144 hours.

8. The method of any one of Claims 1 - 7, further comprising collecting the spent media during culturing.

9. The method of Claim 8, wherein the spent media is collected at about 24 hours, at about 48 hours, at about 72 hours, at about 96 hours, at about 120 hours, at about 144 hours, or any combination thereof.

10. The method of Claims 8 or Claim 9, further comprising concentrating the collected spent media to obtain a conditioned media.

11. The method of Claim 10, wherein the collected spent media is concentrated by at least 5-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, or more than 25-fold.

12. The method of Claim 10, further comprising dividing the conditioned media into an exosomal fraction and a non-exosomal fraction.

13. The method of Claim 12, further comprising subjecting the exosomal fraction to a proteomic analysis and / or genomic analysis.

14. The method of Claim 13, wherein the genomic analysis can comprise a gene expression analysis of genes related to mitochondrial biogenesis, genes related to apoptosis, genesrelated to vascular regeneration, genes related to inflammation, podocyte-specific genes, antioxidant genes, or any combination thereof.

15. The method of Claim 14, wherein the genes related to mitochondrial biogenesis comprise TFAM, ATP5B, NRF1, SDHB, NDUFA1, PGC1A, PRDM16. UCP1, CEBP-A. PPARG. or any combination thereof; wherein the genes related to apoptosis comprise p53, p21, BCL2, CASP3, CASP9, or any combination thereof; wherein the genes related to vascular regeneration comprise VEGF-A, PECAM1, eNOS, KDR, or any combination thereof; wherein podocyte-specific genes comprise NPHS1, SYNPO / O2, WT1, or any combination thereof; wherein the antioxidant genes comprise SOD1, SOD2. SOD3, GPX1, GPX3, CAT, or any combination thereof; wherein genes related to inflammation comprise PTGS2, IL6, TNFa, NFKB, or any combination thereof; or any combination thereof.

16. The method of Claim 13, wherein the MSCs are BM-MSCs, and wherein the gene expression analysis is characterized by an increase in expression of one or more SERPINB3, ARG1, KITLG, SERPINB12, TXNRD3, SFRP1, SERPINA12, MRAS, or any combination thereof.

17. A composition made by the method of any one of Claims 1 - 16.

18. A pharmaceutical formulation, comprising: the composition of Claim 17; and one or more pharmaceutically acceptable excipients, diluents, or carriers.

19. A pharmaceutical formulation, comprising: a composition comprising conditioned media obtained from one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs); and one or more pharmaceutically acceptable excipients, diluents, or carriers.

20. A pharmaceutical formulation, comprising: a composition comprising exosomes obtained from the conditioned media of one or more p53-silenced bone marrow derived mesenchymal stromal cells (BM-MSCs); and one or more pharmaceutically acceptable excipients, diluents, or earners.

21. A method of treating and / or preventing disease progression, the method comprising: administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical formulation of any one of Claims 18 - 20.

22. The method of Claim 21, wherein the a subject has been diagnosed with diabetes, a diabetes- related complication, hyperglycemia, diabetic kidney disease, chronic kidney disease, cardiovascular disease, peripheral vascular disease, nonalcoholic fatty liver disease (NAFLD), a wound healing disease or disorder, or any combination thereof.

23. The method of Claim 21, wherein, following administration, one or more physiological changes is effected in the subject; one or more positive and / or favorable physiological changes is generated in the subject; wound healing is improved and / or enhanced in the subject; one or more diabetes-related symptoms or complications are treated in the subject; one or more diabetes-related vascular issues or diabetes-related vascular complications are treated in the subject; vascular regeneration is improved and / or enhanced and / or stimulated and / or promoted in one or more tissues and / or one or more organs in the subject; apoptosis of cells exposed to hyperglycemia is prevented; the amount and / or degree and / or spread of apoptosis of cells exposed to hyperglycemia is prevented; apoptosis of endothelial cells exposed to hyperglycemic conditions is prevented; the amount and / or degree and / or spread of apoptosis of endothelial cells exposed to hyperglycemia is prevented; endothelial regeneration is improved and / or enhanced and / or stimulated and / or promoted in the subject; systemic inflammation is diminished and / or decreased in the subject; renal function is improved and / or enhanced in the subject; one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation are restored in the subject; or any combination thereof.

24. The method of any one of Claims 21 - 23, wherein, following the administering step, the progression of the subject’s disease is slowed and / or diminished.

25. The method of any one of Claims 21 - 24, further comprising administering to the subject one or more additional therapeutic agents.

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