Polypeptides and polynucleotides encoding same and use thereof in the treatment of medical conditions associated with ischemia

Abstract

An isolated polynucleotide is disclosed comprising a nucleic acid sequence encoding a polypeptide having an amino acid sequence of HIF-1alpha, the polypeptide being stably expressed and constitutively active. Isolated polypeptides encoded by same are also disclosed and uses thereof.

Description

FIELD AND BACKGROUND OF THE INVENTION[0001]The present invention relates to polypeptides and polynucleotides encoding same and use thereof in the treatment of medical conditions associated with ischemia.[0002]Angiogenesis is the budding of new blood vessels from pre-existing ones. It occurs in various physiological conditions such as the female reproductive cycle, as well as pathological conditions which include tumors, tissue ischemia and wound healing.[0003]Ischemic heart disease is the leading cause of mortality in many industrialized countries and is responsible for over 500,000 deaths in the US alone each year. Current treatment options include drug therapy, coronary angioplasty and the more invasive coronary artery bypass grafting (CABG).[0004]However, in all these cases, technical issues including the size of the artery involved, lack of appropriate distal vasculature, the complexity of the arterial lesions that cause the occlusion, and the general clinical conditions of the ...

AI Technical Summary

Benefits of technology

[0044]The present invention successfully addresses the shortcomings of the presently known configurations by providing novel treatments for medical conditions associated with ischemia.

[0045]Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Problems solved by technology

However, in all these cases, technical issues including the size of the artery involved, lack of appropriate distal vasculature, the complexity of the arterial lesions that cause the occlusion, and the general clinical conditions of the patient frequently prevent revascularization of the ischemic tissues.

However, many obstacles still have to be overcome before therapeutic angiogenesis becomes a real clinical alternative for patients suffering from ischemic diseases.

For angiogenic gene therapy, these obstacles include the need for tissue specificity of transgene expression, choice of delivery vehicle, optimization of dose and timing, optimization of route of administration and the potential of adverse events such as edema and tumor development.

Another limitation to the success of angiogenic gene therapy is the lack of maturation of the newly formed vessels and their subsequent regression, thus preventing a significant long-lasting therapeutic effect.

This may be because the delivered angiogenic genes are expressed only for a relatively short period of time which does not allow for vessel maturation and recruitment of smooth muscle cells to take place or because multiple angiogenic factors are required for vessel maturation to occur.

In addition, HIF-1α is expressed in these constructs under the regulation of CMV, a versatile and non-specific promoter, which may limit its application due to non-specific expression and potential side-effects.

However, despite its obvious clinical appeal, the use of this administration route is uncommon due to systemic distribution of the vector leading to low transgene expression in the target organ along with unwanted expression in non-target organs resulting in systemic side-effects, which limit the dose that may be administered.

This limitation, in turn, tends to restrict the efficacy of the treatment.

Unwanted expression of a pro-angiogeneic gene could induce pathological angiogenesis, possibly leading to tumor development and retinopathy, and may therefore be unacceptable.

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