# DDT-BMQ-000079 Establishing Performance Characteristics of the Epidermal Neurite Density (END) Biomarker to Assist Diagnosis of Small Fiber Neuropathy

> **NIH FDA U01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $248,415

## Abstract

In the polyneuropathies, adverse conditions damage the body’s peripheral neurons, causing them to fire
dysfunctionally and sometimes begin to degenerate. Small-fiber neuropathy (SFN) is a very common type.
Many neuropathies, including from diabetes or toxic exposures, often affect the ends of smaller fibers earliest or
most severely. Sensory, chronic tingling, itch, and numbness, typically starting in the feet and lower legs then
spreading upwards are external symptoms of SFN. However, as most of the autonomic axons that innervate and
regulate the body systems are also small-diameter fibers, SFN also causes internal symptoms–intolerance of
usual level of exertion, profound fatigue, lightheadedness, rapid heart rate, and gastrointestinal symptoms.
 SFN is not detected by the standard diagnostic biomarker for large-fiber neuropathies (electromyography
and nerve conduction study). Instead, END (epidermal neurite density) measurements are made from tiny punch
biopsies from the lower leg. Along with clinical indicators, this biomarker is validated to identify suspected
cases. Skin biopsy testing is integral to the first formal case definition of SFN from uncertain cause, formulated
by a global expert ACTTION Committee meeting supported by FDA, NIH, and industry. This group, that
included the P.I., recommended END measurement as mandatory for clinical trial inclusion (Freeman, R. et al.
Neurology, 2020). Hence this request for biomarker qualification for a diagnostic test increasingly used
including for clinical and treatment research, despite sometimes varying methodological details and analyses
between accredited university and commercial U.S. labs. Any inconsistencies increase risk that the same biopsy
could generate different END numbers and/or divergent interpretations. Clinical research studies using END
measurements for inclusion or outcomes might enroll slightly different participants or generate different
efficacy data that could influence FDA approval. In 2022, Dr. Oaklander and others linked SFN to long-COVID
illnesses, so long-COVID studies including NIH’s RECOVER are considering adding END measurement.
 The objective of the proposed studies is to identify and then validate best methods of obtaining and
analyzing the END biomarker. The Aims respond to the applicants’ DDTBMQ000079 LOI approval to generate
a full Biomarker Qualifier Plan. Aim I analyzes anonymized END measurements and other data from a large
US diagnostic skin biopsy lab dataset of healthy controls and patients to identify knowledge gaps, then compare
and validate potential solutions. Aim II adds prospective biopsies where needed. Aim III includes other
stakeholders including outside accredited labs for cross-validation and neurological societies to generate
Guidelines. Standard operating procedures would be improved throughout, and statistical modeling for END
distribution, including selection of variables and algorithms, would be optimized and validated.

## Key facts

- **NIH application ID:** 10619324
- **Project number:** 1U01FD007769-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Anne Louise Oaklander
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** FDA
- **Fiscal year:** 2022
- **Award amount:** $248,415
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10619324

## Citation

> US National Institutes of Health, RePORTER application 10619324, DDT-BMQ-000079 Establishing Performance Characteristics of the Epidermal Neurite Density (END) Biomarker to Assist Diagnosis of Small Fiber Neuropathy (1U01FD007769-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10619324. Licensed CC0.

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