# Complementopathies: Genotype and Phenotype

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $405,000

## Abstract

The overall goal of this project is to develop a personalized approach to the diagnosis and
treatment of human blood diseases where pathophysiology is driven by the alternative pathway
of complement (APC). The APC is an important driver of thrombotic microangiopathies (TMA)
including atypical hemolytic uremic syndrome (aHUS), post-transplant TMAs (ptTMA), hemolysis,
elevated liver function tests, and low platelets (HELLP) syndrome and hypercoagulable states
such as antiphospholipid antibody syndrome (APS) and catastrophic antiphospholipid antibody
syndrome (CAPS). For this proposal we refer to these closely related diseases as
“complementopathies”. Germline mutations in the genes that regulate the APC are found in up to
50% of patients with aHUS and have also been reported in ptTMAs, HELLP, and APS/CAPS.
Unfortunately, the functional consequence of these mutations is not always clear. Terminal
complement inhibition with eculizumab is highly effective for treating aHUS but is not used
routinely because of difficulty in distinguishing aHUS and thrombotic thrombocytopenic purpura
(TTP) and because of the high cost of the drug (~$600,000) annually. There are case reports of
eculizumab being effective in treating ptTMAs, HELLP, and APS/CAPS. Currently, the
pathophysiology of HELLP syndrome, APS/CAPS, and ptTMAs remains obscure and there are
no FDA approved drugs to treat these often fatal or highly morbid diseases. Recently, we
developed a novel serum based assay, modified HAM test, which is highly sensitive and specific
for detecting systemic activation of the APC; the assay is also highly effective in distinguishing
aHUS from thrombotic thrombocytopenic purpura (TTP). We also demonstrate that continued
administration of eculizumab is unnecessary in most aHUS cases if therapy is instituted rapidly.
Our new preliminary data demonstrate that systemic activation of the APC is also a driver of the
HELLP syndrome, APS/CAPS and ptTMAs. In this project we endeavor to solve the most pressing
needs in the field of complement-driven TMAs (aHUS, HELLP, APS/CAPS etc) by: 1) establishing
a rapid diagnosis; 2) predicting which patients will benefit most from complement inhibition
(precision medicine); 3) linking the genotype and phenotype of complementopathies; and 4)
defining “innocent versus guilty” autoantibodies in APS/CAPS. Therefore, this laboratory research
project is hypothesis-driven, translational, and goal-oriented. If successful, our proposal will open
the door to precision medicine for TMAs and potentially APS/CAPS.

## Key facts

- **NIH application ID:** 9927661
- **Project number:** 5R01HL133113-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** ROBERT A BRODSKY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927661

## Citation

> US National Institutes of Health, RePORTER application 9927661, Complementopathies: Genotype and Phenotype (5R01HL133113-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9927661. Licensed CC0.

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