Polymer-doxycycline conjugates as fibril disrupters: An approach towards the treatment of a rare amyloidotic disease

Conejos‐Sánchez, Inmaculada; Cardoso, Isabel; Oteo, Marta; Romero, Eduardo; Paul, Alison; Saurı́, Ana; Morcillo, Miguel A.; Saraiva, Maria João; Vicent, Marı́a J.

doi:10.1016/j.jconrel.2014.12.003

Cited by 27 publications

(17 citation statements)

References 46 publications

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“…Ursodeoxycholic acid is a bile acid with an efficacy similar to that of tauroursodeoxycholic acid and has been used as an alternative in some studies . Chemical modifications, such as polymer‐conjugation of doxycycline, even bear the potential for further improvements of those effects …”

Section: Current Pharmaceutical Approaches In the Treatment Of Attr (mentioning

confidence: 99%

“…67 Chemical modifications, such as polymer-conjugation of doxycycline, even bear the potential for further improvements of those effects. 68 A phase 2 study (n = 20) on ATTRv and -wt patients with daily administration of oral doxycycline (100 mg) and tauroursodeoxycholic acid (3 × 250 mg), reported stable disease over the duration of 12 months. 69…”

Section: Doxycycline and Tauroursodeoxycholic Acidmentioning

confidence: 99%

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Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

Müller

Butler

Heidecker

2020

European J of Heart Fail

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Transthyretin amyloidosis (ATTR) is a rare, yet underdiagnosed disease characterized by progressive impairment of neurologic and cardiac function due to deposition of misfolded transthyretin. Despite great efforts, such as the introduction of orthotopic liver transplant, the devastating prognosis for both variant and wild‐type ATTR patients remained unchanged over the last decades, mainly due to a lack of specific therapies. Fortunately, recent years saw the introduction of promising targeted therapies, which aim to interfere with the deposition of misfolded transthyretin (TTR) at various stages of the cascade underlying ATTR progression. These include TTR tetramer stabilizers (tafamidis, diflunisal, epigallocatechin‐3‐gallate), TTR silencers (inotersen, patisiran) and fibril disruptors (monoclonal antibodies, doxycycline and tauroursodeoxycholic acid). In the context of this review we explain their mechanisms of action, analyse their efficacy on neurologic and cardiac function based on all clinical trials conducted to date and discuss their clinical applicability. Eventually suggestions for future clinical research into the field are provided.

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Section: Current Pharmaceutical Approaches In the Treatment Of Attr (mentioning

confidence: 99%

Section: Doxycycline and Tauroursodeoxycholic Acidmentioning

confidence: 99%

Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

Müller

Butler

Heidecker

2020

European J of Heart Fail

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“…However, polymer conjugation prevents Dox‐related cardiotoxic effects . Nevertheless, polymer conjugation does not always alter the activity of the conjugated agent and, in some cases (e.g., phloridzin (Prz), doxycycline), drug activity is increased.…”

Section: Key Design Features Of Polypeptide Conjugatesmentioning

confidence: 99%

Polypeptide‐Based Conjugates as Therapeutics: Opportunities and Challenges

Zagorodko

Arroyo‐Crespo

Nebot

et al. 2016

Macromolecular Bioscience

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Synthetic polypeptides or polyamino acids have become a useful and multifunctional platform in advanced drug delivery studies. Nonetheless, the full potential of these systems has yet to be achieved. The final structure of polypeptide conjugates and their in vivo behavior are dependent on an extraordinarily complex pattern of interconnected physico-chemical and structural parameters, making sophisticated directional design of such systems difficult and often unachievable. In this review, the authors aim to discuss the role of these parameters in the successful design of different drug delivery architectures and to delineate some basic correlations between structure, properties, and the biological behavior of polypeptide-based conjugates.

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“…In addition, doxycycline is currently being studied in a phase 2 trial as adjunctive therapy for patients receiving plasma cell-directed therapy for AL amyloidosis ( NCT02207556 ). A modified form of doxycycline covalently linked to poly-L-glutamic acid has been shown to further improve bio-distribution and fibril degradation (Conejos-Sánchez et al, 2015). Further clinical studies will be necessary to determine whether doxycycline shows any benefit, and whether the modified doxycycline has any additional therapeutic benefit.…”

Section: Attr Amyloidosis: Ttr Fibril Disruptersmentioning

confidence: 99%

Novel pharmacotherapies for cardiac amyloidosis

Alexander

Singh

Falk

2017

Pharmacology & Therapeutics

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Amyloidosis refers to a range of protein misfolding disorders that can cause organ dysfunction through progressive fibril deposition. Cardiac involvement often leads to significant morbidity and mortality and increasingly has been recognized as an important cause of heart failure. The two main forms of cardiac amyloidosis, light chain (AL) and transthyretin (ATTR) amyloidosis, have distinct mechanisms of pathogenesis. Recent insights have led to the development of novel pharmacotherapies with the potential to significantly impact each disease. This review will summarize the preclinical and clinical data for these emerging treatments for AL and ATTR amyloidosis.

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Polymer-doxycycline conjugates as fibril disrupters: An approach towards the treatment of a rare amyloidotic disease

Cited by 27 publications

References 46 publications

Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

Polypeptide‐Based Conjugates as Therapeutics: Opportunities and Challenges

Novel pharmacotherapies for cardiac amyloidosis

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