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1.
Acta Biomater ; 158: 734-746, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36563772

RESUMO

Methods capable of distributing antitumour therapeutics uniformly throughout an entire tumour and that can suppress metastasis at the same time, would be of great significance in improving cancer treatment. Bacteria-mediated synergistic therapies have been explored for better specificity, temporal and spatial controllability, as well for providing regulation of the immune microenvironment, in order to provide improved cancer treatment. To achieve this goal, here we developed an engineered bacteria delivery system (GDOX@HSEc) using synthetic biology and interfacial chemistry technologies. The engineered bacteria were concurrently modified to express heparin sulfatase 1 (HSulf-1) inside (HSEc), to attach doxorubicin-loaded glycogen nanoparticles (GDOX NPs) on their surface. Here we demonstrate that HSEc can actively target and colonise tumour sites resulting in HSulf-1 overexpression, thereby suppressing angiogenesis and metastasis. Simultaneously, the GDOX NPs were able to penetrate into tumour cells, leading to intracellular DNA damage. Our results confirmed that a combination of biotherapy and chemotherapy using GDOX@HSEc resulted in significant melanoma suppression in murine models, with reduced side effects. This study provides a powerful platform for the simultaneous delivery of biomacromolecules and chemotherapeutic drugs to tumours, representing an innovative strategy potentially more effective in treating solid tumours. STATEMENT OF SIGNIFICANCE: An original engineered bacteria-based system (GDOX@HSEc) was developed using synthetic biology and interfacial chemistry technologies to concurrently produce naturally occurring heparin sulfatase 1 (HSulf-1) inside and anchor doxorubicin-loaded glycogen nanoparticles on the surface. GDOX@HSEc allowed for combined local delivery of chemotherapeutic agents along with the enzymes and immunostimulatory bacterial adjuvants, which resulted in a synergistic action in the inhibition of tumour growth and metastasis. The study provides a potential therapeutic approach that allows therapeutic agents to be distributed in a spatiotemporally controllable manner in tumours for combinatorial enhanced therapy.


Assuntos
Melanoma , Nanopartículas , Animais , Camundongos , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Melanoma/tratamento farmacológico , Nanopartículas/química , Sulfatases/uso terapêutico , Microambiente Tumoral
2.
Mol Genet Metab ; 134(4): 317-322, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34600820

RESUMO

INTRODUCTION: Currently, there is no effective therapy for mucopolysaccharidosis IIIA (MPS IIIA). Intravenously-administered enzyme replacement therapies, while effective in other forms of MPS without neurological involvement, have not been successful in patients with MPS IIIA, as they are unable to cross the blood-brain barrier to improve neurological symptoms. We evaluated the long-term safety, tolerability, and clinical outcomes of recombinant human heparan-N-sulfatase (rhHNS) administered intrathecally (IT) in children with MPS IIIA in a phase 1/2 extension study. METHODS: Patients aged ≥3 years with MPS IIIA who had previously completed a phase 1/2 study and received ≥5 of the 6 planned rhHNS infusions via IT administration, were eligible for inclusion. Patients who received 10 mg in the phase 1/2 study had their dose increased to 45 mg. Patients who were treated with 45 mg or 90 mg rhHNS IT in the phase 1/2 study remained on this monthly dose in the extension study. rhHNS was administered via an intrathecal drug delivery device (IDDD). Primary endpoints included the type and severity of adverse events, presence of anti-rhHNS antibodies in the CSF and serum, and changes in laboratory values. Secondary endpoints included standardized neurocognitive assessments and brain magnetic resonance imaging. RESULTS: In the extension study, 12 patients with a mean (SD) age of 9.6 (7.3) years continued treatment with rhHNS IT for a median of 264.4 weeks. Ten of 12 patients completed the extension study. rhHNS IT was generally well-tolerated. All patients experienced at least one treatment-emergent adverse event (TEAE), most being mild or moderate in severity. No serious adverse events (SAEs) were considered related to the study drug, and no deaths occurred. Most SAEs were related to malfunctions of the IDDD. Declines from baseline in Bayley Scales of Infant Development, Third Edition or Kaufman Assessment Battery for Children, Second Edition, Nonverbal Index developmental quotient scores were evident at all rhHNS dosing groups: -17.97%, -18.99%, and -12.12% in the 10/45, 45, and 90 mg groups, respectively, at Month 54. CONCLUSIONS: Overall, rhHNS IT was well tolerated in the extension study. However, rhHNS IT was unable to slow the neurocognitive decline of patients with MPS IIIA. This study was subsequently terminated early because pre-specified efficacy criteria were not met, and the study did not yield clinical proof of concept. (Clinicaltrials.gov Identifier NCT01299727).


Assuntos
Terapia de Reposição de Enzimas/métodos , Mucopolissacaridose III/tratamento farmacológico , Sulfatases/uso terapêutico , Adolescente , Encéfalo/patologia , Criança , Pré-Escolar , Cognição , Feminino , Heparitina Sulfato/líquido cefalorraquidiano , Humanos , Masculino , Mucopolissacaridose III/patologia , Mucopolissacaridose III/psicologia , Proteínas Recombinantes/uso terapêutico , Sulfatases/administração & dosagem , Sulfatases/efeitos adversos
3.
Mol Genet Metab ; 134(1-2): 175-181, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34247932

RESUMO

Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA) is a rare autosomal recessive lysosomal disorder characterized by deficient heparan-N-sulfatase (HNS) activity, and subsequent accumulation of heparan sulfate, especially in the central nervous system. The disease is associated with progressive neurodegeneration in early childhood. For this open-label extension study of a phase 2b clinical trial, we report on safety and cognitive decline in patients receiving intrathecal (IT) administration of recombinant human HNS (rhHNS). Of 21 patients who completed the phase 2b study, 17 continued in the open-label extension. Patients receiving rhHNS IT 45 mg continued to receive the same treatment regimen (i.e., every 2 weeks or every 4 weeks) throughout the extension. Patients receiving no treatment in the phase 2b study were re-randomized to the treatment groups. Neurocognition was assessed using the Bayley Scales of Infant and Toddler Development®, Third Edition (BSID-III). Adverse events were recorded over the duration of the treatment period. Cognitive decline was observed in most patients in both treatment groups; however, improvements in BSID-III development quotient score were observed for two patients, in receptive and expressive communication scores for three patients each, in fine motor skills for one patient, and in gross motor skills for six patients. Treatment-emergent adverse events that occurred with rhHNS IT were mostly mild, none led to study discontinuation, and there were no deaths. The extension study was terminated early as the primary endpoints of the phase 2b study were not met, and no statistical analyses were carried out. Although cognitive decline was apparent in most patients, improvements were observed in a small group of patients. Greater declines were observed in patients at the higher end of the age range, suggesting earlier intervention may increase the possibility of a response to treatment. rhHNS IT treatment remained generally well tolerated up to 96 weeks.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Mucopolissacaridose III/tratamento farmacológico , Sulfatases/uso terapêutico , Pré-Escolar , Disfunção Cognitiva/tratamento farmacológico , Feminino , Humanos , Lactente , Injeções Espinhais , Masculino , Projetos de Pesquisa , Resultado do Tratamento
4.
Mol Genet Metab ; 126(2): 121-130, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30528227

RESUMO

BACKGROUND: Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA) is a lysosomal disorder wherein deficient heparan-N-sulfatase (HNS) activity results in the accumulation of heparan sulfate in the central nervous system and is associated with progressive neurodegeneration in early childhood. We report on the efficacy, pharmacokinetics, safety, and tolerability of intrathecal (IT) administration of recombinant human HNS (rhHNS) from a phase IIb randomized open-label trial. METHODS: Twenty-one patients, randomized 1:1:1 to rhHNS IT 45 mg administered every 2 weeks (Q2W), every 4 weeks (Q4W), or no treatment, were assessed for amelioration in neurocognitive decline as determined by the Bayley Scales of Infant and Toddler Development®, Third Edition. The primary efficacy goal was defined as ≤10-point decline (responder) in at least three patients in a dosing cohort after 48 weeks. Other efficacy assessments included adaptive behavioral function, assessments of cortical gray matter volume, and glycosaminoglycan (GAG) levels in urine. RESULTS: A clinical response to rhHNS IT was observed in three treated patients (two in the Q2W group, one in the Q4W group). Cerebrospinal fluid heparan sulfate and urine GAG levels were reduced in all treated patients. However, most secondary efficacy assessments were similar between treated patients (n = 14; age, 17.8-47.8 months) and untreated controls (n = 7; age, 12.6-45.0 months). Treatment-emergent adverse events that occurred with rhHNS IT were mostly mild, none led to study discontinuation, and there were no deaths. CONCLUSION: rhHNS IT treatment reduced heparan sulfate and GAG levels in treated patients. Though the primary neurocognitive endpoint was not met, important lessons in the design and endpoints for evaluation of cognitive and behavioral diseases resulted. TRIAL REGISTRATION: ClinicalTrials.govNCT02060526; EudraCT 2013-003450-24.


Assuntos
Injeções Espinhais , Mucopolissacaridose III/tratamento farmacológico , Sulfatases/uso terapêutico , Sistema Nervoso Central , Pré-Escolar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Glicosaminoglicanos/urina , Humanos , Lactente , Masculino , Mucopolissacaridose III/líquido cefalorraquidiano , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Sulfatases/efeitos adversos
5.
Psychopharmacology (Berl) ; 235(6): 1835-1844, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29713786

RESUMO

RATIONALE: Recent preclinical research suggested that histone deacetylase inhibitors (HDACIs) and specifically class I HDAC selective inhibitors might be useful to treat alcohol use disorders (AUDs). OBJECTIVE: The objective of this study was to find a new inhibitor of the HDAC-1 isoenzyme and to test its efficacy in an animal model of AUDs. METHODS: In the present study, we prepared new derivatives bearing sulfonylhydrazide-type zinc-binding group (ZBG) and evaluated these compounds in vitro on HDAC-1 isoenzyme. The most promising compound was tested on ethanol operant self-administration and relapse in rats. RESULTS: We showed that the alkylsulfonylhydrazide-type compound (ASH) reduced by more than 55% the total amount of ethanol consumed after one intracerebroventricular microinjection, while no effect was observed on motivation of the animals to consume ethanol. In addition, one ASH injection in the central amygdala reduced relapse. CONCLUSIONS: Our study demonstrated that a new compound designed to target HDAC-1 is effective in reducing ethanol intake and relapse in rats and further confirm the interest of pursuing research to study the exact mechanism by which such inhibitor may be useful to treat AUDs.


Assuntos
Alcoolismo/tratamento farmacológico , Etanol/administração & dosagem , Histona Desacetilase 1/antagonistas & inibidores , Inibidores de Histona Desacetilases/uso terapêutico , Alcoolismo/enzimologia , Alcoolismo/psicologia , Animais , Histona Desacetilase 1/química , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Masculino , Simulação de Acoplamento Molecular/métodos , Motivação/efeitos dos fármacos , Motivação/fisiologia , Ratos , Ratos Long-Evans , Autoadministração , Sulfatases/química , Sulfatases/farmacologia , Sulfatases/uso terapêutico , Resultado do Tratamento
6.
Metab Brain Dis ; 33(1): 1-10, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28921412

RESUMO

Sanfilippo disease is one of mucopolysaccharidoses (MPS), a group of lysosomal storage diseases characterized by accumulation of partially degraded glycosaminoglycans (GAGs). It is classified as MPS type III, though it is caused by four different genetic defects, determining subtypes A, B, C and D. In each subtype of MPS III, the primary storage GAG is heparan sulfate (HS), but mutations leading to A, B, C, and D subtypes are located in genes coding for heparan N-sulfatase (the SGSH gene), α-N-acetylglucosaminidase (the NAGLU gene), acetyl-CoA:α-glucosaminide acetyltransferase (the HGSNAT gene), and N-acetylglucosamine-6-sulfatase (the GNS gene), respectively. Neurodegenerative changes in the central nervous system (CNS) are major problems in Sanfilippo disease. They cause severe cognitive disabilities and behavioral disturbances. This is the main reason of a current lack of therapeutic options for MPS III patients, while patients from some other MPS types (I, II, IVA, and VI) can be treated with enzyme replacement therapy or bone marrow or hematopoietic stem cell transplantations. Nevertheless, although no therapy is available for Sanfilippo disease now, recent years did bring important breakthroughs in this aspect, and clinical trials are being conducted with enzyme replacement therapy, gene therapy, and substrate reduction therapy. These recent achievements are summarized and discussed in this review.


Assuntos
Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Heparitina Sulfato/uso terapêutico , Sulfatases/uso terapêutico , Acetilglucosaminidase/genética , Terapia Genética/métodos , Humanos , Mutação/genética
7.
J Pediatr ; 152(5): 723-7, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18410781

RESUMO

OBJECTIVES: To assess the opinions of individuals with mucopolysaccharidoses (MPS) and their parents regarding the use of enzyme replacement therapy (ERT). STUDY DESIGN: A validated questionnaire, including hypothetical clinical scenarios about ERT for MPS, was distributed to members of MPS support groups in the United States and Australia. RESULTS: The questionnaire was completed by 249 MPS support group members. Overall, 92% were in favor of ERT where MPS causes severe physical problems but does not affect intellect, and 69% were in favor of ERT where the physical limitations are mild and intellect is spared. Only 47% were in favor of ERT where severe physical and intellectual problems are well established; however, 77% were in favor of ERT in this situation if treatment begun early prolongs life and improves quality of life. CONCLUSION: Most respondents were in favor of ERT for MPS, even where it would not alter the intellectual deterioration. The medical community has a responsibility to advocate for their patients in situations where ERT is appropriate and recognize the economic burden and "family function burden" ERT can incur.


Assuntos
Família/psicologia , Mucopolissacaridoses/tratamento farmacológico , Aceitação pelo Paciente de Cuidados de Saúde , Sulfatases/uso terapêutico , Adulto , Austrália , Criança , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Masculino , Mucopolissacaridoses/psicologia , Sulfatases/efeitos adversos , Resultado do Tratamento , Estados Unidos
14.
Science ; 169(3949): 987-9, 1970 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-4914726

RESUMO

Two patients with Fabry's disease were infused with normal plasma to provide active enzyme (ceramide trihexosidase) for hydrolysis of the plasma substrate, galactosylgalactosylglucosylceramide. Maximum ceramide trihexosidase activity occurred 6 hours after infusion of the plasma, attaining a level approximately 150 percent of that in normal plasma; enzymatic activity was detectable for 7 days. The amount of accumulated substrate in the plasma of these recipients decreased about 50 percent on day 10 after infusion. Thus, periodic replacement of ceramide trihexosidase activity in the plasma of patients with Fabry's disease might lead to consistently lower amounts of substrate in the plasma and a decrease in its rate of accumulation in tissues.


Assuntos
Angioceratoma/enzimologia , Artrite/enzimologia , Glicolipídeos/metabolismo , Glicosídeo Hidrolases/sangue , Erros Inatos do Metabolismo Lipídico/enzimologia , Plasma/enzimologia , Adolescente , Adulto , Cerebrosídeos/sangue , Cerebrosídeos/uso terapêutico , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Esclerose Cerebral Difusa de Schilder/enzimologia , Fator VIII/metabolismo , Feminino , Doença de Gaucher/enzimologia , Glicolipídeos/sangue , Glicosídeo Hidrolases/uso terapêutico , Humanos , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Lipidoses/enzimologia , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Sulfatases/uso terapêutico , Doenças de von Willebrand/tratamento farmacológico
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