Therapies for diseases caused by arthropod-borne parasites

Abstract

The present disclosure provides methods for treating or preventing diseases caused by arthropod-borne parasites by administration of a protein kinase inhibitor to a mammalian subject infected with or at risk of exposure to an arthropod-borne parasite. In some aspects, the therapeutic and prophylactic regimens of the present disclosure are effective in reducing parasite development in arthropods feeding on recipients of the regimens. Additionally, the present disclosure provides methods for screening candidate anti-parasitic agents.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 923,405, filed Jan. 3, 2014, and U.S. Provisional Application No. 61 / 845,920, filed Jul. 12, 2013, which are incorporated herein by reference in their entirety for all purposes.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with Government support under Grant Nos. AI073745 and AI080799, awarded by National Institutes of Health. The Government has certain rights in the invention.FIELD[0003]The present disclosure provides methods for treating or preventing diseases caused by arthropod-borne parasites by administration of a protein kinase inhibitor to a mammalian subject infected with or at risk of exposure to an arthropod-borne parasite. In some aspects, the therapeutic and prophylactic regimens of the present disclosure are effective in reducing parasite development in arthropods feeding on recipients of the regimens. Ad...

AI Technical Summary

Benefits of technology

[0009]The present disclosure provides methods for treating or preventing diseases caused by arthropod-borne parasites by administration of a protein kinase inhibitor to a mammalian subject infected with or at risk of exposure to an arthropod-borne parasite. In some aspects, the therapeutic and prophylactic regimens of the present disclosure are effective in reducing parasite development in arthropods feeding on recipients of the regimens. Additionally, the present disclosure provides methods for screening candidate anti-parasitic agents.

[0012]Furthermore, the present disclosure provides methods of reducing transmission of Trypanosoma cruzi by a Triatominae vector, comprising administering a protein kinase inhibitor to a mammalian subject infected with Trypanosoma cruzi. under conditions effective for reducing transmission of the Trypanosoma cruzi ingested by the Triatominae vector in the subject's blood. The present disclosure also provides methods of reducing transmission of Trypanosoma cruzi by a Triatominae vector, comprising providing a bloodmeal comprising erythrocytes infected with Trypanosoma cruzi to a Triatominae vector in the presence of an effective amount of a protein kinase inhibitor for reducing transmission of the Trypanosoma cruzi ingested by the Triatominae vector in the bloodmeal. In some embodiments, the methods further comprise administering an additional anti-parasitic drug to the mammalian subject. In some embodiments, the bloodmeal is provided to the Triatominae vector in the further presence of an additional antiparasitic drug. In some embodiments, the protein kinase inhibitor comprises a first and a second protein kinase inhibitor. In some embodiments, the protein kinase inhibitor reduces activity of at least one mammalian protein kinase. In some embodiments, the mammalian protein kinase comprises a member of one or more families selected from the group consisting of a protein kinase C (PKC) family, a c-Jun N-terminal kinase (JNK) family, and a p38 mitogen activated protein kinase (MAPK) family. In some preferred embodiments, the protein kinase inhibitor reduces activity of a Triatominae kinase. In some embodiments, the Triatominae kinase comprises one or more of the group consisting of cPKC, nPKC-delta, nPKC-epsilon, aPKC-zeta, PKD, PKN, JNK isoforms, and p38 MAPK isoforms. In some embodiments, the Triatominae kinase comprises aPKC-zeta. In some embodiments, the subject is infected with Trypanosoma cruzi. In some embodiments, the additional anti-parasitic drug comprises a one or both of benznidazole and nifurtimox.

Problems solved by technology

However, in some instances, acute infection can cause severe inflammation of the heart or brain (myocarditis or meningoencephalitis) which can be deadly (Bern et al., supra, 2011).

In the chronic phase, intracellular T. cruzi amastigotes remain in infected tissues, especially in cardiac and skeletal muscle, but the parasitemia levels become undetectable by microscopy.

In about 30% of chronically-infected individuals Chagas disease develops into a life-threatening illness characterized by abnormal heart rhythms leading to an increased risk of sudden death, heart failure, and / or gastrointestinal disturbances.

Thus, Chagas disease is a serious illness affecting a significant portion of the population.

There are only two drugs used to treat acute-phase disease, benznidazole (since 1960s) and nifurtimox (since 1970s), both of which are impractical because of low efficacy and frequent side effects.

Treatment of the chronic form of the disease is still limited to the management of symptoms (e.g., antiarrhythmics, steroids, pacemakers, etc.).

Even heart transplantation cannot ensure a cure, because the parasites hidden within other organs will eventually reinvade the transplanted heart.

Despite the well-recognized limitations of current therapeutic approaches and the general acceptance that specific treatment should be made available to infected individuals, new Chagas disease treatments have not reached the clinic.

Thus, there remains a need for therapy regimens to treat or prevent other diseases caused by arthropod-borne parasites, which are safe and do not encourage development of drug-resistant parasites.

Images