Advanced therapies for the treatment of hemophilia: future perspectives

Monogenic diseases are ideal candidates for treatment by the emerging advanced therapies, which are capable of correcting alterations in protein expression that result from genetic mutation. In hemophilia A and B such alterations affect the activity of coagulation factors VIII and IX, respectively, and are responsible for the development of the disease. Advanced therapies may involve the replacement of a deficient gene by a healthy gene so that it generates a certain functional,structural or transport protein (gene therapy); the incorporation of a full array of healthy genes and proteins through perfusion or transplantation of healthy cells (cell therapy); or tissue transplantation and formation of healthy organs (tissue engineering). For their part, induced pluripotent stem cells have recently been shown to also play a significant role in the fields of cell therapy and tissue engineering.Hemophilia is optimally suited for advanced therapies owing to the fact that, as a monogenic condition, it does not require very high expression levels of a coagulation factor to reach moderate disease status. As a result, significant progress has been possible with respect to these kinds of strategies, especially in the fields of gene therapy (by using viral and non-viral vectors) and cell therapy (by means of several types of target cells). Thus, although still considered a rare disorder, hemophilia is now recognized as a condition amenable to gene therapy, which can be administered in the form of lentiviral and adeno-associated vectors applied to adult stem cells, autologous fibroblasts, platelets and hematopoietic stem cells; by means of non-viral vectors; or through the repair of mutations by chimeric oligonucleotides. In hemophilia, cell therapy approaches have been based mainly on transplantation of healthy cells (adult stem cells or induced pluripotent cell-derived progenitor cells)in order to restore alterations in coagulation factor expression

Cartilage restoration in haemophilia: advanced therapies

Current treatment of joint cartilage lesions is based either on conventional techniques (bone marrow stimulation, osteochondral autograft or allograft transplantation) or on newly developed techniques (chondrocyte implantation and those based on cell therapy that use bioreactors, growth factors, mesenchymal stem cells [MSCs] and genetically modified cells). The aim of this article is to review the therapeutic strategies above mentioned and to determine whether the chondral damage seen in haemophilia could benefit from any of them. The different conventional techniques have shown similar results whereas autologous chondrocyte implantation, which is in common use at the present time, has not been shown to produce any conclusive results or to lead to the formation of hyaline cartilage. MSCs hold promise for the repair of joint cartilage given their differentiation capacity and the therapeutic effect. The use of bioreactors and growth factors, which stimulate cartilage formation, may optimize such strategies in the context of reimplantation of chondrocytes, differentiated MSCs and cartilage progenitor cells. The aim of cell therapy is restoration of function through the repair of damaged tissue or the stimulation of growth factor synthesis. Implantation of autologous chondrocytes or MSCs was up to now able to address only highly localized chondral lesions. Adequate control of the differentiation process as well as the use of growth factors and appropriate bioreactors could transform cell-based therapies into a more efficient and longer term treatment even for patients with haemophilia. Nevertheless, raising false expectations in these patients should be avoided. There are a number of approaches to cartilage restoration in haemophilic arthropathy, which are currently being explored for other joint related degenerative disorders. If it can be proven to be effective for the disorders in which clinical trials are ongoing and costs could be limited, it might be an useful palliative approach to haemophilic arthropathy. However, we still have a long way to go for use in haemophilic arthropathy

Efficacy of a Binuclear Cyclopalladated Compound Therapy for Cutaneous Leishmaniasis in the Murine Model of Infection with Leishmania amazonensis and Its Inhibitory Effect on Topoisomerase 1B

Submitted by Sandra Infurna ([email protected]) on 2018-05-30T11:44:58Z No. of bitstreams: 1 elmo_amaral_etal_IOC_2017.pdf: 1249508 bytes, checksum: 02577de795abd5559d0181f9b44fe388 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2018-05-30T12:07:03Z (GMT) No. of bitstreams: 1 elmo_amaral_etal_IOC_2017.pdf: 1249508 bytes, checksum: 02577de795abd5559d0181f9b44fe388 (MD5)Made available in DSpace on 2018-05-30T12:07:03Z (GMT). No. of bitstreams: 1 elmo_amaral_etal_IOC_2017.pdf: 1249508 bytes, checksum: 02577de795abd5559d0181f9b44fe388 (MD5) Previous issue date: 2017Universidade de São Paulo. Escola de Ciências Farmacêuticas. Araraquara, SP, Brasil / Universidade do Estado de São Paulo. Instituto de Química. Araraquara, SP, Brasil.Universidade de São Paulo. Escola de Ciências Farmacêuticas. Araraquara, SP, Brasil.University of Rome. TorVergata, Rome, Italy.University of Rome. TorVergata, Rome, Italy.University of Rome. TorVergata, Rome, Italy.Universidade de São Paulo. Escola de Ciências Farmacêuticas. Araraquara, SP, Brasil.Universidade do Estado de São Paulo. Instituto de Química. Araraquara, SP, Brasil.Universidade Estadual de Campinas. Instituto de Biologia. Campinas, SP, Brasil.Universidade de São Paulo. Escola de Ciências Farmacêuticas. Araraquara, SP, Brasil / Universidade Estadual de São Paulo. Instituto de Químca. Araraquara, SP, Brasil.Universidade de São Paulo. Escola de Ciências Farmacêuticas. Araraquara, SP, Brasil.Universidade de São Paulo. Escola de Ciências Farmacêuticas. Araraquara, SP, Brasil.Universidade do Estado de São Paulo. Instituto de Química. Araraquara, SP, Brasil.University of Rome. TorVergata, Rome, Italy..Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.Universidade de São Paulo. Escola de Ciências Farmacêuticas. Araraquara, SP, Brasil.Leishmaniasis is a disease found throughout the (sub)tropical parts of the world caused by protozoan parasites of the Leishmania genus. Despite the numerous problems associated with existing treatments, pharmaceutical companies continue to neglect the development of better ones. The high toxicity of current drugs combined with emerging resistance makes the discovery of new therapeutic alternatives urgent. We report here the evaluation of a binuclear cyclopalladated complex containing Pd(II) and N,N'-dimethylbenzylamine (Hdmba) against Leishmania amazonensis The compound [Pd(dmba)(μ-N3)]2 (CP2) inhibits promastigote growth (50% inhibitory concentration [IC50] = 13.2 ± 0.7 μM) and decreases the proliferation of intracellular amastigotes in in vitro incubated macrophages (IC50 = 10.2 ± 2.2 μM) without a cytotoxic effect when tested against peritoneal macrophages (50% cytotoxic concentration = 506.0 ± 10.7 μM). In addition, CP2 was also active against T. cruzi intracellular amastigotes (IC50 = 2.3 ± 0.5 μM, selective index = 225), an indication of its potential for use in Chagas disease therapy. In vivo assays using L. amazonensis-infected BALB/c showed an 80% reduction in parasite load compared to infected and nontreated animals. Also, compared to amphotericin B treatment, CP2 did not show any side effects, which was corroborated by the analysis of plasma levels of different hepatic and renal biomarkers. Furthermore, CP2 was able to inhibit Leishmania donovani topoisomerase 1B (Ldtopo1B), a potentially important target in this parasite. (This study has been registered at ClinicalTrials.gov under identifier NCT02169141.)