Inhibition of degradation of extracellular matrix

An extracellular matrix and cell technology, applied in the field of heparanase inhibitors, can solve problems such as islet function loss

Inactive Publication Date: 2009-11-25
AUSTRALIEN NAT UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite this progress, the heavy use of the immunosuppressive drugs needed to prevent rejection of islet transplants has severely limited its use to adult subjects with uncontrolled diabetes alone
Furthermore, in the long run, islet function is eventually lost and insulin therapy is again required

Method used

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  • Inhibition of degradation of extracellular matrix
  • Inhibition of degradation of extracellular matrix
  • Inhibition of degradation of extracellular matrix

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0173] The role of heparanase in triggering destructive insulitis and clinical diabetes

[0174] Studies performed by the present inventors have shown a 7-fold increase in heparanase transcripts in pre-diabetic and diabetic-onset NOD mice compared to neonatal NOD mice; only background levels were detected in normal CBA / H mice (See Table 1). These results have been strengthened by evidence that treatment of 10-11 week old female NOD / Lt mice with the heparanase inhibitor PI-88(9) prevents clinical diabetes in mice up to 24 weeks of age onset (see image 3 ). Furthermore, the inventors have found that delivery of purified human platelet-derived heparanase via the pancreatic duct into conventional (non-autoimmune) mice results in in situ destruction of islet BM and intraislet HS ( See Figure 4 ). These results are consistent with a role for heparanase in triggering destructive insulitis in NOD mice and demonstrate the ability of PI-88 to protect NOD mice from onset of clinic...

Embodiment 2

[0179] Intragraft expression kinetics of heparanase mRNA in islet isografts undergoing autoimmune destruction in diabetic NOD mice

[0180] In general, histopathology of pancreas from prediabetic female NOD and autoimmune destruction of syngeneic islets transplanted into diabetic NOD mice showed that autoreactive T cells and other MNCs did not enter islets via intraislet blood vessels . Instead, invasive leukemia moves from the periislet location into the islet cell mass after disintegration of the islet BM by degradative enzymes such as heparanase produced locally at the islet BM interface by activated leukocytes. Thereafter, the process of MNC infiltration can lead to the degradation of ECM heparan sulfate in the islets and the destruction of the islets.

[0181] Investigations into whether this enzyme-dependent leukocyte invasion mechanism is functional in the autoimmune destruction of islet isografts in diabetic NOD mice include general experiments such as examining islet...

Embodiment 3

[0190] In situ expression of heparan sulfate (HS) in NOD islets and degradation of HS in islets during destructive insulitis

[0191]In addition to the trechanin / HS present in the islet BM, HSPG is also a component of the more widely distributed ECM. The ECM consists of a network of macromolecules whose function is to fill the extracellular space in tissues and provide tissue-specific cells with a scaffold on which invading leukocytes can migrate (3). Indeed, it has been shown that the survival and function of β cells depend on the maintenance of their interaction with the intraislet ECM (23, 24). Therefore, heparanase may not only facilitate the entry of activated MNCs through the islet BM, but also degrade intraislet ECM, thereby not only promoting the migration of invading MNCs but also reducing the viability of adjacent β cells.

[0192] General experiments to confirm the relationship of islet-associated heparan sulfate and heparanase to islet integrity included not only ...

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Abstract

This application realtes to a method of inhibiting the degradation of an extracellular matrix associated with islet beta cells, the method comprising contacting the extracellular matrix with an effective amount of a heparanase inhibitor.

Description

[0001] Cross references to related patent applications [0002] This application claims priority based on Australian Provisional Patent Application No. 2006905854 filed on October 20, 2006, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to the use of heparanase inhibitors in the treatment of disorders associated with degradation of the extracellular matrix, such as insulitis or autoimmune type 1 diabetes. In particular, the present invention relates to improvements in the efficacy of transplantation for the treatment of insulitis or type 1 diabetes. Background technique [0004] Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing beta cells of the pancreatic islets are destroyed. In humans, the disease has a dramatic impact on lifestyle, and imperfect control of hyperglycemia by exogenous insulin therapy inevitably leads to microvascular disease. This complication may eventually le...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/737A61K31/785A61K31/706A61K31/734A61K31/7125A61K31/7024A61K31/445A61K31/403A61K31/712A61K31/185A61K31/775A61K31/255A61K31/404A61K31/795A61K31/223A61K31/09A61P37/00
CPCA61K31/223A61K31/737A61K31/785A61K31/706A61K31/734A61K31/185A61K31/445A61K31/403A61K31/7125A61K31/775A61K31/7024A61K31/712A61K31/795A61K31/404A61K31/09A61K31/255A61P1/18A61P3/10A61P37/00A61P37/02A61P37/06A61P43/00
Inventor C·西米恩维克C·R·帕里什A·齐奥考斯基
Owner AUSTRALIEN NAT UNIV
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