# Autosomal Dominant Osteopetrosis: A Natural History Study

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $255,022

## Abstract

Abstract NIAMS Natural Hx Proposal
Abstract
Autosomal dominant osteopetrosis type 2 (ADO2) is a rare osteosclerotic disorder resulting from impaired
osteoclastic bone resorption most commonly due to mutations in the Chloride Channel 7 gene, which cause
disease by a dominant negative mechanism. Penetrance is approximately 66% and disease severity varies
widely. Affected individuals typically have at least one significant clinical manifestation including fractures,
osteonecrosis, osteomyelitis, blindness, or bone marrow failure. Ten of our patients have died (out of >80 with
clinical manifestations) either of disease manifestations or from attempts at therapy for severe disease. The
natural progression of disease manifestations in ADO2 is unknown, although limited data suggests that the
disease gets worse with age. Although no effective therapy is currently available, studies in animal models
have generated promising data and human trials on are on the horizon. Therefore, it is imperative to
understand the natural history of ADO2, including reliable biological markers and relevant patient centered
outcomes, to measure therapeutic effect, and to guide the design of clinical trials. The proposed natural history
study will establish a cohort of serially phenotyped subjects to capture clinically important outcomes and
characterize variations in disease severity, progression of disease, and novel biomarkers for current or future
disease severity. The goals of this study are to 1) identify clinically relevant biological and patient-reported
outcomes; and 2) use previously obtained data along with data obtained during this 3-year study to determine
the natural history of ADO2, including the rate of disease progression. We will focus on the following specific
aims:
Specific Aim 1: Determine key markers of disease severity and endpoints for a clinical trial.
A. Refine and validate a composite clinical severity grading scale.
B. Determine which clinical, biological, radiological, and densitometric endpoints best define current disease
 severity and predict future disease severity and outcomes (combining samples and data obtained in our
 prior studies with new prospective serial measurements in participating subjects).
C. Test the hypothesis that ADO2 disease severity gets worse with age.
Specific Aim 2: Expand an electronic patient registry, to collect population-based, longitudinal quality-of-life,
pain, disability and other survey-based data from any individual with osteopetrosis, using a secure REDCap
platform. This registry will provide 1) long-term follow-up data continuing beyond the completion of this grant,
2) validation of the ADO2 clinical severity grading scale developed in Aim 1, and 3) be an additional ongoing
source of potential recruits to future studies using novel therapies.

## Key facts

- **NIH application ID:** 10881270
- **Project number:** 1R01AR084202-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Michael J Econs
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $255,022
- **Award type:** 1
- **Project period:** 2024-05-17 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881270

## Citation

> US National Institutes of Health, RePORTER application 10881270, Autosomal Dominant Osteopetrosis: A Natural History Study (1R01AR084202-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10881270. Licensed CC0.

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