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Targeting the complement cascade: novel treatments coming down the pike.

ABSTRACT: The complement cascade is a vital component of both the innate and adaptive immune systems. Complement activation also contributes to the pathogenesis of many diseases, however, and the kidney is particularly susceptible to complement-mediated injury. Drugs that block complement activation can rapidly reduce tissue inflammation and also attenuate the adaptive immune response to foreign and tissue antigens. Eculizumab is a monoclonal antibody that prevents the cleavage of C5. It has been approved for the treatment of atypical hemolytic uremic syndrome, and it has been used in selected patients with other kidney diseases. Many additional drugs are also in development for blocking the complement cascade, including new monoclonal antibodies, recombinant proteins, small molecules, and small interfering RNA agents. Validation of these new drugs as effective treatments for kidney diseases faces several challenges. Many complement-mediated kidney diseases are rare, so it is not feasible to test all of the new drugs in numerous different rare diseases. The onset and course of the diseases are heterogeneous; many of these diseases also carry a lifelong risk of recurrence, and it is not clear how long complement inhibition must be maintained. In spite of these challenges, new therapeutic options for targeting the complement system will likely become available in the near future and may prove useful for treating patients with kidney disease.

SUBMITTER: Thurman JM

PROVIDER: S-EPMC5026560 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Targeting the complement cascade: novel treatments coming down the pike.

Thurman Joshua M JM Le Quintrec Moglie M

Kidney international 20160618 4

The complement cascade is a vital component of both the innate and adaptive immune systems. Complement activation also contributes to the pathogenesis of many diseases, however, and the kidney is particularly susceptible to complement-mediated injury. Drugs that block complement activation can rapidly reduce tissue inflammation and also attenuate the adaptive immune response to foreign and tissue antigens. Eculizumab is a monoclonal antibody that prevents the cleavage of C5. It has been approved ...[more]

PMID: 27325183

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Project description:Overexpression of Dual-specificity tyrosine-phosphorylated regulated kinase 1A (DYRK1A), located on human chromosome 21, may alter molecular processes linked to developmental deficits in Down syndrome (DS). Trisomic DYRK1A is a rational therapeutic target, and although reductions in Dyrk1a genetic dosage have shown improvements in trisomic mouse models, attempts to reduce Dyrk1a activity by pharmacological mechanisms and correct these DS-associated phenotypes have been largely unsuccessful. Epigallocatechin-3-gallate (EGCG) inhibits DYRK1A activity in vitro and this action has been postulated to account for improvement of some DS-associated phenotypes that have been reported in preclinical studies and clinical trials. However, the beneficial effects of EGCG are inconsistent and there is no direct evidence that any observed improvement actually occurs through Dyrk1a inhibition. Inconclusive outcomes likely reflect a lack of knowledge about the tissue-specific patterns of spatial and temporal overexpression and elevated activity of Dyrk1a that may contribute to emerging DS traits during development. Emerging evidence indicates that Dyrk1a expression varies over the life span in DS mouse models, yet preclinical therapeutic treatments targeting Dyrk1a have largely not considered these developmental changes. Therapies intended to improve DS phenotypes through normalizing trisomic Dyrk1a need to optimize the timing and dose of treatment to match the spatiotemporal patterning of excessive Dyrk1a activity in relevant tissues. This will require more precise identification of developmental periods of vulnerability to enduring adverse effects of elevated Dyrk1a, representing the concurrence of increased Dyrk1a expression together with hypothesized tissue-specific-sensitive periods when Dyrk1a regulates cellular processes that shape the long-term functional properties of the tissue. Future efforts targeting inhibition of trisomic Dyrk1a should identify these putative spatiotemporally specific developmental sensitive periods and determine whether normalizing Dyrk1a activity then can lead to improved outcomes in DS phenotypes.

Dataset Information

Targeting the complement cascade: novel treatments coming down the pike.

Publications

Targeting the complement cascade: novel treatments coming down the pike.

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