Invented by Darwin J. Prockop, Joo Youn Oh, Barry Berkowitz, Gavin W. Roddy, Robert Rosa, Temple Therapeutics Inc, Texas A&M University System, Scott and White Healthcare

The market for adult stem cells/progenitor cells and stem cell proteins for the treatment of eye injuries and diseases is rapidly growing. Stem cell therapy has emerged as a promising solution for various ocular conditions, offering hope for patients suffering from vision loss and eye-related injuries. The eye is a complex organ, consisting of numerous specialized cells and tissues. When these cells are damaged or degenerate due to injury or disease, vision impairment or even blindness can occur. Traditional treatments for eye injuries and diseases often focus on managing symptoms rather than addressing the underlying cause. However, stem cell therapy has the potential to revolutionize the field of ophthalmology by promoting tissue regeneration and restoring visual function. Adult stem cells and progenitor cells are found in various tissues throughout the body, including the eye. These cells have the ability to differentiate into specialized cell types, making them ideal candidates for regenerative medicine. Stem cell therapy for eye injuries and diseases involves the transplantation of these cells into the affected area, where they can replace damaged or lost cells and promote tissue repair. One of the most promising applications of stem cell therapy in ophthalmology is the treatment of age-related macular degeneration (AMD). AMD is a leading cause of vision loss in older adults, affecting the macula, the central part of the retina responsible for sharp, central vision. Stem cell therapy aims to replace the damaged retinal pigment epithelium (RPE) cells in the macula, which are crucial for maintaining the health of the photoreceptor cells responsible for vision. Another area where stem cell therapy shows great potential is in the treatment of corneal injuries and diseases. The cornea is the transparent outer layer of the eye that plays a vital role in focusing light onto the retina. Damage to the cornea can lead to vision impairment and even blindness. Stem cell therapy offers a promising solution by utilizing corneal stem cells to regenerate and repair damaged corneal tissue. In addition to stem cells, stem cell proteins also play a crucial role in the treatment of eye injuries and diseases. These proteins, known as growth factors, cytokines, and chemokines, are secreted by stem cells and have the ability to regulate cell behavior and promote tissue regeneration. By harnessing the therapeutic potential of these proteins, researchers are developing innovative approaches to enhance the effectiveness of stem cell therapy in ophthalmology. The market for adult stem cells/progenitor cells and stem cell proteins in the field of ophthalmology is witnessing significant growth. The increasing prevalence of eye injuries and diseases, coupled with the growing demand for effective treatments, is driving the market’s expansion. Moreover, advancements in stem cell research, including the development of novel techniques for isolating and culturing stem cells, are fueling the market’s progress. However, challenges remain in the widespread adoption of stem cell therapy for eye injuries and diseases. Regulatory hurdles, ethical concerns, and the high cost associated with stem cell-based treatments are some of the barriers that need to be overcome. Additionally, long-term safety and efficacy studies are essential to establish the credibility and reliability of these therapies. In conclusion, the market for adult stem cells/progenitor cells and stem cell proteins for the treatment of eye injuries and diseases is a rapidly evolving field with immense potential. Stem cell therapy offers hope for patients suffering from vision loss and eye-related injuries by promoting tissue regeneration and restoring visual function. Continued research, technological advancements, and regulatory support are crucial to unlocking the full potential of stem cell therapy in ophthalmology and improving the lives of millions affected by eye diseases.

The Temple Therapeutics Inc, Texas A&M University System, Scott and White Healthcare invention works as follows

The present invention comprises methods and compositions to treat an ocular disorder, disease or condition. The invention comprises a population mesenchymal cells with anti-inflammatory properties, anti-apoptotic properties, immune modulatory properties, and anti-tumorigenic characteristics. The invention involves administration of TSG-6 or STC-1 to the ocular in order to treat an ocular disorder, disease or condition.

Background for Adult Stem Cells/Progenitor Cells and Stem Cell Proteins for Treatment of Eye Injuries and Diseases

Stem cell therapy has a significant therapeutic potential.” The present invention has a non-limiting aspect that is directed at using mesenchymal cells to treat eye diseases and injuries. Other non-limiting aspects of the present invention are directed at the therapeutic use mesenchymal cells to treat diseases such as those of the heart and lung. “Another non-limiting aspect is the use of antiapoptotic, anti-inflammatory, and STC-1, TSG-6 proteins expressed by mesenchymal cells to treat the diseases and disorders mentioned above.

The cornea is not only an essential component of the retinal refractive system, but also serves as a biological and physical barrier, protecting the inner structures of the eyes from external insults. The integrity and function of the epithelium, which is the outermost layer of the cornea, are essential to its transparency and visual acuity. The majority of corneal epithelium diseases (i.e. corneal surface disease) are associated with sterile inflammation or defects in wound healing. The treatments for these diseases are still problematic.

The most severe corneal surface disease is limbal stem cell deficiency. Primary corneal surface diseases can result from inherited eye conditions, but are more often acquired due to conditions like Stevens-Johnson Syndrome, thermal or chemical burns, systemic autoimmunity, contact lens keratopathy or recurrent ocular surgery. Chemical burns account for 7-18% of the 2,5 million cases of ocular injury seen each year at emergency departments in the U.S. The incidence of severe LSCD caused by SJS is 2.6 to 7.1 per million people, or approximately 200,000 in the U.S. (Foster et. al. 2008). LSCD is not only a psychological burden on the patient, but also a financial one in the form of lost productivity and prohibitive costs of health care over their lifetime.

The current treatment of LSCD includes anti-inflammatory drug therapy, e.g. In the early stage, steroids are used. Later on, limbal epithelial cells (LESCs), which have been transplanted (Limb & Daniels 2008), can be transplanted. The anti-inflammatory drugs that are currently available do not work and cannot prevent the loss of LESCS. Current strategies to correct LSCI, such as transplanting LESCs of a healthy eye from a patient (limbal autograft), a relative living or cadaveric donor (limbal alograft), have several drawbacks. 2002; Solomon et al, 2002; Cauchi et al. 2008). The limbal autograft carries a risk of causing LSCD to the donor eye. It cannot be used for patients with bilateral LSCD. Due to the presence of HLA DR antigens in the graft and Langerhans cell, limbal allografts need long-term immunosuppression. Immunological rejection can occur even with immunosuppression in 42.9% to a 64.0% of patients following limbal allografts. (Rao and al. 1999; Tseng and al. 1998; Shi et. al. 2008; Reinhard, et. al. 2004; Tsubota, et. al. 1999). In some centers, LESCs are currently being grown ex vivo and then transplanted for LSCD (summarized by Shortt et. al., 2007). The putative stem cell observed in the limbus has not been isolated or fully characterised. The availability of autologous tissue is also the major clinical barrier to using LESCs in culture for therapeutic purposes. Allogeneic cultured cells can be used with systemic immune suppression, but donor allogeneic LESCs will not survive past 9 months (Daya, Sharpe, et. al., 2006). Success depends on the ability to suppress inflammation at the ocular surface. The therapies that are the focus of this application could be a significant advance in current treatment.

In addition, vision-threatening LSCD is not the only ocular surface disease that can cause damage to your eyesight. There are also a number ocular surface disorders accompanied by corneal irritation and wound healing defects, such as keratoconjunctivitis, recurrent keratitis, or post-refractive surgical keratitis. Dry eye syndrome is the most common and affects almost 10% of Americans (Moss, Sehaumberg, 2003, Moss, et. al. 2008). In the United States, 20-30 million people have shown early signs and symptoms of dry eyes. An estimated 6 to 3 million women and 30 million men are affected by the advanced effects of the condition that affect their quality of life. 2005; Miljanovic et al., 2007). Sadly, the majority of currently available therapeutic agents only provide palliative relief and none eliminates all signs and symptoms associated with dry eye (Pflugfelder 2007). In several studies (Clegg and colleagues, 2006, Reddy and associates, 2004, Callaghan and colleagues, 2007), it was found that dry eye syndrome has a significant economic impact, both in terms of direct medical costs. Medications and doctor visits are direct costs. Indirect costs include lost work time and impaired productivity. Lost work time and reduced productivity). There are no effective and safe treatment strategies for corneal diseases.

The United States’ leading cause of legal blindness is age-related macular (AMD), followed by retinitis Pigmentosa (RP). AMD and RP have similar clinical and pathologic characteristics, including blindness at the end of the disease due to cell death in photoreceptors and/or retinal epithelium cells (RPE). Apoptosis in photoreceptors is a feature of human AMD that has been demonstrated (Dunaief et.al., Arch. Ophthalmol., Vol. 120, No. 11, pgs. 1435-1442 (2002); Xu, et al., Trans. Am. Ophthalmol. Soc., Vol. 94, pgs. 411-430 (1996)). and RP (Cottet, et al., Curr. Mol. Med., Vol. 9, No. 3, pgs. 375-383 (2009); Doonan, et al., Curr. Neurosci. Res., Vol 1, No. 1, pgs. 47-53 (2004)), and it is a feature of many animal models of degeneration of the retina (Doonan 2004; Yu, Invest. Ophthalmol. Vis. Sci., Vol. 45, No. 6, pgs. 2013-2019 (2004); Katai, et al., Invest. Ophthalmol. Vis. Sci., Vol. 40, No. 8, pgs. 1802-1807 (1999); Katai, et al., Jpn. J. Ophthalmol. Vol. 50, No. 2, pgs. 121-127 (2006)). The ROS have been implicated as a cause or exacerbation in AMD (Fletcher et. al., Ophthalmic Res. Vol. 44, No. 3, pgs. 191-198 (2010); Beatty, et al., Surv. Ophthalmol., Vol. 45, No. 2, pgs. 115-134 (2000); Winkler, Mol. Vis., Vol. 5, pg. 32 (1999); Johnson, Curr. Opin. Cln. Nutr. Metab. Care, Vol. 13, pgs. 28-33 (2010); Totan, et al., Curr. Eye Res. 34, No. 12, pgs. 1089-1093 (2009)), and antioxidant vitamin therapy has become a mainstay of treatment for non-exudative AMD (Johnson 2010; Hartong et. al., Lancet Vol. 368, pgs. 1795-1809 (2006)). However, although not curative in nature, antioxidant vitamin therapy has been shown to reduce the risk of disease as well as stabilize vision (Flectcher 2010; Beatty 2000; Johnson 2010; Hartong 2006). Smoking and light exposure, which are two of the most modifiable AMD risk factors, may also damage photoreceptors through ROS (Flectcher 2010; Johnson 2010). In addition, oxidative injury studies in animal models for RP implicated ROS to be partially responsible for apoptotic photoreceptor loss (Komeima et.al., Proc. Nat. Acad. Sci., Vol. 103, No. 30, pgs. 11300-11305 (2006); Shen, et al., J. Cell. Physiol., Vol. 203, No. 3, pgs. 457-464 (2005)). Other studies have shown that antioxidant-based therapies can slow the death of photoreceptors in animal models with RP. (Komeima et al., J. Cell. Physiol., Vol. 213, No. 3, pgs. 809-815 (2007); Galbinar, et al., J. Ocul. Pharmacol. Ther. Vol. 25, No. 6, pgs. 475-482 (2009); Chen, et al., Nat. Nanotechnol., Vol. 1, No. 2, pgs. 142-150 (2005)) and decrease the primary retinal cells (Chen 2006; Chucair et. al., Invest. Ophthalmol. Vis. Sci., Vol. 48, No. 11, pgs. 5168-5177 (2007; Cao et.al., Experimental Eye Research, Vol. Eye Res. 91, No. 1, pgs. 15-25 (2010); Kim, et al., Invest. Ophthalmol. Vis. Sci., Vol. 51, No. 1, pgs. 561-566 (2010)). Photoreceptors can be particularly sensitive to oxidative stresses for several reasons. (a) Oxygen consumption by the retina (Beatty 2000) is higher than that of any other tissue. (b) The outer segments of the photoreceptors have a high concentration of polyunsaturated fats (PUFAs), which are oxidized when oxygen is present. (Winkler 1999). (c) Lipofuscin is accumulated in the RPE with age and is believed to be a This finding, along with our preliminary results, provides a strong reason to test new stem-cell based therapies that reduce ROS mediated apoptosis.

Inflammation plays a growing role in many diseases such as myocardial ischemia, stroke, Alzheimer?s disease, and atherosclerosis. The present invention is, therefore, directed in a nonlimiting aspect to the use mesenchymal cells and certain proteins such as TSG-6 in treating myocardial ischemia and lung diseases.

In conclusion, there are currently no drugs that can effectively treat corneal ulceration and inflammation caused by chemical injury. There is also a need for new therapies to treat macular degeneration. Also, there is a need for additional therapies to treat diseases of the heart and lungs. The present invention is aimed at the use of stem cells and mesenchymal cell proteins as therapeutic agents.

The present invention is based on the discovery that adult stem/progenitor cell types such as mesenchymal-stromal cells (MSCs), possess novel therapeutic properties and can therefore be used in the treatment of a desired condition such as an eye disease. MSCs, for example, can be used in the treatment of diseases such as noninfectious inflammatory corneal diseases. The MSCs can be modified to have therapeutic properties, including, but not limited, to the expression of anti-inflammatory proteins, anti-apoptotic proteins, a hematopoietic protein, one that controls immune response, one that regulates the homing cells, or a regulating protein of immune response.

The present invention is based upon the discovery that MSCs are capable of treating inflammatory diseases and disorders of the cornea by intraocular injections of recombinant therapeutic protein MSCs, which are produced in response signals from injured tissue. This therapy is based upon the discovery that MSCs, or conditioned media from MSCs, reduced inflammation and revascularization after a chemical injury to the cornea in a rat. “In another non-limiting embodiment of this invention, inflammation and revascularization can be reduced and other eye diseases and disorders may be treated with one or more therapeutic protein produced by activated MSCs. These include the anti-inflammatory and anti-apoptotic proteins TSG-6 and biologically-active fragments or analogues thereof, as well as the antiapoptotic and anti-inflammatory protein STC-1.

According to an aspect of this invention, a method is provided for treating or preventing eye disease in a patient. The method involves administering mesenchymal cells to a patient that have been cultured to express a greater amount of one of the anti-apoptotic and/or the anti-inflammatory proteins. The mesenchymal cells are administered at a dose that is effective in treating or preventing the disease or disorder in the eye of the patient.

In a non-limiting example, at least one of the proteins is an antiapoptotic. In another non-limiting example, the anti-apoptotic proteins are selected from the group of stanniocalcin-1(STC-1), stanniocalcin-2(STC-2), and biologically active analogs or fragments thereof. In a third non-limiting example, the anti-apoptotic proteins are STC-1 and biologically active fragments or analogs thereof.

In another non-limiting embodiment the at least one of the proteins is an anti-inflammatory. In yet another nonlimiting embodiment, TSG-6 is the anti-inflammatory proteins or biologically active fragments or analogs thereof.

In another non-limiting embodiment the anti-inflammatory proteins may include, but are not limited to STC-1, or biologically active fragments or analogs thereof. The scope of this embodiment does not limit itself to any particular theoretical reasoning. However, an increase in ROS may contribute to unresolved inflammatory conditions. Recent studies have shown that STC-1 reduces reactive oxygen species through increased expression of uncoupling proteins-2. This makes mitochondria more efficient at reducing ROS. Anti-apoptotic molecules, such as STC-1 and cells that express at least one of these proteins, including MSCs, could be helpful in reducing ROS in diseases and disorders of eye. These anti-apoptotic molecules and cells may also be anti-inflammatory in addition to anti-apoptotic.

In another aspect of this invention, a method is provided for treating or preventing an eye disease or disorder in a patient. This involves administering to that patient at least one of the anti-apoptotic and anti-inflammatory protein in an effective amount to treat or prevent eye disease or disorders in the patient.

In a non-limiting example, at least one of the proteins is an antiapoptotic. In a further non-limiting embodiment the anti-apoptotic proteins are STC-1, STC-2, or biologically active analogs or fragments thereof. In a third non-limiting example, the antiapoptotic proteins is STC-1.

In another non-limiting embodiment the at least one of the proteins is an anti-inflammatory. In a further non-limiting embodiment the anti-inflammatory is TSG-6, or a biologically-active fragment or analog thereof.

The present invention is not limited to the treatment of diseases of the cornea but can be used to treat any eye disease, such as macular degeneration, retinal disease, or macula disease. The invention can be used to treat eye diseases, disorders or conditions associated with inflammation or degradation of eye tissue.

Definitions

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The articles?a? and?an? The articles?a? Here,?an? and?an? At least one) of a grammatical article’s object. As an example, “an element” means one or more elements. “An element” means one or more elements.

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