…of autoimmune diseases, other therapeutic targets, and associated market opportunities. The therapeutic target classes are autoimmune diseases, like psoriasis, Type 1 diabetes, Lupus, rheumatoid arthritis, and multiple sclerosis, as well as, other inflammatory conditions like GVHD, transplant rejection, stroke, and inflammatory neurodegenerative disorders. The seemingly ubiquitous role of chronic inflammation as an exacerbating element in many illnesses is perfectly demonstrated by the range of application for our technology. The fact that a singular approach, represented by our tolerogenic induction platform, can impact such a broad array of disease centers on the pivotal role of immuno-inflammatory pathology.
AUTOIMMUNE DISEASE
The immune system forms a dynamic shield to protect us, but under certain conditions it can attack the very cells it is meant to protect. This can lead to a variety of autoimmune diseases, of which there are over 100 permutations, affecting virtually every tissue and organ in the body.
The world is a harsh environment in which to live, and without the immune system we would not be able to survive. The immune system recognizes and discriminates between safe and pathogenic antigens in the body and mounts an appropriate response to those antigens it deems to be dangerous or foreign. The mechanisms involved are complex, interactive, redundant, and normally highly effective. Even so, there are issues. People do get sick from pathogens that slip by the intense surveillance or those that simply overwhelm the immune system altogether.
Conversely, the immune system can erroneously interpret a completely benign component of “self” as dangerous and then mount an inflammatory attack against it. When this occurs, the immune system attacks the source of that mistakenly-identified component, destroying the organ or tissue from which it originated, resulting in compromised functionality. This is autoimmune disease – literally an inflammatory immune response against self. Immune cells undergo an educational process during development to condition the cells for appropriate responses to stimuli, but in autoimmune disease this is compromised and the immune system turns on its own healthy tissues, destroying the fabric of its own existence. The results of this can be devastating. According to the American Autoimmune Related Diseases Association (AARDA) there are over 50 million Americans suffering with some kind of autoimmune disease. CLICK HERE (AARDA) for a comprehensive list of autoimmune diseases.
PLAQUE PSORIASIS
Plaque Psoriasis has been chosen by TregTherapeutics management as the first disease state in which to demonstrate human proof of concept. Rationale for this choice is based on the skin’s ease of access and treatment, as well as, the availability of definitive and well-recognized treatment assessment tools. Plaque Psoriasis is an immuno-inflammatory skin condition that is the most prevalent autoimmune disease in the United States, affecting approximately 7.5 million adults. It is a chronic, itchy and/or painful, disfiguring, and disabling disease. Psoriasis is associated with an increased risk of early mortality, and an increased prevalence of co-morbidity such as psoriatic arthritis, cardiovascular disease, and diabetes. The physical, psychologic, social, and economic impact of psoriasis, plus the associated stigma, result in cumulative impairment over a patient’s lifetime.
There is no cure for psoriasis and the approach to therapy is largely governed by the extent and severity of disease. Available treatments focus primarily on the use of anti-inflammatory or immunomodulatory agents to control the symptoms and prevent further relapses. The management of mild psoriasis usually consists of topical treatments (e.g., corticosteroids, calcipotriene, retinoids, salicylic acid, coal tar, dithranol, and emollients). Treatments for patients with moderate to severe psoriasis include phototherapy and systemic treatment with oral agents, such as methotrexate, cyclosporin, retinoids, fumaric acid esters, and more recently, injectable biotechnology-derived monoclonal antibody products, like Humera®, Cosentyx®, and Enbrel®.
TregTherapeutics intends to sponsor a phase 1/2a clinical study in patients with the disease is planned and a highly-respected center specializing in dermatology research has been designated to conduct the study.
MULTIPLE SCLEROSIS (MS)
Multiple sclerosis (MS) is a chronic inflammatory disease that results in autoimmune demyelination of neurons in the human central nervous system (CNS). This produces a devastating impact for those afflicted with no curative treatment. In total, MS affects over 2.5 million people worldwide, including up to 1,000,000 cases in the US. The types of MS are categorized according to different flare-up patterns (exacerbations); these patterns are described as either remitting/recurring, progressive, or a combination of patterns called secondary progressive, where remissions grow fewer and fewer until the disease in consistently progressive. Regardless of the type, it is an expensive disease to treat. Direct and indirect health care costs range from $8,500 to $54,000 per patient/year in the United States.
The traditional treatment for MS is to employ intravenous steroids during acute attacks. Steroids have not been shown to decrease the risk of future attacks or change the natural progression of the disease; however, they have been useful to hasten recovery from acute attacks. IFN-β, an anti-inflammatory cytokine, is another well-recognized treatment that has provided relief and reduction of symptoms. Today, there are many immunomodulation agents on the market that are used on an on-going basis to modify the course of the disease. These drugs can slow progression of the disease and relieve chronic and acute symptoms, although use of these agents can result in enhanced risk of infection and other adverse effects due to broad immunological compromise. It is important to note that current therapies do not cure the disease, they provide only palliative attempts to alleviate symptoms and/or slow down progression.
From a developmental and regulatory standpoint MS is a challenging disease to address, primarily because of the mercurial nature of the disease. The most prevalent type of MS is remitting-relapsing, characterized by indeterminant periods where the patient seems to be in remission with symptoms improving, followed by periods of relapse with the reappearance of symptoms. The inconsistencies in disease manifestation and progression present considerable impediments for evaluating a new therapeutic approach. Typically, large patient populations and extended study durations characterize regulatory requirements. Despite these issues MS remains high our priority list, as our technical assessment team believes that success with the TILAC platform is highly probable, we are in search of a pathway to move forward.
RHEUMATOID ARTHRITIS
As indicated in other applications of the TILAC platform, regulatory T cell (Treg) therapy can play a crucial role in regulating the immune system and preventing excessive inflammatory immune responses. In the context of rheumatoid arthritis (RA), Tregs have gained significant interest as a potential therapeutic approach and the TILAC™ platform is designed to accomplish that safely and efficiently.
In rheumatoid arthritis (RA), the immune system mistakenly attacks the synovium, the lining of the membranes that surround the joints. This autoimmune response leads to chronic inflammation, pain, and joint damage. Tregs can play a critical role in ameliorating this inflammation and regulating the immune response and ultimately creating immune tolerance. Here’s a likely mechanism of action for how Tregs interact with rheumatoid arthritis:
In the context of RA, Tregs can suppress the activity of effector T cells and B cells, which are responsible for the inflammation and joint damage seen in RA. Tregs achieve this suppression through cell-to-cell contact and the release of immunosuppressive molecules, such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β).
The impact is:
- Dampen inflammation: Tregs can directly inhibit the production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17), which are elevated in RA patients. By reducing the levels of these inflammatory molecules, Tregs help decrease the overall inflammatory response in the joints.
- Autoantibody suppression: In RA, the immune system produces autoantibodies, such as rheumatoid factor and anti-citrullinated protein antibodies (ACPAs), which contribute to joint damage. Tregs can suppress the production of these autoantibodies, thereby reducing the autoimmune attack on the synovium.
- Modulate APC behavior: Tregs interact with antigen-presenting cells (APCs), such as dendritic cells, in a reciprocal fashion to modulate their function and thus, prevent activation of effector t cells specific to self-antigen. This is one way that the TILAC™ approach creates and maintains immune tolerance.
- Tissue Repair: Tregs are involved in tissue repair processes and promote tissue healing in the affected joints. Tregs support the healing process which helps mitigate the long-term damage caused by RA.
- Create Homeostasis: Tregs play a crucial role in maintaining immune homeostasis, ensuring that the immune system responds appropriately to threats while avoiding excessive responses against self-tissues.
In summary, Tregs exert their beneficial effects in rheumatoid arthritis by suppressing autoimmune responses, dampening inflammation, regulating autoantibodies, modulating antigen-presenting cells, promoting tissue repair, and maintaining immune homeostasis. Enhancing Treg function or utilizing Treg-based therapies could potentially help control the autoimmune response and mitigate the symptoms and progression of RA . The TILAC™ approach is designed to achieve that outcome.
INFLAMMATORY BOWEL DISEASE
Inflammatory Bowel Disease (IBD) is a group of chronic inflammatory disorders of the gastrointestinal tract, primarily encompassing Crohn’s disease and ulcerative colitis. These conditions are characterized by inflammation of the digestive system, leading to symptoms such as abdominal pain, diarrhea, weight loss, and fatigue. Extensive research suggests that autoimmune mechanisms play a significant role in the development and progression of these disorders.
In individuals with IBD, the immune system is dysregulated, meaning that it fails to distinguish between harmful bacteria and the body’s own cells. This confusion results in the immune system attacking the intestinal lining, causing inflammation and ulceration.
The imbalance between pro-inflammatory and anti-inflammatory mechanisms, plays a crucial role in the pathogenesis of IBD., and as in other autoimmune diseases, conventional treatments often target global immune suppression, which can lead to increased susceptibility to infections and other adverse effects.
The TILAC™ platform is designed to propagate a repertoire of Tregs in response to the dysregulated predominance of Th17 and other pro-inflammatory immune cells. Th17 cells release inflammatory molecules that contribute to the destruction of the intestinal lining, further fueling the autoimmune response. Tregs can promote immune tolerance in IBD through several mechanisms:
- Suppress Effector T Cells: Tregs inhibit the activation and proliferation of effector T cells, including Th1 and Th17 cells, which are implicated in the pathogenesis of IBD.
- Modulate APC activity: Tregs can affect dendritic cell maturation and function, leading to reduced antigen presentation and dampening of immune responses.
- Produce anti-inflammatory cytokines: Tregs secrete anti-inflammatory cytokines such as IL-10 and TGF-β, which suppress pro-inflammatory responses and promote tissue repair.
- Cause effector T cell apoptosis: Tregs induce apoptosis in effector T cells, limiting their survival and preventing sustained inflammation.
Continued research into the complex interplay between genetics, immunity, and gut microbiota will provide valuable insights into optimal TILAC™ delivery modalities and administration protocols for optimal Treg efficacy for patients suffering from IBD.
TYPE I DIABETES
Type 1 diabetes (T1D) is an autoimmune disease that specifically affects the insulin-producing beta cells in the pancreas. Insulin is a hormone that helps regulate blood sugar (glucose) levels, and when the beta cells are destroyed, the body cannot produce enough insulin, leading to high blood sugar levels, which can cause various complications.
Factors that contribute to the development of T1D include familial genetic predisposition and
environmental triggers like viral infections. Viruses using molecular mimicry as a disguise to thwart the body’s defenses, lead the immune system to mistakenly target healthy beta cells as foreign. An inflammatory attack is mounted against these cells, killing them, causing reduced production if insulin.
Understanding these connections between the immune system and the development of type 1 diabetes is essential for ongoing research and the development of potential treatments, including immunotherapies aimed at modulating the immune response to preserve or restore beta cell function.
The TILAC™ approach is designed to create a repertoire if regulatory T cells (Tregs). These cells play a crucial role in regulating the inflammatory immune response to endogenous antigens associated with pancreatic beta cells. In so doing beta cell function is preserved and glycemic control in T1D patients is achieved. Research is needed to determine optimal delivery and dosing protocols. In addition, combination therapy may be useful in treating intransigent cases.
SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that can affect various organs and tissues in the body.
The exact cause of SLE is not well understood, but it is believed to involve a combination of genetic, hormonal, and environmental factors. Certain genes may predispose individuals to develop SLE, and hormonal factors, such as estrogen, are thought to play a role; SLE is more prevalent in women than in men. As in other autoimmune diseases, inflammation is the primary immune response to auto-antigens, and tissue damage in SLE can affect a wide range of organs, including the skin, joints, kidneys, heart, lungs, brain, blood cells, and other tissues.
The symptoms of SLE can vary widely and may include joint pain and swelling, skin rashes (especially a characteristic butterfly-shaped rash on the face), fatigue, fever, chest pain, photosensitivity (sensitivity to sunlight), and mouth ulcers. SLE can also cause complications such as kidney damage, cardiovascular problems, and neurological disorders.
Current treatments for SLE are palliative, attempting to control symptoms, prevent flares, and minimize organ damage. The treatment regimen is similar to that of other chronic inflammatory conditions, often involving a combination of medications that includes NSAIDs, corticosteroids, immunosuppressants, and biologic therapies.
Tregs have the ability to suppress immune responses and prevent the immune system from attacking the body’s own tissues and the TILAC™ approach is perfectly designed to promote the expression of these cells that are specific for implicated self-antigens.
Clinical trials are need to evaluate the potential of the TILAC™ approach, and investigators are urged to contact us for further discussion.
STROKE
Neurons are the primary functional units of the brain and they rely on a constant supply of oxygen and nutrients carried by the blood to meet metabolic needs and function optimally. That blood flows through specialized vasculature that is structurally and functionally distinct from the rest of the cardiovascular system. The defining feature of this vasculature is the blood-brain barrier (BBB), which regulates interaction between the blood and the brain, controlling the entry and exit of components as they pass from the blood compartment into the microenvironment of the brain. This included ions, nutrients, macromolecules, energy metabolites and cells. There is constant communication taking place between cells of the vasculature and the neurons and glia that border the vasculature. These communicating components can be thought of as a “module” comprised of neurons, astrocytes, pericytes, microglia, as well as, the blood vessels themselves. This module concept is called the neurovascular unit (NVU) and its proper function enables tight regulation of what passes between the brain and the blood that flows outside of the brain.
Stroke is a serious medical condition that occurs when there is a sudden interruption in the blood supply to the brain. It can result from a blockage in the blood vessels supplying the brain (ischemic stroke) or from bleeding in the brain (hemorrhagic stroke), but in either case, this is a catastrophic event that leads to brain cell damage or death. Stroke is rarely survived without devastating effects that can include a wide range of symptoms such as paralysis, speech difficulties, and cognitive impairments.
During a stroke, the NVU is severely disrupted. The lack of blood flow deprives neurons of essential nutrients and oxygen, leading to their dysfunction and, ultimately, cell death. Additionally, the breakdown of the BBB further exacerbates the damage. As a result, the surrounding tissue becomes inflamed, and the brain’s overall function is compromised, as complex processes are set in motion to cope with the chaos imposed by this traumatic stress.
Tregs-based therapy potentially can provide diverse benefits to stroke survivors and could be possibly be efficacious in all phases of post-stroke recovery, from hyperacute through the chronic phase. Although clinical trials are needed to access the safety and efficacy of the TILAC™ platform as a Treg-based therapy in stroke victims, possible benefits from this approach are compelling. Outcomes that could be expected include:
- Reduced neuroinflammation Excessive inflammation, which is a significant contributor to brain damage after a stroke, could be dampened by enhanced Treg presence. By suppressing pro-inflammatory immune cells, Tregs may help reduce inflammation around the stroke area, limiting secondary damage to the brain tissue.
- Blood-brain barrier repair Tregs have been shown to support the integrity of the blood-brain barrier. Re-establishing proper BBB function is critical after a stroke to prevent further damage from infiltrating harmful substances.
- Regeneration Treg’s phenotypic fluidity in response to environmental conditions can influence the behavior of other immune cells, promoting a regenerative environment that supports tissue repair and the brain’s natural healing processes.
- Neuroprotection Tregs can secrete neuroprotective factors to support the survival of neurons and other brain cells. Enhanced neuroprotection could limit the extent of brain damage caused by the stroke.
- Cardiovascular risk reduction Stroke survivors have an increased risk of secondary strokes, but an enhanced repertoire of Tregs could modulate the immune system to reduce inflammation in the cardiovascular system thus reducing the risk of recurrent strokes by contributing to the maintenance of overall cardiovascular health.
- Combination enhancement Treg enhancement therapy could be combined with other stroke treatments, such as thrombolytic therapy or rehabilitation programs, to enhance their efficacy and provide a more comprehensive approach to stroke recovery.
