# VAL-0914 Decreases PAO to Protect Against Cardiac Proteinopathies

> **NIH NIH R41** · ENABLE THERAPEUTICS LLC · 2021 · $450,022

## Abstract

PROJECT SUMMARY
Soluble pre-amyloid oligomers (PAO) are the most potent mediators of cytotoxicity, despite common focus on
autophagy as a means to clear larger misfolded protein aggregates. Specifically, PAO, rather than aggresomes,
are most correlated with desmin-related cardiomyopathy (DRC) caused by an Arg120Gly missense mutation of
αB-Crystallin (CryABR120G). In addition to causing DRC, emerging evidence suggests that increased PAO and
resulting proteotoxic stress play an important role in the progression from a large subset of heart diseases to
heart failure, a common condition in the United States. Despite substantial progress in our understanding of PAO
and related diseases, no experimental therapeutics exist that clear these toxic species from the cytoplasm.
Notably, a recent study demonstrated that up-regulation of myocardial Neprilysin (NEP) protein levels was
implicated as a major mediator for voluntary exercise to reduce misfolded cytotoxic protein levels and slow down
disease progression in a model of DRC. Treatment of cardiac proteinopathies such as DRC by increasing cardiac
NEP levels to reduce PAO levels appears to be a promising therapeutic strategy.
In order to deliver NEP to the cytoplasm of heart muscle cells, Valerion Therapeutics uses a commercializable
cell-penetrating 3E10 antibody Fab fragment that is uniquely capable of delivering full-length protein cargo to the
cytoplasm. 3E10 gains entry to the cells via the equilibrative nucleoside transporter 2 (ENT2; SLC29A2), a
receptor found in many cell types but is highly expressed in skeletal and cardiac muscle. We are currently testing
several Fab fusions, including Fab-GAA (VAL-1221) that recently demonstrated positive Phase 1 clinical results
in Pompe disease (NCT02898753). Valerion has recently developed a new Fab fusion protein with NEP (VAL-
0914) that is uniquely capable of penetrating cells and degrades overexpressed cytoplasmic beta-amyloid(1-42).
Therefore, VAL-0914 presents an innovative therapeutic strategy to treat cardiac proteinopathies such
as desmin-related cardiomyopathy by delivering active NEP to the cytoplasm of affected cells.
The proposed research in phase I will focus on (Aim 1) in vitro characterization of VAL-0914 in cultured
cardiomyocyte and mouse heart models of cardiac proteinopathy to establish mechanistic proof-of-concept and
(Aim 2) in vivo characterization of VAL-0914 effects on heart function and misfolded protein clearance in a mouse
model of cardiac proteinopathy to establish preclinical models for subsequent IND-enabling phase II studies. A
successful outcome of this work will create an immediate actionable impact on underserved cardiac
proteinopathy patient populations such as those with DRC and a subset of heart failure patients.

## Key facts

- **NIH application ID:** 10138203
- **Project number:** 1R41HL152919-01A1
- **Recipient organization:** ENABLE THERAPEUTICS LLC
- **Principal Investigator:** Robert Shaffer
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $450,022
- **Award type:** 1
- **Project period:** 2021-02-16 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138203

## Citation

> US National Institutes of Health, RePORTER application 10138203, VAL-0914 Decreases PAO to Protect Against Cardiac Proteinopathies (1R41HL152919-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10138203. Licensed CC0.

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