# Development of lysyl oxidase inhibitors for the treatment of fibrosis

> **NIH NIH R43** · ANOVIA, LLC · 2020 · $198,281

## Abstract

SUMMARY
Myeloproliferative disorders (MPD) are chronic myeloid blood disorders that present as clonal
proliferation of one or more myeloid lineages, and are characterized by activating mutations in
the JAK-STAT pathway. There are more than 175,000 MPD patients, such that these are the
most common leukemias observed in the United States. MPD patients have an increased risk of
thrombosis and bleeding, and progress to end stage bone marrow (BM) fibrosis or acute
leukemia. The JAK inhibitors ruxolitinib and, more recently, fedratinib have been approved for
the treatment of myelofibrosis (MF). JAK inhibitor therapy with ruxolitinib, fedratinib, or with
other JAK inhibitors in clinical development ameliorates splenomegaly and constitutional
symptoms in MF patients. However JAK inhibitor therapy does not lead to significant molecular
or pathologic remissions in the majority of MPD patients. This is in contrast to the molecular
responses seen with ABL kinase inhibitors in chronic myeloid leukemia. As such there is a
pressing need for novel therapies to improve outcomes for MPD patients. This proposal is
based on the hypothesis that lysyl oxidase (LOX)-mediated collagen crosslinking and LOX-
driven megakaryocyte proliferation is involved in establishing a growth-permissive fibrotic
microenvironment and that targeting LOX can abrogate the extent to which fibrosis manifests in
MPD patients, and potentially in other diseases with a fibroproliferative component. The
objective of this proposal is to evaluate whether targeting LOX is a potential novel therapeutic
approach to reduce BM fibrosis in MPD patients by performing two specific aims: SA1: To
elucidate cellular mechanisms by which LOX inhibition attenuates fibrosis in MPD. SA2: To
assess the impact of different LOX and LOXL inhibitors on fibrosis, alone and in combination
with JAK inhibitor ruxolitinib. In sum, this proposal aims to improve our understanding of the role
of LOX enzymes in collagen formation in fibrotic BM diseases and to use that knowledge to
develop a novel anti-fibrogenic therapeutic approach for a spectrum of human diseases
associated with pathologic BM fibrosis.

## Key facts

- **NIH application ID:** 10080412
- **Project number:** 1R43HL147651-01A1
- **Recipient organization:** ANOVIA, LLC
- **Principal Investigator:** Maria Kleppe
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $198,281
- **Award type:** 1
- **Project period:** 2020-08-15 → 2022-02-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10080412

## Citation

> US National Institutes of Health, RePORTER application 10080412, Development of lysyl oxidase inhibitors for the treatment of fibrosis (1R43HL147651-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10080412. Licensed CC0.

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