# Targeting FSH for the Therapy of Osteoporosis, Obesity and Neurodegeneration

> **NIH NIH U19** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $804,105

## Abstract

PROJECT SUMMARY
 We and others have shown that blocking FSH action either pharmacologically or genetically prevents both
osteoporosis and obesity [e.g. Cell, 2006, PMID: 16630814; Nature, 2017, PMID: 28538730]1-7. More recently,
we reported that FSH also acts on hippocampal neurons to trigger neurodegeneration in Alzheimer's disease
(AD) mice, and that blocking FSH action prevents the onset of AD–like features [Nature, 2022, PMID:
35236988]8. Towards intercepting FSH actions on bone, body fat and brain, we recently developed a therapeutic
FSH–blocking antibody––MS-Hu6––that acts by binding to a 13–amino–acid–long epitope on FSHβ to prevent
its access to the FSH receptor (FSHR)9. Towards its future use in people, MS-Hu6 has undergone early–stage
testing. We find that it has a high affinity for FSH (KD=7,52 nM), displays a β phase t1/2 of 7.5 days, distributes
to bone, fat and brain, is safe when injected into monkeys, and is thermostable [PNAS, 2020, PMD: 33127753;
eLife, 2022, PMID: 36125123]2,9. The NIA–sponsored SWAN Study teaches us that, during the menopausal
transition, when serum FSH rises in the face of unperturbed estrogen, there is a sharp reduction in bone mass,
onset of visceral adiposity, and spikes in cognitive decline10-12. We believe that MS-Hu6 could potentially be
used to prevent three diseases of public health magnitude—all at once––within this FSH–high/estrogen–replete
window. A broader question, however, arises whether, in addition to preventing their onset, can MS-Hu6 be
purposed for treating established osteoporosis, obesity and AD—the armamentarium of therapies for which
pales in comparison to that for diabetes, hypertension or cancer. Contemporaneously reproduced in the Rosen
lab, we find that MS-Hu6 does stimulate new bone formation, and, in doing so, reverses lost bone in young mice.
We hypothesize that MS-Hu6 will not only prevent, but also cure established osteoporosis, obesity and AD in
aged mice. For this, we will use a two–pronged approach for blocking FSH action: pharmacologic by MS-Hu6
and/or genetic by abrogating the Fshr conditionally in 18–month–old mice. Specific Aim 1 will study the effects
of this strategy by comprehensively phenotyping skeletons of old gonadectomized male and female mice
following FSH blockade. In Specific Aim 2, we will induce obesity in old mice and administer MS-Hu6 or delete
FSHRs globally, followed by detailed body composition and metabolic studies, with the expectation of achieving
a lean, thermogenic phenotype. For Specific Aim 3, we will age APP-KI mice, which harbor human APP
substitutions, and begin injecting MS-Hu6 once deficits in cued and recognition memory set in—followed by
detailed neurophenotyping. Together, these studies should not only allow us to understand how aging bone, fat
tissue and brain respond to FSH perturbations, but also provide proof–of–concept for future clinical studies.
These experiments will be performed on our Good Laboratory Practice (GLP) Platform [per...

## Key facts

- **NIH application ID:** 10764104
- **Project number:** 2U19AG060917-06
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Mone Zaidi
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $804,105
- **Award type:** 2
- **Project period:** 2019-02-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764104

## Citation

> US National Institutes of Health, RePORTER application 10764104, Targeting FSH for the Therapy of Osteoporosis, Obesity and Neurodegeneration (2U19AG060917-06). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10764104. Licensed CC0.

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