# Targeting aldose reductase: A Phase IIb/III trial for the novel use of Epalrestat to treat Congenital Disorders of Glycosylation (PMM2-CDG)

> **NIH NIH R44** · MAGGIE'S PEARL, LLC · 2022 · $699,884

## Abstract

SUMMARY
Congenital Disorders of Glycosylation (CDG) is a group of over 150 diseases characterized by limited ability to
attach glycans to proteins and lipids. The most common form, loss of phosphomannose mutatase-2 activity
(PMM2-CDG), is an orphan disease affecting approximately 1500 patients worldwide. CDG typically presents as
severe disease in the first few years of life and is lethal in 20% of infantile cases. Children with PMM2-CDG have
a range of symptoms, including hypotonia, ataxia, neuropathy, severely delayed language and motor
development, inability to walk, and IQ of 40 to 70. Adult patients display mild to severe physical and mental
disabilities.
Current treatment for CDG consists only of palliative care. No therapeutic is approved for use. Replacement
therapies with monosaccharides, such as mannose-1-phosphate, galactose, fucose, as well as other dietary
supplements, have shown little efficacy in PMM2-CDG. Severity of disease is correlated with degree of enzyme
loss: <7% enzyme activity is lethal, whereas >50% activity yields no symptoms.
Maggie’s Pearl has discovered several compounds that increase the activity of the mutant PMM2 enzyme in
several models of PMM2-CDG, including fibroblasts derived from PMM2 patients. Many of these compounds are
aldose reductase inhibitors (ARIs), and one of them, Epalrestat, appears to be a safe drug candidate. It has been
used for over 27 years in Japan for treatment of diabetic neuropathy in adults. However, the drug is not approved
for any indication in the US.
Maggie’s Pearl has tested Epalrestat in a single-patient trial. The young patient showed positive results after just
4 months of treatment, with no adverse effects after 18 months of Epalrestat. The proposed SBIR will expand
this study to a double blind, single-crossover trial of 30 childhood PMM2-CDG patients over the course of three
years. Similar success of Epalrestat in this trial would offer life-changing improvements for patients worldwide.

## Key facts

- **NIH application ID:** 10480649
- **Project number:** 1R44DK131708-01A1
- **Recipient organization:** MAGGIE'S PEARL, LLC
- **Principal Investigator:** Ethan Perlstein
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $699,884
- **Award type:** 1
- **Project period:** 2022-05-03 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10480649

## Citation

> US National Institutes of Health, RePORTER application 10480649, Targeting aldose reductase: A Phase IIb/III trial for the novel use of Epalrestat to treat Congenital Disorders of Glycosylation (PMM2-CDG) (1R44DK131708-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10480649. Licensed CC0.

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