Targeted Thrombolysis for Treatment of Microvascular Thrombosis

Abstract

The present invention provides fusion proteins for targeted delivery of plasminogen activators to platelet-VWF complexes, or alternatively to the site where these are located, in a fibrin-independent manner. The fusion protein of the invention are for use in methods for the prevention or treatment of diseases or conditions associated with such platelet-VWF complexes, which may cause microvascular thrombosis in diseases such as e.g. thrombotic thrombocytopenic purpura. Preferred targeting agents for incorporation into the fusion proteins are e.g. nanobodies against VWF or platelets. Preferred plasminogen activators for use in the fusion proteins comprise the protease domains of uPA or tPA. The invention further pertains to nucleic acid molecule encoding the fusion proteins of the invention, e.g. a gene therapy vector, and to pharmaceutical compositions comprising the fusion proteins of the invention or such gene therapy vectors.

Description

FIELD OF THE INVENTION[0001]The present invention relates to the field of medicine and pharmacy, in particular to the field of biopharmaceuticals for use in the prevention or treatment of a disease or condition associated with microvascular thrombosis, such as e.g. thrombotic thrombocytopenic purpura. More specifically, the invention relates to fusion proteins comprising a targeting agent and a plasminogen activator, wherein the targeting agent targets the plasminogen activator to at least one of VWF, platelets and activated vascular endothelium with the aim to enzymatically degrade vascular obstructions in a fibrin-independent manner. The invention further relates to gene therapy vectors encoding such fusion proteins.BACKGROUND ART[0002]Microvascular thrombosis (MVT) is characterized by the formation of microvascular platelet aggregates. They are minimally composed of platelets and VWF. This becomes clear in thrombotic thrombocytopenic purpura (TTP), where platelet- and VWF-rich, b...

AI Technical Summary

Benefits of technology

[0024]A “nucleic acid construct” or “nucleic acid vector” is herein understood to mean a man-made nucleic acid molecule resulting from the use of recombinant DNA technology. The term “nucleic acid construct” therefore does not include naturally occurring nucleic acid molecules although a nucleic acid construct may comprise (parts of) naturally occurring nucleic acid molecules. The terms “expression vector” or expression construct” refer to nucleic acid molecules that are capable of effecting expression of a nucleotide sequence or gene in host cells or host organisms compatible with such expression vectors or constructs. These expression vectors typically include regulatory sequence elements that are operably linked to the nucleotide sequence to be expressed to effect its expression. Such regulatory elements usually at least include suitable transcription regulatory sequences and optionally, 3′ transcription termination signals. Additional elements necessary or helpful in effecting expression may also be present, such as expression enhancer elements. The expression vector will be introduced into a suitable host cell and be able to effect expression of the coding sequence in an in vitro cell culture of the host cell. The expression vector will be suitable for replication in the host cell or organism of the invention whereas an expression construct will usually integrate in the host cell's genome for it to

Problems solved by technology

This becomes clear in thrombotic thrombocytopenic purpura (TTP), where platelet- and VWF-rich, but fibrin-poor microthrombi obstruct microvasculature with life-threatening consequences.

In severe cases of MVT, multi-organ failure can occur with lethal consequences.

Even in less severe cases, organ damage may form and reducing both the quality of life, as well as the life expectancy of the patient.

This is ultimately thought to cause heart failure, in particular in females.

However, persistent autoantibodies impede elimination of microthrombi.

This makes thera

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