A Growth Hormone-Releasing Hormone Agonist Improves Muscle and Nerve Health in Spinal Muscular Atrophy Mice | Research

The takeaway

Daily treatment with the GHRH agonist MR-409 improved body weight, motor behavior, muscle health, and motor neuron survival in a mouse model of spinal muscular atrophy.

Multi-system improvement in SMA mice
MR-409 simultaneously protected muscles, improved nerve-muscle connections, and delayed motor neuron death — targeting multiple aspects of SMA pathology

What the researchers found

Daily subcutaneous MR-409 treatment from postnatal day 2 to day 12 in SMNΔ7 SMA mice produced multiple beneficial effects, particularly at 2 mg/kg:

- Increased body weight and improved motor behavior

- Reduced muscle atrophy with increased fiber size in quadriceps and gastrocnemius

- Upregulated myogenic genes and inhibited proteolytic (muscle-degrading) pathways

- Promoted neuromuscular junction maturation (fewer multi-innervated endplates, more mono-innervated)

- Delayed alpha motor neuron death in the spinal cord

- Reduced neuroinflammation in the spinal cord

The breadth of effects — spanning muscle, nerve, and immune pathways — suggests GHRH agonists target multiple aspects of SMA pathology simultaneously.

Why it matters

Current SMA treatments focus on increasing SMN protein production through gene therapy or splice-modifying drugs. While revolutionary, these treatments don't fully correct the disease in all patients. GHRH agonists like MR-409 work through a completely different mechanism — protecting muscles and neurons independently of SMN levels. Combining GHRH agonists with existing SMN-targeted therapies could potentially achieve more complete disease control than either approach alone.

The numbers in context

1 or 2 mg/kg MR-409 daily; P2-P12 treatment; increased body weight, fiber size, NMJ maturation; delayed motor neuron death; reduced neuroinflammation

How the study worked

SMNΔ7 mice (established severe SMA model) received daily subcutaneous MR-409 at 1 or 2 mg/kg from postnatal day 2 to day 12. Outcomes included body weight, motor behavior testing, muscle histology (fiber size in quadriceps and gastrocnemius), gene expression analysis (myogenic and proteolytic pathways), neuromuscular junction maturation assessment (innervation patterns), spinal cord motor neuron counts, and neuroinflammation markers.

Who was studied

SMNΔ7 mice (neonatal model of severe spinal muscular atrophy)

What this study cannot tell us

Mouse model only; short 10-day treatment window; severe SMA model with short lifespan; no survival data in abstract; no comparison with current SMA therapies; long-term effects unknown.

How to read the evidence

Well-designed preclinical study published in PNAS using an established SMA mouse model with dose-response analysis and multiple outcome measures. However, it remains an animal study with no human data, placing it at moderate-preclinical evidence strength.

When this study was published

Published in 2023, this is recent research. GHRH agonists for SMA are still at the preclinical stage, but the results provide a rationale for advancing toward clinical investigation.

The bigger picture

This study represents part of a broader effort to find complementary treatments for SMA beyond SMN gene restoration. GHRH agonists are known to have protective effects across multiple tissues — muscle, heart, brain — making them potentially useful in multi-system diseases like SMA. Published in PNAS, this work from Andrew Schally's group (a Nobel laureate for GHRH research) lends credibility to the GHRH agonist approach and could open a new therapeutic avenue for neuromuscular diseases.

Questions still open

Would combining MR-409 with existing SMN-targeted therapies (nusinersen, onasemnogene) produce additive benefits?
Does MR-409 extend lifespan in SMA mice, or only improve quality of life during the treatment period?
Could GHRH agonists benefit other motor neuron diseases like ALS?

Common questions

What is spinal muscular atrophy and how is it currently treated?

SMA is a genetic disease caused by mutations in the SMN1 gene that leads to death of motor neurons and progressive muscle weakness. It primarily affects infants and children. Current treatments include nusinersen (Spinraza), onasemnogene abeparvovec (Zolgensma), and risdiplam (Evrysdi), all of which work by increasing SMN protein levels. While transformative, these treatments don't fully correct the disease in all patients.

How would a GHRH agonist help SMA patients differently than current treatments?

Current SMA drugs target the genetic root cause by boosting SMN protein. A GHRH agonist like MR-409 works through a completely different pathway — directly protecting muscles from wasting, promoting healthy nerve-muscle connections, and reducing inflammation. It addresses the downstream damage rather than the upstream genetic defect. The idea would be to use both approaches together for more complete disease management.

Read the original research

Agonist of growth hormone-releasing hormone improves the disease features of spinal muscular atrophy mice.

Proceedings of the National Academy of Sciences of the United States of America, 120(2), e2216814120

View on PubMed ↗Publisher’s paper ↗

Citation

Boido, Marina; Gesmundo, Iacopo; Caretto, Anna; Pedrolli, Francesca; Schellino, Roberta; Leone, Sheila; Cai, Renzhi; Sha, Wei; Ghigo, Ezio; Schally, Andrew V; Vercelli, Alessandro; Granata, Riccarda. (2023). Agonist of growth hormone-releasing hormone improves the disease features of spinal muscular atrophy mice.. Proceedings of the National Academy of Sciences of the United States of America, 120(2), e2216814120. https://doi.org/10.1073/pnas.2216814120