An In-Depth Analysis of JadiCell (Allogeneic Umbilical Cord MSCs): Therapeutic Potential, Clinical Development, and Regulatory Trajectory

Section 1: Executive Summary

1.1. Overview of JadiCell

JadiCell is an investigational advanced therapy medicinal product (ATMP) being developed by Therapeutic Solutions International, Inc. (TSOI), an immune-modulation focused biotechnology company.[1] The therapeutic agent consists of allogeneic mesenchymal stem cells (MSCs) derived from the umbilical cord, positioning it as a universal donor, "off-the-shelf" cell therapy candidate.[3] TSOI is developing JadiCell as a potential platform technology for a range of conditions characterized by severe inflammation and tissue damage, with primary programs in respiratory and neurological diseases.[2]

1.2. Core Thesis

This report provides a comprehensive analysis of the scientific, clinical, regulatory, and corporate dimensions of the JadiCell program. The central finding of this analysis is that JadiCell is a scientifically compelling therapeutic candidate, supported by statistically significant and clinically meaningful data from an early-stage, randomized controlled trial in a condition with profound unmet medical need—Acute Respiratory Distress Syndrome (ARDS). The company has further supported this clinical potential with a multifaceted research program elucidating several plausible mechanisms of action and a sophisticated, multi-pronged regulatory and intellectual property strategy. However, this high scientific and clinical potential is inextricably linked to the considerable operational, financial, and transparency risks associated with its parent company, TSOI. The company's status as an OTC-traded entity with a history of delisting and regulatory delinquency presents a stark juxtaposition to the capital-intensive and rigorous demands of late-stage clinical development. Therefore, any evaluation of JadiCell must balance its significant promise against the substantial challenges inherent in its corporate and financial structure.

1.3. Key Clinical and Regulatory Highlights

The foundation of the JadiCell program rests on positive results from a Phase 1/2a double-blind, randomized, placebo-controlled trial in 24 patients with COVID-19-associated ARDS. The study demonstrated a dramatic and statistically significant survival benefit, with 91% of patients treated with JadiCell surviving at 31 days compared to only 42% in the placebo group (P=.015).[3] The treatment was also associated with a significantly shorter time to recovery (

P=.03) and a favorable safety profile, with no serious adverse events attributed to the infusion.[3]

Building on this success, TSOI has received clearance from the U.S. Food and Drug Administration (FDA) to initiate a pivotal Phase III clinical trial for COVID-19 ARDS and has subsequently filed a new Investigational New Drug (IND) application to expand its investigation into the broader, all-cause ARDS population.[3] The company's development pipeline is ambitious, extending into other areas of high unmet need, including Phase I programs for Chronic Traumatic Encephalopathy (CTE) and Chronic Obstructive Pulmonary Disease (COPD).[8] This clinical strategy is complemented by an aggressive regulatory approach that leverages multiple FDA programs, including numerous IND filings for distinct indications, Emergency Use INDs for expanded access, and filings for Orphan Drug Designation in both ARDS and Frontotemporal Dementia.[9]

Table 1: Therapeutic Solutions International (TSOI) JadiCell Development Pipeline
Indication	Highest Development Phase	Key Regulatory Milestone(s) / IND Number
Acute Respiratory Distress Syndrome (ARDS) - COVID-19	Phase 3	FDA Clearance for Pivotal Trial; Emergency IND #28685 Granted 10
Acute Respiratory Distress Syndrome (ARDS) - All-Cause	Phase 3 (Filed)	New IND Application Filed with FDA 3
Chronic Traumatic Encephalopathy (CTE)	Phase 1	IND #27377 Granted 8
Chronic Obstructive Pulmonary Disease (COPD)	Phase 1	IND #28508 Granted 8
Frontotemporal Dementia	Preclinical	Orphan Drug Designation Filed 4
Epilepsy	Preclinical	Preclinical Development 8
Schizophrenia	Preclinical	Preclinical Development 8
Idiopathic Pulmonary Fibrosis	Preclinical	Preclinical Development 8

1.4. Summary of Analysis and Outlook

The forward-looking outlook for JadiCell is one of cautious optimism, contingent on TSOI's ability to navigate significant hurdles. The scientific rationale is sound and the early clinical data in ARDS is exceptionally strong. The company's strategic moves to bring manufacturing in-house, build a robust intellectual property portfolio, and engage proactively with the FDA demonstrate a sophisticated understanding of the cell therapy development process. However, the path forward is fraught with risk. The primary challenge will be the execution and funding of the pivotal Phase III ARDS trial. Success in this trial would be a transformative event, validating the therapy and potentially establishing a new standard of care. Failure, on the other hand, would call the entire platform into question. Key milestones for stakeholders to monitor include the official initiation and public registration of the all-cause ARDS Phase III trial, FDA decisions on the pending Orphan Drug applications, and the peer-reviewed publication of the company's extensive mechanistic research. Ultimately, JadiCell represents a high-risk, high-reward asset where profound therapeutic potential is counterbalanced by significant corporate and financial uncertainty.

Section 2: Profile of the Therapeutic Agent: JadiCell

2.1. Cellular Origin and Characteristics

JadiCell is an allogeneic cell therapy product composed of mesenchymal stem cells, also referred to as mesenchymal stromal cells (MSCs), derived from the tissue lining of the human umbilical cord.[3] The use of an allogeneic, or "universal donor," source is a critical feature, as it allows for the creation of large, cryopreserved banks of cells from a single donor that can be administered to multiple, immunologically unmatched recipients.[15] This "off-the-shelf" model contrasts sharply with autologous therapies, which require harvesting, processing, and administering cells from and to the same individual, a logistically complex and costly process.[15] Umbilical cord-derived MSCs are readily available from tissue that is otherwise discarded after birth, can be expanded to clinically relevant numbers, and are generally considered to have low immunogenicity.[16]

Therapeutic Solutions International has frequently described JadiCells as being "supercharged," with the stated intention of providing elevated levels of therapeutic factors in comparison to other types of stem cells.[3] While this terminology suggests a proprietary process for cell selection or enhancement, specific, peer-reviewed data quantitatively comparing the secretome or functional activity of JadiCells against other umbilical cord-derived MSC products is not extensively detailed in the available documentation. This claim should therefore be viewed as a corporate descriptor pending further scientific substantiation.

2.2. Foundational Properties of MSCs

To understand the therapeutic rationale for JadiCell, it is essential to consider the well-established biological properties of MSCs, which have made them one of the most widely studied platforms in regenerative medicine.[15] MSCs are multipotent cells that can be isolated from numerous tissues and are defined by their ability to adhere to plastic, express a specific set of surface markers, and differentiate into mesenchymal lineages such as bone, cartilage, and fat cells.[1]

Their therapeutic potential, however, is believed to derive less from their differentiation capacity and more from their potent paracrine and immunomodulatory functions.[1] MSCs function as a "cytokine pump," secreting a wide array of bioactive molecules, including growth factors, cytokines, and extracellular vesicles (such as exosomes).[1] These factors collectively orchestrate a therapeutic response in injured tissue by:

• Modulating the Immune System: MSCs can suppress the proliferation and function of various immune cells, including T-cells and B-cells, and can polarize macrophages towards an anti-inflammatory, pro-regenerative M2 phenotype. This helps to quell the excessive inflammation that drives pathology in diseases like ARDS.[1]
• Promoting Tissue Repair: They secrete neurotrophic and angiogenic factors, such as brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), that protect existing cells from death and stimulate the formation of new blood vessels, which is critical for healing.[22]
• Homing to Injury Sites: MSCs possess an intrinsic ability to migrate toward and accumulate at sites of inflammation and tissue damage, a process known as "homing." This ensures that their therapeutic payload is delivered precisely where it is needed most, maximizing efficacy while minimizing off-target effects.[5]

2.3. Manufacturing, Control, and Commercial Readiness

A pivotal non-clinical development for the JadiCell program was Therapeutic Solutions International's strategic decision to establish in-house manufacturing capabilities. This was accomplished through its subsidiary, Allogen Biologics Inc., which successfully generated a quality control-tested Master Cell Bank of the JadiCell product.[4] This is a milestone of profound strategic importance for any company developing a cell therapy.

The Chemistry, Manufacturing, and Controls (CMC) aspect of cell therapy development is a major area of focus for regulatory agencies like the FDA. Ensuring the consistency, purity, potency, and safety of a living cellular product from batch to batch is a formidable challenge. By previously relying on third-party manufacturing, TSOI faced significant risks related to cost, production timelines, technology transfer, and potential regulatory uncertainty.[4]

The creation of an internal Master Cell Bank addresses these challenges directly. It provides a single, well-characterized, and extensively tested source of cells from which all subsequent Working Cell Banks are derived. This ensures that the cells used for expanded access programs, the pivotal Phase III clinical trial, and the potential future commercial product are all derived from the same starting material, a critical requirement for regulatory approval. TSOI has stated that these newly manufactured cells possess the functional and phenotypic characteristics that the FDA had previously agreed upon in its clearance for the Phase III trial.[4] This vertical integration of manufacturing represents a significant de-risking of the program's commercialization pathway, demonstrating a serious commitment to late-stage development and giving the company direct control over one of the most complex and critical components of its therapeutic platform.

Section 3: Elucidating the Multifaceted Mechanism of Action

Therapeutic Solutions International has dedicated significant resources to investigating the biological mechanisms through which JadiCell exerts its therapeutic effects. This research has yielded a multi-faceted and increasingly detailed picture of the therapy's immunomodulatory and regenerative activities. This approach is not merely academic; it is deeply integrated into the company's corporate strategy, with each significant mechanistic discovery being followed by the filing of new patent applications. This "discover-and-protect" strategy serves to build a robust intellectual property estate that extends beyond the core composition of matter of the cells, creating a defensible moat around the entire therapeutic platform.

3.1. Core Immunomodulatory Pathways

JadiCell appears to orchestrate a complex immunomodulatory response by influencing several key immune cell populations.

• Monocyte and T-Cell Interplay: Research using an animal model of inflammation-induced lung injury revealed a critical interplay between two immune cell types following JadiCell administration. The company reported an increase in monocytes expressing the potent anti-inflammatory cytokine interleukin-35 (IL-35), alongside an increase in T-cells expressing transforming growth factor-beta (TGF-β), another key anti-inflammatory molecule.[4] The therapeutic importance of this interaction was demonstrated in experiments where the depletion of either of these cell populations significantly diminished the healing effects of JadiCell.[13] Furthermore, the transfer of monocytes and T-cells from JadiCell-treated animals was sufficient to confer protection against lung injury in naive animals. This finding was accompanied by a patent filing and suggests a potential avenue for therapeutic enhancement; the administration of GM-CSF (Leukine), a drug known to increase circulating monocytes, was shown to amplify the therapeutic effect of JadiCells.[13]
• Role of B-Regulatory Cells: In a separate line of investigation, TSOI identified a correlation between patient responsiveness to JadiCell therapy and alterations in a specific subset of B-cells known as B-regulatory cells (Bregs).[8] These cells are characterized by their production of the anti-inflammatory cytokine interleukin-10 (IL-10) and are involved in controlling pathological immunity.[28] In a preclinical model of COPD, the therapeutic activity of JadiCell was nullified by the depletion of B-cells. Conversely, the protective effect could be transferred to naive animals by administering this unique B-cell population from treated animals.[8] This discovery is of immense strategic importance. The ability to identify a biomarker that predicts patient response could fundamentally reshape the clinical development and commercial viability of JadiCell. A major challenge for therapies with variable efficacy is demonstrating a statistically significant benefit in a large, heterogeneous patient population. If the B-reg cell signature is validated as a predictive biomarker, TSOI could enrich future clinical trials with patients most likely to benefit. This would dramatically increase the probability of trial success, potentially reduce the required trial size and cost, and provide a clear rationale for targeted patient selection upon commercialization, marking a significant step toward personalized regenerative medicine.[28]

3.2. Paracrine Signaling and Exosome Function

A substantial portion of the therapeutic effect of MSCs is mediated by paracrine signaling, where the cells release bioactive factors into their microenvironment without direct cell-to-cell contact. TSOI has investigated this pathway, focusing on the role of exosomes.

• Suppression of Neutrophil Extracellular Traps (NETs): TSOI announced laboratory data demonstrating that exosomes—small vesicles secreted by cells that carry proteins, mRNA, and miRNA—produced by JadiCells can suppress the formation of Neutrophil Extracellular Traps (NETs).[29] NETs are web-like structures of DNA, histones, and enzymes released by neutrophils to trap pathogens. However, in conditions like severe COVID-19, their overproduction contributes significantly to inflammation, tissue damage, and thrombosis.[29] The ability of JadiCell-derived exosomes to inhibit NETosis represents a key anti-inflammatory mechanism. The company has also noted that the exosomes themselves, as a potential cell-free therapeutic, demonstrated potent lung-protective activity in animal models of lung injury, opening a potential new product pipeline.[29] This discovery was also protected by a patent application.[29]
• Other Paracrine Mechanisms: Further research has pointed to the involvement of other cell types and their secreted factors. The company has identified CD103-expressing dendritic cells and their exosomes as another novel mechanism contributing to JadiCell-mediated lung protection.[3]

3.3. Tissue Regeneration and Anti-Inflammatory Action

Beyond broad immunomodulation, JadiCell is believed to act directly on pathways involved in tissue damage and repair.

• Inhibition of Inflammasome Activation: In the context of neurodegenerative diseases such as CTE and Frontotemporal Dementia, TSOI highlights the ability of JadiCells to inhibit the activation of the inflammasome.[11] The inflammasome is an intracellular protein complex that, when activated, triggers the release of highly pro-inflammatory cytokines, driving neuroinflammation and cell death. Blocking this pathway is a key therapeutic goal in many neurodegenerative conditions.[11]
• Stimulation of Regeneration: Concurrently with its anti-inflammatory effects, JadiCell is proposed to directly stimulate regenerative processes. This includes promoting the regeneration of damaged neurons, enhancing the survival of injured cells, and stimulating the proliferation of resident stem cells within the affected tissue.[5] This dual action—reducing destructive inflammation while simultaneously promoting repair—forms the core of its therapeutic rationale across multiple disease indications.

Section 4: Clinical Development Portfolio: Respiratory Diseases

The most advanced and clinically validated component of the JadiCell program is in the treatment of severe respiratory diseases. The compelling data generated in Acute Respiratory Distress Syndrome (ARDS) serves as the foundation for the company's entire clinical strategy and has catalyzed its expansion into other pulmonary conditions like Chronic Obstructive Pulmonary Disease (COPD).

4.1. Acute Respiratory Distress Syndrome (ARDS): A Flagship Indication

4.1.1. Unmet Need and Standard of Care in ARDS

Acute Respiratory Distress Syndrome is a devastating form of acute respiratory failure characterized by diffuse inflammation and fluid accumulation in the lungs, leading to severe hypoxemia.[7] ARDS is responsible for approximately 10% of all admissions to intensive care units (ICUs) and is associated with a very high in-hospital mortality rate, ranging from 46% to 60% in its most severe forms.[9] Despite decades of research, there are no FDA-approved pharmacological therapies that can cure ARDS or reverse the underlying lung injury.[34] The current standard of care is entirely supportive and focuses on mitigating further lung damage and maintaining organ function. This includes protective mechanical ventilation using low tidal volumes and high positive end-expiratory pressure (PEEP), placing patients in a prone (face-down) position to improve oxygenation, conservative fluid management to prevent further lung edema, and prophylaxis for complications like venous thromboembolism.[32] This lack of effective treatments represents a profound unmet medical need for the approximately 190,000 Americans affected by ARDS annually.[7]

4.1.2. Analysis of Phase 1/2a Trial Data in COVID-19 ARDS (Lanzoni et al., 2021)

The most critical evidence supporting the potential of JadiCell comes from a double-blind, randomized, placebo-controlled Phase 1/2a trial conducted at the University of Miami in patients with ARDS secondary to severe COVID-19.[3] The results of this study, published in

Stem Cells Translational Medicine, form the cornerstone of TSOI's clinical program.[3]

The trial enrolled 24 critically ill patients who were randomized 1:1. The treatment group (n=12) received two intravenous infusions of 100 million JadiCells each, administered on day 0 and day 3. The control group (n=12) received two infusions of a vehicle solution on the same schedule. Both cohorts received the best available standard of care.[6] The trial's findings were remarkably positive, as detailed in Table 2.

Table 2: Summary of Efficacy and Safety Outcomes from the Phase 1/2a Trial in COVID-19 ARDS (Lanzoni et al., 2021)
Endpoint	JadiCell Group (n=12)	Control Group (n=12)	Statistic	P-Value
Primary Safety Endpoint
Infusion-Associated AEs	1 patient (worsening bradycardia)	1 patient (cardiac arrest)	N/A	N/A
SAEs Related to Infusion	0	0	N/A	N/A
Secondary Efficacy Endpoints
Survival at Day 31	91% (10 of 11 evaluable)	42% (5 of 12)	HR for Death: 8.76 (Control vs. JadiCell)	.015
Time to Recovery	Median not reached (faster)	Median not reached (slower)	HR for Recovery: 0.29 (Control vs. JadiCell)	.03
SAE-Free Survival	Significantly improved	Significantly worse	HR for SAE: 6.22 (Control vs. JadiCell)	.008
Other Safety Outcomes
Total Number of SAEs	2	16	N/A	N/A
Patients with at least one SAE	16.7% (2 of 12)	66.7% (8 of 12)	N/A	.04
Exploratory Endpoints
Change in Inflammatory Cytokines (Day 0 to Day 6)	Significant decrease in IL-6, TNF-α, etc.	No significant change	N/A	<.05

Data compiled from sources.[3]

The primary endpoint of safety was met, with no serious adverse events (SAEs) deemed related to the JadiCell infusion.[3] Strikingly, the treatment group experienced significantly fewer overall SAEs than the control group, suggesting a protective effect.[6] The efficacy results were highly statistically significant. The survival rate in the JadiCell arm was more than double that of the control arm (91% vs. 42%).[3] For patients under the age of 85, the survival rate in the treatment group was 100%.[7] This survival benefit was accompanied by a significantly faster time to recovery and a significant reduction in key inflammatory cytokines associated with the "cytokine storm" of severe COVID-19.[6]

4.1.3. Status and Design of the Phase III Program

Leveraging this robust early-stage data, TSOI has advanced the JadiCell program into late-stage development. The company received FDA clearance to initiate a pivotal Phase III registration trial for COVID-19 ARDS.[13] In a key strategic move, TSOI later purchased the IND for this trial from the University of Miami, transitioning it from an "Investigator Initiated" study to an "Industry Sponsored" investigation. This gives TSOI full operational and strategic control over the trial's conduct.[40]

Recognizing the evolving nature of the pandemic and the broader therapeutic potential of JadiCell, TSOI has made a critical strategic pivot to expand the indication to all-cause ARDS. The underlying pathophysiology of ARDS—diffuse alveolar damage, endothelial injury, and hyperinflammation—is largely consistent regardless of the initial trigger, be it a virus, sepsis, or trauma.[32] An all-cause ARDS indication dramatically expands the addressable market and ensures the long-term relevance of the therapy beyond COVID-19. To this end, the company announced in April 2023 the filing of a new IND application with the FDA to initiate a Phase III trial specifically for the broader ARDS population.[3] This followed an earlier attempt in August 2022 to amend the existing COVID-19 trial to include all-cause ARDS patients.[42]

Despite numerous press releases announcing the launch and filing of these Phase III trials, a significant transparency issue persists: the lack of a readily identifiable and verifiable NCT number on ClinicalTrials.gov for a TSOI-sponsored ARDS trial. The original University of Miami study is registered (NCT04355728), but the pivotal follow-up trial sponsored by TSOI does not appear in the provided documentation.[43] For a company's lead asset, this absence of public registration is a notable gap that makes independent verification of the trial's status, design, and progress challenging.

4.1.4. Expanded Access

In parallel with its formal clinical trial program, TSOI has actively utilized FDA pathways for expanded access to provide JadiCell to critically ill patients. In July 2022, the FDA granted the company Emergency IND (eIND) number #28685, providing a mechanism to treat patients with advanced COVID-19 ARDS who are not enrolled in the clinical trial.[3] The company has also provided the therapy to "no option patients" under the Right to Try Law, which allows access to investigational drugs that have completed Phase I testing.[9]

4.2. Chronic Obstructive Pulmonary Disease (COPD)

TSOI is expanding its respiratory franchise by targeting COPD, a chronic, progressive lung disease characterized by persistent inflammation and airflow limitation.

4.2.1. Therapeutic Rationale and Preclinical Evidence

The therapeutic rationale for using JadiCell in COPD is based on the same core anti-inflammatory and regenerative properties demonstrated in ARDS.[5] The goal is to modulate the chronic inflammation that drives lung tissue destruction and potentially stimulate repair processes. TSOI has reported positive preclinical data from animal models of COPD, showing that JadiCell administration reduced lung injury and preserved lung function.[30] Notably, these studies suggested that JadiCell was superior to MSCs derived from other sources, such as bone marrow or adipose tissue, in this model.[47]

4.2.2. Status of the Phase I/II Clinical Program

Based on its preclinical data, TSOI has advanced the COPD program to the clinical stage. The company announced it has received Investigational New Drug (IND) application number #28508 from the FDA for a proposed Phase I/II clinical trial of JadiCell in patients with COPD.[8] As part of this process, the FDA assigned the official product name "Allogeneic Umbilical Cord Mesenchymal Stem Cells, JadiCell; Intravenous injection".[8] The company has entered into discussions with the FDA regarding the specific design and patient population for this trial.[12]

Section 5: Clinical Development Portfolio: Neurological and CNS Disorders

Building on its platform in inflammatory diseases, Therapeutic Solutions International is pursuing an ambitious expansion into neurological and central nervous system (CNS) disorders. This area is characterized by immense unmet medical need but is also notoriously challenging for clinical development. The company's strategy in this space is led by its program in Chronic Traumatic Encephalopathy (CTE).

5.1. Chronic Traumatic Encephalopathy (CTE)

5.1.1. Unmet Need and Current Management of CTE

Chronic Traumatic Encephalopathy is a progressive neurodegenerative disease believed to be caused by repetitive head impacts, commonly affecting athletes in contact sports and military veterans.[14] The disease is characterized by the accumulation of hyperphosphorylated tau protein in the brain, leading to a range of debilitating symptoms including memory loss, impaired judgment, aggression, depression, and eventually, dementia.[14] A major challenge is that a definitive diagnosis can currently only be made through post-mortem examination of brain tissue.[14] There are no approved cures or disease-modifying treatments for CTE; current management is entirely symptomatic and supportive, utilizing cognitive therapies and medications to manage behavioral and mood disturbances.[49]

5.1.2. Status of the Phase I/II Program and Right to Try Experience

TSOI has established a formal regulatory pathway for JadiCell in CTE. In April 2021, the company was granted IND number #27377 by the FDA for a proposed clinical trial.[14] TSOI has highlighted the FDA's acceptance of its proposed clinical trial protocol, which includes criteria for diagnosing CTE in living patients, as a significant regulatory accomplishment that validates the disease as a viable therapeutic indication.[14] In August 2021, the company announced the successful completion of a series of FDA-requested preclinical experiments designed to confirm the properties of JadiCells, a necessary step before initiating the Phase I/II human trial.[55]

In parallel with this formal regulatory process, TSOI has pursued a dual-track strategy by providing JadiCells to CTE patients under the federal Right to Try Law. This law allows patients with life-threatening conditions who cannot participate in a clinical trial to access investigational drugs that have cleared Phase I safety studies.[45] The company has reported successfully treating multiple CTE patients through this pathway, including a notable case of a veteran U.S. Navy SEAL.[14] This approach allows the company to generate early, real-world human data and maintain program momentum while navigating the slower, more rigorous formal IND process. However, it is critical to note that these are anecdotal case reports and do not carry the scientific weight of data from a randomized, controlled clinical trial.

5.1.3. Corporate Strategy: The Role of CTE Biologics, Inc.

To sharpen the focus on its neurology program, TSOI announced the creation of a dedicated subsidiary, CTE Biologics, Inc..[14] This entity is tasked with commercializing the JadiCell platform specifically for the treatment of CTE. This corporate structuring can be interpreted as a strategic financial maneuver as much as an operational one. For a small parent company with a broad platform technology, funding multiple, expensive clinical programs simultaneously is a major challenge. By spinning out the CTE asset into a separate legal entity, TSOI creates a new, more focused vehicle for investment. This subsidiary could potentially attract specialized investors or partners interested specifically in neurodegenerative diseases without diluting the equity of the parent company across its entire portfolio. This modular approach to financing and deal-making may allow the company to fund its diverse pipeline more effectively and isolates the risks and rewards of the CTE program.

5.2. Emerging Preclinical and Anecdotal Indications

TSOI is exploring the potential of JadiCell in several other CNS disorders, though these programs are at a much earlier stage of development.

• Frontotemporal Dementia (FTD): Citing molecular similarities between FTD and CTE, TSOI has filed an application with the FDA for Orphan Drug Designation for JadiCell in the treatment of FTD.[4] FTD is the leading cause of dementia in people under 60 and currently has no therapies proven to slow its progression.[11] The company's rationale is based on preclinical data suggesting JadiCell's ability to inhibit inflammasome activation and stimulate the regeneration of damaged neurons, both of which are relevant to FTD pathology.[11]
• Other CNS Disorders: The development pipeline also includes preclinical programs investigating JadiCell in models of Epilepsy and Schizophrenia.[8] Additionally, the Veltmeyer Institute for Advanced Biologics, founded by TSOI's Chief Medical Officer, has issued press releases claiming observational improvements in individual patients with amyotrophic lateral sclerosis (ALS), schizophrenia, and autism following JadiCell infusions provided under expanded access programs.[56] For the ALS patient, a significant increase in T-regulatory cells was reported post-infusion.[56] These anecdotal reports, while intriguing, must be interpreted with extreme caution and require validation in rigorously designed, controlled clinical trials before any conclusions about efficacy can be drawn.

Section 6: Regulatory Strategy and Competitive Landscape

Therapeutic Solutions International has pursued a notably proactive and sophisticated regulatory strategy, leveraging multiple FDA programs designed to accelerate the development of therapies for serious and life-threatening conditions. This approach, combined with a diligent intellectual property strategy, aims to build a durable competitive advantage for the JadiCell platform.

6.1. FDA Engagement and Strategic Filings

TSOI has engaged with the FDA across its entire pipeline, securing multiple INDs that permit the initiation of clinical trials in human subjects. An IND application is a comprehensive submission containing data from preclinical studies and manufacturing information, which the FDA reviews to ensure that subjects will not be exposed to unreasonable risk.[58] The company's active INDs represent formal clearance from the agency to proceed with clinical investigation. A consolidated summary of these filings is presented in Table 3.

6.2. Orphan Drug Designations (ODD)

The company is also strategically utilizing the Orphan Drug Act, which provides significant incentives to encourage the development of treatments for rare diseases (defined as affecting fewer than 200,000 people in the U.S.).[59] TSOI has announced filings for Orphan Drug Designation for JadiCell in two indications:

• Acute Respiratory Distress Syndrome (ARDS): Filed in June 2023.[9]
• Frontotemporal Dementia (FTD): Filed in July 2023.[4]

If granted by the FDA, ODD provides substantial benefits, including seven years of market exclusivity following drug approval, a 25% federal tax credit for qualified clinical trial expenses, a waiver of the expensive Prescription Drug User Fee Act (PDUFA) fees (valued at approximately $2.9 million in 2021), and eligibility for federal research grants.[9] The public FDA database does not yet reflect a granted status for these applications, indicating they are likely still under review.[64]

6.3. Intellectual Property Portfolio

A strong intellectual property portfolio is critical for any biotechnology company. The cornerstone of TSOI's protection for JadiCell is an exclusive license to U.S. Patent No. 9,803,176 B2, which covers the composition of matter of the cells for use in lung and brain diseases.[7] The strength of this patent was significantly reinforced when its validity was upheld by the U.S. Patent Trial and Appeal Board following a legal challenge (an Inter Partes Review), a major victory for the company that it cited as a factor in its decision to accelerate the ARDS program.[3] In addition to this foundational patent, TSOI has been aggressive in filing its own patent applications covering novel uses and newly discovered mechanisms of action, such as the role of B-regulatory cells and the suppression of NETs by exosomes, thereby creating a layered and more comprehensive IP estate.[8]

Table 3: Key Regulatory Filings and Intellectual Property for JadiCell
Filing/Asset Type	Identifier	Indication(s)	Status/Date
IND Application	Acquired from U. of Miami	COVID-19 ARDS	Cleared for Phase III 40
IND Application	Not specified	All-Cause ARDS	Filed (April 2023) 3
IND Application	#27377	Chronic Traumatic Encephalopathy (CTE)	Granted (April 2021) 14
IND Application	#28508	Chronic Obstructive Pulmonary Disease (COPD)	Granted (May 2022) 10
Emergency IND (eIND)	#28685	Expanded Access for COVID-19 ARDS	Granted (July 2022) 10
Orphan Drug Designation	Application Filed	Acute Respiratory Distress Syndrome (ARDS)	Filed (June 2023) 9
Orphan Drug Designation	Application Filed	Frontotemporal Dementia (FTD)	Filed (July 2023) 4
Composition of Matter Patent	U.S. Patent No. 9,803,176 B2	Lung and Brain Diseases	Licensed; Validity Upheld 7
Mechanism of Action Patents	Multiple Applications	Various (e.g., B-cells, Exosomes)	Filed 8

6.4. Competitive Analysis in ARDS

The therapeutic potential of MSCs for ARDS has attracted several companies, creating a competitive landscape. The experience of these competitors provides important context for TSOI's own development path.

• Mesoblast (Remestemcel-L): A global leader in allogeneic cell therapy, Mesoblast conducted a 222-patient Phase III trial (NCT04371393) of its bone marrow-derived MSC product, remestemcel-L, in ventilator-dependent COVID-19 ARDS patients.[65] The trial was halted early after a Data Safety Monitoring Board determined it was unlikely to meet its primary endpoint of a 43% reduction in 30-day mortality across the entire population.[67] This outcome serves as a significant cautionary tale about the difficulty of demonstrating efficacy in this critically ill and heterogeneous population. However, a pre-specified analysis of patients under the age of 65 (n=123) did show a statistically significant 48% reduction in mortality at 90 days ( P=.038).[67] This suggests that MSC therapy may be effective, but patient selection is critical. Novartis had previously signed a major licensing deal with Mesoblast for this asset, but the agreement was contingent on the trial's results, highlighting the high stakes of these late-stage studies.[67]
• Citius Pharmaceuticals (NoveCite i-MSCs): Citius is developing a next-generation MSC therapy for ARDS derived from induced pluripotent stem cells (iPSCs) rather than adult donor tissue.[35] This i-MSC platform, currently in preclinical development, is claimed to offer advantages over donor-derived cells, such as those used by TSOI and Mesoblast, by providing a clonal, genetically homogeneous cell source that may lead to higher potency, consistency, and more efficient manufacturing at scale.[71] While earlier stage, Citius represents a potential long-term competitive threat based on its technology platform.[35]

The mixed results from Mesoblast's trial offer a crucial strategic lesson for TSOI. The failure to meet the primary endpoint in the broad population underscores the risks TSOI faces in its own Phase III trial. However, the positive signal in a specific subgroup reinforces the importance of TSOI's own research into predictive biomarkers, such as the B-regulatory cell signature. If TSOI can successfully stratify its patient population or enrich its trial for likely responders, it may be able to avoid the pitfalls that challenged its most prominent competitor.

Section 7: Synthesis and Forward-Looking Analysis

7.1. Critical Assessment of Evidence

A comprehensive evaluation of the JadiCell program reveals a profile of significant strengths counterbalanced by notable weaknesses and uncertainties.

• Strengths: The program's foremost strength is the robust, peer-reviewed, and statistically significant clinical data from the Phase 1/2a randomized controlled trial in COVID-19 ARDS.[3] A 91% vs. 42% survival benefit ( P=.015) in a double-blind study is a powerful signal of therapeutic activity that is rare in early-stage clinical development. This clinical finding is supported by a growing body of mechanistic research that provides a plausible, multi-faceted biological rationale for its immunomodulatory and regenerative effects.[4] Furthermore, the therapy has demonstrated a favorable safety profile across multiple uses, including in the controlled trial and under expanded access programs.[3] The company's strategic actions—establishing in-house manufacturing, defending and expanding its IP portfolio, and proactively engaging with the FDA—indicate a high level of operational and regulatory sophistication.[4]
• Weaknesses: A primary weakness is the program's heavy reliance on corporate press releases to communicate major scientific and clinical milestones. Beyond the foundational Lanzoni et al. publication, there is a relative scarcity of peer-reviewed data validating the company's extensive mechanistic claims or preclinical findings in other indications. While the company has reported positive outcomes from patients treated under the Right to Try Law, these anecdotal case reports are not a substitute for data from controlled clinical trials and must be viewed with appropriate scientific skepticism.[14] The most significant weakness from a due diligence perspective is the lack of a clear, publicly verifiable registration (i.e., an NCT number on ClinicalTrials.gov) for the company's pivotal, TSOI-sponsored Phase III ARDS trial, which represents a critical transparency gap for its most valuable asset.

7.2. Identified Risks and Challenges

The path to commercialization for JadiCell is subject to several profound risks that must be carefully considered.

• Clinical Risk: The single greatest risk is the challenge of translating the highly promising Phase 1/2a ARDS results into a successful, adequately powered Phase III trial. The history of drug development is replete with therapies that failed in late-stage trials despite strong early signals. The experience of Mesoblast, whose remestemcel-L failed to meet its primary endpoint in a similar patient population, serves as a stark and immediate reminder of this "valley of death" in clinical development.[67] Successfully replicating the magnitude of effect seen in the 24-patient study in a larger, multi-center trial of 128 patients will be a formidable task.[39]
• Financial and Corporate Risk: This represents the most significant non-clinical threat to the program. Therapeutic Solutions International is traded on the OTC Pink Sheets market, has a history of delisting from higher exchanges, and has been noted as being SEC delinquent.[27] The company's very low stock price and market capitalization (reported at $5,122.71 in one source) present an extreme challenge to raising the substantial capital required to fund a multi-national Phase III trial, let alone the multiple other Phase I/II trials in its pipeline, without incurring massive shareholder dilution.[75] The company's ability to secure the necessary financing to see its lead program through to completion is a major uncertainty.
• Manufacturing and Commercialization Risk: While the establishment of a Master Cell Bank is a crucial de-risking milestone, the journey from a clinical-scale bank to full commercial-scale manufacturing is complex, expensive, and technically demanding. Scaling up the production of a consistent, high-quality allogeneic cell therapy to meet market demand presents significant logistical and regulatory hurdles that the company has yet to face.

7.3. Future Outlook and Potential Milestones

Despite the risks, JadiCell remains a therapeutic candidate of significant interest due to its potential to address diseases with high mortality and morbidity. The company's future trajectory will be defined by its ability to execute on a series of critical, near-term milestones that will serve as major catalysts and value inflection points.

• Key Catalysts to Monitor:

1. Phase III ARDS Trial Initiation: The official commencement of patient enrollment in the pivotal, all-cause ARDS Phase III trial, accompanied by the publication of a verifiable NCT number on ClinicalTrials.gov. This would resolve the current transparency gap and signal the true start of its most important study.
2. Phase III ARDS Trial Data: The release of top-line data from this pivotal trial will be the single most important event in the company's history. A positive outcome would be transformative, while a negative result would be devastating.
3. FDA Regulatory Decisions: A formal decision from the FDA on the Orphan Drug Designation applications for ARDS and Frontotemporal Dementia. A grant of ODD would provide significant financial and commercial advantages.
4. Initiation of Other Trials: The formal initiation of patient dosing in the IND-cleared Phase I/II trials for CTE (IND #27377) and COPD (IND #28508).
5. Peer-Reviewed Publications: The publication of the company's mechanistic data (e.g., on B-regulatory cells, NET suppression) in reputable scientific journals would lend significant third-party validation to its claims.

• Concluding Perspective: JadiCell is a scientifically promising asset with best-in-class potential, supported by exceptionally strong early clinical data in ARDS. The company has demonstrated strategic acumen in its regulatory, IP, and manufacturing approaches. However, this potential is held within a corporate entity facing profound financial and structural challenges. The profound disconnect between the asset's value and the company's market valuation creates a classic high-risk, high-reward scenario. The successful funding and execution of the Phase III ARDS trial is the crucible in which the future of both JadiCell and Therapeutic Solutions International will be forged. It is the single most important factor that will determine whether this promising therapy can transition from a speculative asset to a new standard of care.

Works cited

1. Mesenchymal Stromal Cell-Based Products: Challenges and Clinical Therapeutic Options, accessed September 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11173248/
2. TSOI chart - Therapeutic Solutions International, Inc. - TradingView, accessed September 8, 2025, https://www.tradingview.com/symbols/OTC-TSOI/
3. Therapeutic Solutions International Seeks to Expand JadiCell Treatment to Broader ARDS Population - CGTLive®, accessed September 8, 2025, https://www.cgtlive.com/view/therapeutic-solutions-international-seeks-expand-jadicell-treatment-broader-ards-population
4. JadiCell (allogeneic umbilical cord mesenchymal stem cells) / Therapeutic Solutions - LARVOL DELTA, accessed September 8, 2025, https://delta.larvol.com/Products/?ProductId=288df09d-0dae-44dc-b0eb-e25281b09cf0
5. What is JadiCell used for? - Patsnap Synapse, accessed September 8, 2025, https://synapse.patsnap.com/article/what-is-jadicell-used-for
6. (PDF) Umbilical cord mesenchymal stem cells for COVID‐19 acute ..., accessed September 8, 2025, https://www.researchgate.net/publication/348272429_Umbilical_cord_mesenchymal_stem_cells_for_COVID-19_acute_respiratory_distress_syndrome_A_double-blind_phase_12a_randomized_controlled_trial
7. Therapeutic Solutions International Files to Initiate Phase III Clinical Trial for Acute Respiratory Distress Syndrome (ARDS) Leveraging Positive COVID-19 Data with JadiCell Stem Cell Therapy - Business Wire, accessed September 8, 2025, https://www.businesswire.com/news/home/20230420005538/en/Therapeutic-Solutions-International-Files-to-Initiate-Phase-III-Clinical-Trial-for-Acute-Respiratory-Distress-Syndrome-ARDS-Leveraging-Positive-COVID-19-Data-with-JadiCell-Stem-Cell-Therapy
8. Mesenchymal stem cells (Therapeutic Solutions International) - Drug ..., accessed September 8, 2025, https://synapse.patsnap.com/drug/086e40d4d94647cc8e982e8841d37aad
9. Therapeutic Solutions International Files for Orphan Drug Designation Using JadiCell Adult Universal Donor Stem Cells for Treatment of Acute Respiratory Distress Syndrome - BioSpace, accessed September 8, 2025, https://www.biospace.com/therapeutic-solutions-international-files-for-orphan-drug-designation-using-jadicell-adult-universal-donor-stem-cells-for-treatment-of-acute-respiratory-distress-syndrome
10. Therapeutic Solutions International Granted Emergency IND by FDA for Expanded Patient Access to JadiCell™ Universal Donor Stem Cell for COVID-19 ARDS Outside of Ongoing Phase III Clinical Trial - Stock Titan, accessed September 8, 2025, https://www.stocktitan.net/news/TSOI/therapeutic-solutions-international-granted-emergency-ind-by-fda-for-davfq15xkcc6.html
11. Therapeutic Solutions International Files for Orphan Drug Designation Use of JadiCell Adult Stem Cells for Treatment of Frontotemporal Dementia - BioSpace, accessed September 8, 2025, https://www.biospace.com/therapeutic-solutions-international-files-for-orphan-drug-designation-use-of-jadicell-adult-stem-cells-for-treatment-of-frontotemporal-dementia
12. Therapeutic Solutions International Receives IND Number 28508 for Chronic Obstructive Pulmonary Disease Clinical Trial and Enters Binding Discussions with FDA for Initiation of Phase I/II Clinical Trial - Business Wire, accessed September 8, 2025, https://www.businesswire.com/news/home/20220523005584/en/Therapeutic-Solutions-International-Receives-IND-Number-28508-for-Chronic-Obstructive-Pulmonary-Disease-Clinical-Trial-and-Enters-Binding-Discussions-with-FDA-for-Initiation-of-Phase-III-Clinical-Trial
13. Therapeutic Solutions International Announces Landmark Finding Regarding Mechanism of Action of its JadiCell Stem Cell Product - BioSpace, accessed September 8, 2025, https://www.biospace.com/therapeutic-solutions-international-announces-landmark-finding-regarding-mechanism-of-action-of-its-jadicell-stem-cell-product
14. Therapeutic Solutions International Launches Subsidiary Company to Commercialize Clinical Data and IND for Treatment of Chronic Traumatic Encephalopathy (CTE) with JadiCell Universal Adult Stem Cells - Business Wire, accessed September 8, 2025, https://www.businesswire.com/news/home/20230525005475/en/Therapeutic-Solutions-International-Launches-Subsidiary-Company-to-Commercialize-Clinical-Data-and-IND-for-Treatment-of-Chronic-Traumatic-Encephalopathy-CTE-with-JadiCell-Universal-Adult-Stem-Cells
15. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities - PMC, accessed September 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6434696/
16. Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized c - FIU Digital Commons, accessed September 8, 2025, https://digitalcommons.fiu.edu/cgi/viewcontent.cgi?article=1619&context=all_faculty
17. JadiCell™ Stem Cells Licensed by Therapeutic Solutions International for Brain Injury Significantly Increased Survival of COVID-19 Patients in Double Blind FDA Clinical Trial - BioSpace, accessed September 8, 2025, https://www.biospace.com/jadicell-stem-cells-licensed-by-therapeutic-solutions-international-for-brain-injury-significantly-increased-survival-of-covid-19-patients-in-double-blind-fda-clinical-trial
18. JadiCell™ Stem Cells Licensed by Therapeutic Solutions International for Brain Injury Significantly Increased Survival of COVID-19 Patients in Double Blind FDA Clinical Trial - PR Newswire, accessed September 8, 2025, https://www.prnewswire.com/news-releases/jadicell-stem-cells-licensed-by-therapeutic-solutions-international-for-brain-injury-significantly-increased-survival-of-covid-19-patients-in-double-blind-fda-clinical-trial-301161910.html
19. Therapeutic Potential of Mesenchymal Stem Cells for Cancer Therapy - Frontiers, accessed September 8, 2025, https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2020.00043/full
20. An overview of mesenchymal stem cells and their potential therapeutic benefits in cancer therapy (Review) - Spandidos Publications, accessed September 8, 2025, https://www.spandidos-publications.com/10.3892/ol.2021.13046
21. Editorial: Mesenchymal Stromal Cell Therapy for Regenerative Medicine - Frontiers, accessed September 8, 2025, https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2022.932281/full
22. Mesenchymal Stromal Cell Therapies for Neurodegenerative Diseases - PMC - PubMed Central, accessed September 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6643282/
23. Mesenchymal stem cell therapy: A review of clinical trials for multiple sclerosis - PMC, accessed September 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9420954/
24. Traumatic Brain Injury and CTE - Stem Cell Therapy - Boulder, Colorado | Boulder Biologics | Jason Glowney, MD |Lauren Rudolph, MD | Stem Cells - Denver, Colorado | PRP | Regenerative Medicine | EPAT | Dr. Jason Glowney | Boulder Biologics, accessed September 8, 2025, https://www.boulderbiologics.com/stem-cell-therapy-3
25. MSC-Based Cell Therapy in Neurological Diseases: A Concise Review of the Literature in Pre-Clinical and Clinical Research - MDPI, accessed September 8, 2025, https://www.mdpi.com/2218-273X/14/5/538
26. A revealing review of mesenchymal stem cells therapy, clinical perspectives and Modification strategies, accessed September 8, 2025, https://sci.amegroups.org/article/view/29629/html
27. THERAPEUTIC SOLUTIONS INTL INC (TSOI) News Flow - Moomoo, accessed September 8, 2025, https://www.moomoo.com/stock/TSOI-US/news
28. Therapeutic Solutions International Identifies Novel Cellular Marker Associated with Therapeutic Response to JadiCell Stem Cell Treatment - FirstWord Pharma, accessed September 8, 2025, https://firstwordpharma.com/story/5694763
29. Therapeutic Solutions International Utilizes Mesenchymal Stem Cell Exosomes to Effectively Suppress Neutrophil Extracellular Trap Production - FirstWord Pharma, accessed September 8, 2025, https://firstwordpharma.com/story/5412365
30. therapeutic solutions international News and Press Releases | PR ..., accessed September 8, 2025, https://www.prnewswire.com/news/therapeutic-solutions-international/
31. Cell therapy weekly: Orphan Drug Designation filed for Frontotemporal Dementia stem cell treatment - RegMedNet, accessed September 8, 2025, https://www.regmednet.com/cell-therapy-weekly-orphan-drug-designation-filed-for-frontotemporal-dementia-stem-cell-treatment/
32. Acute Respiratory Distress Syndrome: Diagnosis and Management - AAFP, accessed September 8, 2025, https://www.aafp.org/pubs/afp/issues/2012/0215/p352.html
33. Acute Respiratory Distress Syndrome: Diagnosis and Management - AAFP, accessed September 8, 2025, https://www.aafp.org/pubs/afp/issues/2020/0615/p730.html
34. What Is Chronic Obstructive Pulmonary Disease (COPD)? - Cleveland Clinic, accessed September 8, 2025, https://my.clevelandclinic.org/health/diseases/8709-chronic-obstructive-pulmonary-disease-copd
35. Pipeline - Stem Cell Platform - Citius Pharmaceuticals, Inc., accessed September 8, 2025, https://citiuspharma.com/pipeline/stem-cell-platform/default.aspx
36. ARDS - Diagnosis and treatment - Mayo Clinic, accessed September 8, 2025, https://www.mayoclinic.org/diseases-conditions/ards/diagnosis-treatment/drc-20355581
37. Guidelines on the management of acute respiratory distress syndrome, accessed September 8, 2025, https://bmjopenrespres.bmj.com/content/6/1/e000420
38. Umbilical cord mesenchymal stem cells for COVID‐19 acute respiratory distress syndrome: A double‐blind, phase 1/2a, randomized controlled trial, accessed September 8, 2025, https://telomerixstemcells.com/umbilical-cord-mesenchymal-stem-cells-for-covid%E2%80%9019-acute-respiratory-distress-syndrome-a-double%E2%80%90blind-phase-1-2a-randomized-controlled-trial/
39. Therapeutic Solutions International Announces Launching of Phase III Clinical Trial for Treating COVID-19 Lung Damage Using its JadiCell™ Universal Donor Stem Cell Drug - BioSpace, accessed September 8, 2025, https://www.biospace.com/therapeutic-solutions-international-announces-launching-of-phase-iii-clinical-trial-for-treating-covid-19-lung-damage-using-its-jadicell-universal-donor-stem-cell-drug
40. Therapeutic Solutions International Completes Purchase of FDA Phase III JadiCell Stem Cell Investigational New Drug Application from University of Miami - TrialStat, accessed September 8, 2025, https://trialstat.com/2022/04/therapeutic-solutions-international-completes-purchase-of-fda-phase-iii-jadicell-stem-cell-investigational-new-drug-application-from-university-of-miami/
41. TSOI News for Therapeutic Solutions International - Barchart.com, accessed September 8, 2025, https://www.barchart.com/stocks/quotes/TSOI/news
42. Therapeutic Solutions International Files with FDA to Expand ongoing Phase III Clinical Trial to Include All Causes of Acute Respiratory Distress Syndrome - FirstWord Pharma, accessed September 8, 2025, https://firstwordpharma.com/story/5644665
43. Mesenchymal stem/stromal cell therapy for COVID-19 pneumonia: potential mechanisms, current clinical evidence, and future perspectives - PMC, accessed September 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8942612/
44. Therapeutic Solutions International Granted Emergency IND by FDA for Expanded Patient Access to JadiCell™ Universal Donor Stem Cell for COVID-19 ARDS Outside of Ongoing Phase III Clinical Trial - Business Wire, accessed September 8, 2025, https://www.businesswire.com/news/home/20220718005434/en/Therapeutic-Solutions-International-Granted-Emergency-IND-by-FDA-for-Expanded-Patient-Access-to-JadiCell-Universal-Donor-Stem-Cell-for-COVID-19-ARDS-Outside-of-Ongoing-Phase-III-Clinical-Trial
45. Therapeutic Solutions International Successfully Treats “No Option, accessed September 8, 2025, https://www.biospace.com/therapeutic-solutions-international-successfully-treats-no-option-patients-with-its-jadicell-stem-cell-therapy-while-advancing-preparations-for-phase-iii-covid-19-clinical-trial
46. Therapeutic Solutions International News - Markets Insider, accessed September 8, 2025, https://markets.businessinsider.com/news/tsoi-stock
47. TSOI Nets IND Number Ahead of Proposed JadiCell Clinical Trial - COPD News Today, accessed September 8, 2025, https://copdnewstoday.com/news/study-evaluate-jadicells-copd-given-go-ahead-fda/
48. Chronic Traumatic Encephalopathy (CTE): What It Is - Cleveland Clinic, accessed September 8, 2025, https://my.clevelandclinic.org/health/diseases/17686-chronic-traumatic-encephalopathy-cte
49. A Healthcare Provider's Guide To Chronic Traumatic Encephalopathy (CTE): - UCSF Memory and Aging Center, accessed September 8, 2025, https://memory.ucsf.edu/sites/memory.ucsf.edu/files/wysiwyg/UCSF_CTE_Providers_7-13-17.pdf
50. Chronic traumatic encephalopathy - Diagnosis and treatment - Mayo Clinic, accessed September 8, 2025, https://www.mayoclinic.org/diseases-conditions/chronic-traumatic-encephalopathy/diagnosis-treatment/drc-20370925
51. Chronic Traumatic Encephalopathy - StatPearls - NCBI Bookshelf, accessed September 8, 2025, https://www.ncbi.nlm.nih.gov/books/NBK541013/
52. Suspected CTE Treatments | Concussion Legacy Foundation, accessed September 8, 2025, https://concussionfoundation.org/cte-resources/treatments/
53. Therapeutic Solutions International Comes to Agreement with FDA on Clinical Trial Design for First Stem Cell Clinical Trial in Chronic Traumatic Encephalopathy (CTE) Patients - BioSpace, accessed September 8, 2025, https://www.biospace.com/therapeutic-solutions-international-comes-to-agreement-with-fda-on-clinical-trial-design-for-first-stem-cell-clinical-trial-in-chronic-traumatic-encephalopathy-cte-patients
54. Therapeutic Solutions International Launches Subsidiary Company to Commercialize Clinical Data and IND for Treatment of Chronic Traumatic Encephalopathy (CTE) with JadiCell Universal Adult Stem Cells - Stock Titan, accessed September 8, 2025, https://www.stocktitan.net/news/TSOI/therapeutic-solutions-international-launches-subsidiary-company-to-kkra42nozmeg.html
55. Therapeutic Solutions International Completes FDA Requested Studies to Initiate JadiCell™ Chronic Traumatic Encephalopathy (CTE) Clinical Trial - PR Newswire, accessed September 8, 2025, https://www.prnewswire.com/news-releases/therapeutic-solutions-international-completes-fda-requested-studies-to-initiate-jadicell-chronic-traumatic-encephalopathy-cte-clinical-trial-301350965.html
56. Stem Cell Therapy May Have Effect in Patients With ALS, Schizophrenia, and Autism, accessed September 8, 2025, https://www.cgtlive.com/view/stem-cell-therapy-may-have-effect-patients-als-schizophrenia-autism
57. Therapeutic Solutions International Launches Veltmeyer Institute for Advanced Biologics, accessed September 8, 2025, https://www.businesswire.com/news/home/20230221005540/en/Therapeutic-Solutions-International-Launches-Veltmeyer-Institute-for-Advanced-Biologics
58. Investigational New Drug (IND) Application - FDA, accessed September 8, 2025, https://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-application
59. Orphan Drug Designation: Benefits & Eligibility Guide - Allucent, accessed September 8, 2025, https://www.allucent.com/resources/blog/fda-orphan-drug-designation-rare-diseases
60. Therapeutic Solutions International Files for Orphan Drug Designation Using JadiCell Adult Universal Donor Stem Cells for Treatment of Acute Respiratory Distress Syndrome - Business Wire, accessed September 8, 2025, https://www.businesswire.com/news/home/20230626834673/en/Therapeutic-Solutions-International-Files-for-Orphan-Drug-Designation-Using-JadiCell-Adult-Universal-Donor-Stem-Cells-for-Treatment-of-Acute-Respiratory-Distress-Syndrome
61. Therapeutic Solutions International Files for Orphan Drug Designation Using JadiCell Adult Universal Donor Stem Cells for Treatment of Acute Respiratory Distress Syndrome - FirstWord Pharma, accessed September 8, 2025, https://firstwordpharma.com/story/5755058
62. Therapeutic Solutions International Files for Orphan Drug Designation Use of JadiCell Adult Stem Cells for Treatment of Frontotemporal Dementia - Business Wire, accessed September 8, 2025, https://www.businesswire.com/news/home/20230712101628/en/Therapeutic-Solutions-International-Files-for-Orphan-Drug-Designation-Use-of-JadiCell-Adult-Stem-Cells-for-Treatment-of-Frontotemporal-Dementia
63. Designating an Orphan Product: Drugs and Biological Products | FDA, accessed September 8, 2025, https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/designating-orphan-product-drugs-and-biological-products
64. Search Orphan Drug Designations and Approvals - accessdata.fda.gov, accessed September 8, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/
65. Stem cell therapy's avant-garde: Eight companies leading the way - Labiotech.eu, accessed September 8, 2025, https://www.labiotech.eu/best-biotech/stem-cell-therapy-company/
66. Clinical Trials - Mesoblast Ltd, accessed September 8, 2025, https://www.mesoblast.com/product-candidates/clinical-trials
67. ninety day survival outcomes in covid-19 ards trial of remestemcel-l - Mesoblast, accessed September 8, 2025, https://investorsmedia.mesoblast.com/static-files/876a2e51-6238-4172-9504-fa246f303c1c
68. MESOBLAST UPDATE ON COVID-19 ARDS TRIAL, accessed September 8, 2025, http://investorsmedia.mesoblast.com/static-files/bc0ce366-1c50-46ce-a9d4-d06b7ce403e5
69. A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19 - PubMed, accessed September 8, 2025, https://pubmed.ncbi.nlm.nih.gov/36099435/
70. Novartis secures exclusive rights for potential acute respiratory distress syndrome cell therapy, accessed September 8, 2025, https://www.novartis.com/news/media-releases/novartis-secures-exclusive-rights-potential-acute-respiratory-distress-syndrome-cell-therapy
71. Citius Pharmaceuticals Signs an Exclusive Worldwide Licensing Agreement with Novellus Therapeutics for Unique iMSC-Therapy for Acute Inflammatory Respiratory Conditions including COVID-19 Related Acute Respiratory Distress Syndrome (ARDS) - PR Newswire, accessed September 8, 2025, https://www.prnewswire.com/news-releases/citius-pharmaceuticals-signs-an-exclusive-worldwide-licensing-agreement-with-novellus-therapeutics-for-unique-imsc-therapy-for-acute-inflammatory-respiratory-conditions-including-covid-19-related-acute-respiratory-distress-syndrom-301147409.html
72. NoveCite to develop stem cell therapies for COVID-19 related respiratory distress, accessed September 8, 2025, https://www.europeanpharmaceuticalreview.com/news/129919/novecite-to-develop-stem-cell-therapies-for-covid-19-related-respiratory-distress/
73. Citius to Pursue IND for Use of iMSCs in COVID-19 Induced ARDS - BioInformant, accessed September 8, 2025, https://bioinformant.com/citius-imsc-covid19-ards/
74. Therapeutic Solutions International Inc (TSOI) Press Releases - Nasdaq, accessed September 8, 2025, https://www.nasdaq.com/market-activity/stocks/tsoi/press-releases
75. Therapeutic Solutions International Inc (CE) Stock Price - TSOI | ADVFN, accessed September 8, 2025, https://www.advfn.com/stock-market/USOTC/TSOI/stock-price