TB4-7^™ Peptide from AdiStem

TB4-7^™ Peptide applied topically or given systemically promotes angiogenesis and wound healing, cardioprotective and immuno-potentiating effects, hair growth and thickness, hair coloration change (from grey back to its original darker colour) and has very potent anti-aging, anti-wrinkle and anti-scarring properties. Trials amongst body builders have also shown increased muscle growth and strength together with improved energy levels and other benefits.

TB4-7 (patent pending) is a synthetic peptide analogue of the active region of Thymosin B4.

Thymosin β4, a ubiquitous 4.9-kDa polypeptide of 43 amino acids length originally isolated in 1981 from the thymus gland, is a potent mediator of cell migration and differentiation^1-6.

It is a member of a ubiquitous family of 16 related molecules with a high conservation of sequence and localization in most tissues and circulating cells¹³ and circulating levels in the serum reduce with age. TB4 binds to actin, blocks actin polymerization, and is the actin-sequestering molecule in eukaryotic cells^14-20).

It was identified as a gene that was up-regulated four- to six fold during early endothelial cell tube (blood vessel) formation and found to promote angiogenesis. It is present in wound fluid⁷, and when applied topically or given systemically, it promotes angiogenesis and wound healing³).

Thymus extracts (which contain small amounts of Thymosin beta 4), have been used successfully both orally and by injection in patients since the 1960's in Europe (see Biofactor). Derived from our autologous adipose-derived stem cell clinical trials and research, we have uncovered that one of the main factors that the stem cells secrete to induce repair and an anti-aging effect were various peptides belonging to the TB4 family. TB4-7 (patent pending) was the most potent fragment from this family of secreted peptides that we discovered.

Wound-Healing

TB4 elicits cell migration through a specific interaction with actin in the cell cytoskeleton^8,9. Recently, it was demonstrated that a central small amino acid long actin binding domain has both angiogenic and wound healing activity while other domains of the protein are inactive¹⁰.

In angiogenesis and in wound healing, TB4 acts by accelerating the migration of endothelial cells and keratinocytes and increasing the production of extracellular matrix-degrading enzymes^4,9. TB4 has also shown to increase corneal epithelial cell migration in vitro and in vivo, with activity in the nanogram range¹. Thymosin beta 4 is found in high concentrations in platelets²². TB4 also has anti-inflammatory activity^1,11 and more recently has also been shown to stimulate epidermal stem cell differentiation¹².

Together, these data show that TB4 is a potent, naturally occurring wound repair factor. It is different from other repair factors, such as growth factors, in that it promotes endothelial and keratinocyte migration, does not bind to the extracellular matrix, and has a very low molecular weight, and thus can diffuse relatively long distances through tissues^4,21.

It has also been demonstrated that TB4 promotes hair growth in various rat and mice models including a transgenic TB4 overexpressing mouse²⁴. The mechanism by which TB4 acts to promote hair growth is by its stimulatory effects on follicle stem cell growth, migration, differentiation, and protease production.

Anti-Aging Properties

Applied topically on the skin (as a spray or cream), TB4-7b has very potent anti-aging, anti-wrinkle, anti-scarring and wound healing properties. No adverse or unwanted effects have been observed in case studies and in a phase I/II clinical trial involving 30 patients. Applied topically on the scalp, promotion of hair thickness, change in coloration (from grey back to its original darker colour), and hair growth have also been clearly observed.

Large Clinical Trial About to Be Initiated

When injected into patients it promotes activation of circulating and various organ stem cells in a safe manner, leading to a very potent anti-aging effect. Benefits have so far been observed in patients with a variety of degenerative diseases, such as heart disease, neuromuscular disease, diabetes and emphysema, to name a few. A large clinical trial under FDA regulations is about to be initiated on the efficacy of TB4-7 in patients with Type II diabetes, Duchenes Muscular dystrophy and emphysema.

As has been shown in cardiac tissue, TB4-7 promotes the activation of cardiac muscle and endothelial progenitor cells, and their survival, and decreases muscle apoptosis²⁵. Similarly in the cornea, TB4 promotes cell migration and wound healing, has anti-inflammatory properties, and suppresses apoptosis²⁶. Another group's results indicate that TB4 also promotes the survival and neurite outgrowth of cultured spinal cord neurons²⁷. We have observed similar promotive effects of TB4 on the survival and stimulation of skeletal muscle progenitors and myocytes.

Already Used By Body Builders

Human trial candidates have noticed the following in an ongoing trial in body builders where they inject 10mg of TB4-7 twice weekly for four weeks:

• Increased muscle girth.
• Faster recovery time (wear and tear) from training.
• Increased muscular endurance.
• Increased muscular strength.
• Decreased musculoskeletal pain.
• Improved hand-eye coordination.
• Increased energy levels.
• Improved mood (decreased anxiety).
• Improved sleeping patterns.
• Improved concentration span and short-term memory.
• Improved hair growth.

AdiStem TB4-7^™ Peptide is an injectable formulation of TB4. A similar formulation has just completed Phase I clinical trials and has been shown to be safe and well-tolerated. The product candidate has been developed to address medical indications where subcutaneous administration is warranted. AdiStem Ltd. is currently planning a Phase I/II clinical trial to evaluate AdiStem TB4-7^™ in type II diabetic patients although other indications such as motorneurons disease, emphysema, and Duchene's muscular dystrophy have been identified as potential targets.

Available in a Cream for Hair Growth through ActiStem Ltd.

AdiStem TB4-7^™ Peptide is now available in a cream for hair growth. You can purchase or view more information on our distributor's website, ActiStem.com.

About AdiStem Ltd.

Aside from autologous adipose-derived stem cell therapy, AdiStem Ltd. is focused on the discovery and development of novel stem cell derived peptides to accelerate tissue and organ repair. Currently, AdiStem Ltd. is developing a product candidate, TB4-7, for Type II diabetes. AdiStem Ltd. is also developing other product candidates for use on other diseases. These product candidates are based on TB4, a synthetic derivative copy of the 43-amino acid, naturally occurring peptide. AdiStem Ltd. holds and has applied for over 6 world-wide patents and patent applications related to novel peptides to date.

CONTACT US

You can also reach us by completing and returning the Inquiry Form.

References

1 Sosne, G., Szliter, E. A., Barrett, R., Kernacki, K. A., Kleinman, H., and Hazlett, L. D. (2002) Thymosin beta 4 promotes corneal wound healing and decreases inflammation in vivo following alkali injury. Exp. Eye Res. 74, 293ñ299

2 Sosne, G., Hafeez, S., Greenberry, A. L., II, and Kurpakus-Wheater, M. (2002) Thymosin beta4 promotes human conjunctival epithelial cell migration. Curr. Eye Res. 24, 268ñ273

3 Malinda, K. M., Sidhu, G. S., Mani, H., Banaudha, K., Maheshwari, R. K., Goldstein, A. L., and Kleinman, H. K. (1999) Thymosin beta4 accelerates wound healing. J. Invest. Dermatol. 113, 364ñ368

4 Malinda, K. M., Goldstein, A. L., and Kleinman, H. K. (1997) Thymosin beta 4 stimulates directional migration of human umbilical vein endothelial cells. FASEB J. 11, 474ñ481

5 Grant, D. S., Kinsella, J. L., Kibbey, M. C., LaFlamme, S., Burbelo, P. D., Goldstein, A. L., and Kleinman, H. K. (1995) Matrigel induces thymosin beta 4 gene in differentiating endothelial cells. J. Cell Sci. 108, 3685ñ3694

6 Low, T. L., Hu, S. K., and Goldstein, A. L. (1981) Complete amino acid sequence of bovine thymosin beta 4: a thymic hormone that induces terminal deoxynucleotidyl transferase activity in thymocyte populations. Proc. Natl. Acad. Sci. USA 78, 1162ñ1166

7 Frohm, M., Gunne, H., Bergman, A. C., Agerberth, B., Bergman, T., Boman, A., Liden, S., Jornvall, H., and Boman, H. G. (1996) Biochemical and antibacterial analysis of human wound and blister fluid. Eur. J. Biochem. 237, 86ñ92

8 Kobayashi, T., Okada, F., Fujii, N., Tomita, N., Ito, S., Tazawa, H., Aoyama, T., Choi, S. K., Shibata, T., Fujita, H., et al. (2002) Thymosin-beta4 regulates motility and metastasis of malignant mouse fibrosarcoma cells. Am. J. Pathol. 160, 869ñ882

9 Roy, P., Rajfur, Z., Jones, D., Marriott, G., Loew, L., and Jacobson, K. (2001) Local photorelease of caged thymosin beta4 in locomoting keratocytes causes cell turning. J. Cell Biol. 153, 1035ñ1048

10 Philp, D., Badamchian, M., Scheremeta, B., Nguyen, M., Goldstein, A. L., and Kleinman, H. K. (2003) Thymosin beta 4 and a synthetic peptide containing its actin-binding domain promote dermal wound repair in db/db diabetic mice and in aged mice. Wound Repair Regen. 11, 19ñ24

11 Young, J. D., Lawrence, A. J., MacLean, A. G., Leung, B. P., McInnes, I. B., Canas, B., Pappin, D. J., and Stevenson, R. D. (1999) Thymosin beta 4 sulfoxide is an anti- inflammatory agent generated by monocytes in the presence of glucocorticoids. Nat. Med. 5, 1424ñ1427

12 Philp, D., Nguyen, M., Scheremeta, B., St-Surin, S., Villa, A.N., Orgel, A., Kleinman, H.K., and Elkin, M. (2003) Thymosin β4 increases hair growth by activation of hair follicle stem cells. FASEB J. express article 10.1096/fj.03-0244fje.

13 Huff T, Muller CS, Otto AM, Netzker R, Hannappel E. beta-Thymosins, small acidic peptides with multiple functions. Int J Biochem Cell Biol 2001;33:205-20.

14 Safer D, Nachmias VT. Beta thymosins as actin binding proteins. Bioessays 1994;16:473-9.

15 Cassimeris L, Safer D, Nachmias VT, Zigmond SH. Thymosin b4 sequesters the majority of G-Actin in resting human polymorphonu- clear leukocytes. J Cell Biol 1992;119:1261-70.

16 Sanders MC, Goldstein AL, Wang Y-L. Thymosin b4 (Fx peptide) is a potent regulator of actin polymerization in living cells. Proc Natl Acad Sci USA 1992;89:4678-82.

17 Sanger JM, Golla R, Safer D, Choi JK, Yu K, Sanger JW, Nachmias VT. Increasing intracellular concentrations of thymosin b4 in PtK2 cells: effects on stress fibers, cytokinesis, and cell spreading. Cell Motil Cytoskel 1995;31:307-22.

18 Weber A, Nachmias VT, Pennise CR, Pring M, Safer D. Interaction of thymosin beta 4 with muscle and platelet actin: implications for actin sequestration in resting platelets. Biochemistry 1992;31: 6179-85.

19 Yu F-X, Lin S-C, Morrison-Bogorad M, Atkinson MA, Yin HL. Thymosin beta 10 and thymosin beta 4 are both actin monomer sequestering proteins. J Biol Chem 1993;268:502-9.

20 Yu F-X, Lin S-C, Morrison-Bogorad M, Yin HL. Effects of thymosin b4 and thymosin b10 on actin structures in living cells. Cell Motil Cytoskel 1994;27:13-25.

21 Malinda KM, Sidhu GS, Mani H, Banaudha K, Maheshwari RK, Gold- stein AL, Kleinman HK. Thymosin beta 4 accelerates wound healing. J Invest Dermatol 1999;113:364-8

22 Mihelic M, Voelter W. Distribution and biological activity of b-thymosins. Amino Acids 1994;6:1-13.

23 Philp D, St-Surin S, Cha HJ, Moon HS, Kleinman HK, Elkin M. Thymosin beta 4 induces hair growth via stem cell migration and differentiation. Ann N Y Acad Sci. 2007 Sep;1112:95-103.

24 Philp D, St-Surin S, Cha HJ, Moon HS, Kleinman HK, Elkin M. Thymosin beta 4 induces hair growth via stem cell migration and differentiation. Ann N Y Acad Sci. 2007 Sep;1112:95-103.

25 Bock-Marquette A, Saxena M, White MD, et al. 2004. Thymosin beta 4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature, 432:466-72.

26 Sosne G, Qiu P, and Kurpakus- Wheater M. Thymosin beta 4: A novel corneal wound healing and anti-inflammatory agent. Clinical Ophthalmology 2007:1(3) 201-207.

27 Yang H, Cheng X, Yao Q, Li J, Ju G. The promotive effects of thymosin beta4 on neuronal survival and neurite outgrowth by upregulating L1 expression. Neurochem Res. 2008 Nov;33(11):2269-80.