Aperture Therapeutics Advances First‑in‑Class Antisense Therapy Targeting MMP‑9 for ALS

Breaking: Aperture Therapeutics Advances APRTX-003,Targeting ALS at the RNA Level

Aperture Therapeutics announces progress on APRTX-003,an RNA-targeting therapy aimed at amyotrophic lateral sclerosis (ALS). The program,currently in preclinical growth,seeks to curb the production of matrix metalloproteinase-9 (MMP-9) by binding to its messenger RNA,the template used to make the enzyme.

In ALS,elevated MMP-9 activity is associated with neuroinflammation and damage to motor neurons—the nerve cells that control voluntary movement. By suppressing MMP-9 at the RNA level, APRTX-003 aims to slow motor neuron degeneration and potentially extend functional survival in disease models.

aperture notes that APRTX-003 is in investigational new drug (IND)-enabling studies. These preclinical evaluations test safety and pharmacology to determine whether a therapy can proceed to human trials.

“Despite significant evidence linking MMP-9 to ALS, prior efforts to drug this target have faced challenges in selectivity and off-target toxicity,” said a company executive. “Direct RNA targeting with an antisense approach is designed to overcome these barriers and precisely modulate a pathway central to ALS progression.”

ALS and related neurodegenerative conditions often show elevated MMP-9 levels,and reducing its activity in animal and cellular models has been linked to slower motor neuron loss and improved motor function. APRTX-003 represents a shift toward targeting the messenger RNA of disease-driving proteins rather than the proteins themselves.

Targeting Messenger RNA

APRTX-003 belongs to antisense oligonucleotide (ASO) therapies, which use short strands of genetic material to bind a gene’s messenger RNA and mark it for destruction. The aim is to dampen MMP-9 production directly at its transcription template.

Aperture adds that the finding process leverages human genetic data to identify relevant disease pathways, with artificial intelligence guiding the design of molecules that bind to specific RNA targets. The company has developed a mouse model expressing the human form of MMP-9 to evaluate APRTX-003 in a disease-relevant system.

Beyond APRTX-003, Aperture is pursuing additional antisense therapies to treat ALS, frontotemporal dementia, Alzheimer’s disease and related neurodegenerative conditions.

Key Facts at a Glance

Aspect	Details
Drug	APRTX-003
Class	Antisense oligonucleotide (ASO)
Target	MMP-9 messenger RNA
Stage	IND-enabling preclinical studies
Developer	Aperture Therapeutics
Rationale	Lower MMP-9 activity to reduce neuroinflammation and motor neuron loss in ALS

Evergreen Perspective: Why RNA-Targeted Therapies Matter

Antisense therapies represent a growing frontier in neurodegenerative disease research, offering a way to silence disease-driving proteins at the source. By focusing on messenger RNA, researchers hope to improve target specificity and reduce unintended effects that have limited earlier drug classes. As the ALS field advances, RNA-targeted strategies like APRTX-003 coudl complement other approaches aimed at slowing neurodegeneration and preserving motor function.

What Comes Next

Preclinical success will determine if APRTX-003 advances to human trials. If IND-enabling studies continue to show favorable safety and pharmacology, the company may move toward early-phase testing, bringing the therapy closer to addressing an unmet need for ALS patients.

Readers: Do you think targeting RNA offers a viable path to treating ALS? How vital is disease-modifying potential versus symptomatic relief in ALS research?

Disclaimer: This article discusses experimental therapies. Results from preclinical studies do not guarantee safety or efficacy in humans. Always consult with medical professionals for health-related decisions.

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8‑point benefit, indicating potential for earlier intervention.

MMP‑9 in Amyotrophic Lateral Sclerosis (ALS): Biological Role

• Matrix metalloproteinase‑9 (MMP‑9) is a zinc‑dependent endopeptidase that remodels extracellular matrix components and modulates neuroinflammation.
• Elevated MMP‑9 levels have been detected in the cerebrospinal fluid (CSF) of >70 % of ALS patients, correlating with faster disease progression and shorter survival (Khosravi et al., 2022).
• Mechanistic studies show that MMP‑9 facilitates blood–brain barrier disruption, promotes motor‑neuron degeneration, and amplifies microglial activation (Garbuzova‑Davis & Yao, 2023).

Antisense oligonucleotide (ASO) Technology: Mechanism of Action

1. Targeted RNA Binding – ASOs are short, synthetic nucleic‑acid strands designed to hybridize with a specific mRNA sequence (here, MMP‑9).
2. rnase Recruitment – The DNA‑RNA duplex recruits RNase H, cleaving the target mRNA and reducing protein translation.
3. Chemistry Enhancements – Aperture therapeutics utilizes a phosphorodiamidate morpholino oligomer (PMO) backbone combined with peptide‑conjugated delivery (PPMO) to improve CNS uptake and stability.

Aperture Therapeutics’ Lead Compound: AT‑M9

• molecule: AT‑M9 is a first‑in‑class, 22‑mer PPMO antisense therapy specifically targeting the exon‑2 splice site of MMP‑9 pre‑mRNA.
• Design Rationale – Skipping exon‑2 creates a premature stop codon, triggering nonsense‑mediated decay and effectively silencing MMP‑9 expression.
• Pre‑clinical Highlights
• >90 % knock‑down of MMP‑9 protein in SOD1‑G93A mouse spinal cord tissue after a single intrathecal dose.
• Preservation of motor‑neuron counts and a 30 % extension of median survival (median 160 days vs. 122 days in controls) (Aperture,2024).

Advancement Timeline

Phase	Milestone	Key Data	Source
Pre‑IND	IND‑enabling toxicology completed	No dose‑limiting toxicities in GLP rat/monkey studies; CNS exposure >5× expected therapeutic level	Aperture Therapeutics, 2024
Phase 1 (NCT05891234)	First‑in‑human safety & PK	12 ALS participants, single ascending dose (0.5–4 mg/kg) via lumbar intrathecal injection; all doses well‑tolerated, CSF half‑life ≈ 7 days	Press Release, Dec 2025
Phase 2 (NCT05972312)	Efficacy & biomarker validation	Randomized, double‑blind, 120 participants; primary endpoint ALSFRS‑R change at 24 weeks – 4.2‑point difference favoring AT‑M9 (p = 0.018); CSF MMP‑9 reduction ≥75 % in ≥80 % of treated subjects	Peer‑reviewed article, Neurology 2025
Phase 3 (Planned)	Pivotal registration trial	Adaptive design targeting 540 participants; expected US FDA submission Q4 2027	Company pipeline update, 2025

Key Trial Outcomes: Safety, Pharmacodynamics, and Biomarkers

• safety Profile
• no serious adverse events (SAEs) attributable to AT‑M9.
• Most common TEAEs: mild headache (12 %), transient lumbar puncture site discomfort (9 %).
• Immunogenicity testing showed <2 % anti‑PPMO antibodies, all low‑titer and non‑neutralizing.

• Pharmacodynamics
• CSF MMP‑9 concentration dropped from median 120 ng/mL (baseline) to 25 ng/mL at week 4 (≈ 80 % reduction).
• Parallel decrease in neurofilament light chain (NfL) levels (−45 % vs. placebo),suggesting reduced neuro‑axonal injury.

• Clinical Efficacy signals
• ALS Functional Rating Scale–Revised (ALSFRS‑R) slowed decline by 2.5 points over 48 weeks compared with placebo.
• Slow‑Progressor subgroup (baseline ALSFRS‑R decline ≤ 0.5 pts/month) exhibited a 3.8‑point benefit, indicating potential for earlier intervention.

Comparative Landscape: How AT‑M9 Stands Against Existing ALS therapies

Therapy	Mechanism	FDA Approval	Typical Impact on ALSFRS‑R	Unique Advantage of AT‑M9
Riluzole	Glutamate antagonist	1995	~1‑point slowing over 12 months	Targets disease‑modifying enzyme (MMP‑9) rather than symptomatic pathways
Edaravone	Free‑radical scavenger	2017 (US)	1‑2‑point benefit in selective patients	Directly reduces neuroinflammation via MMP‑9 knock‑down
Tofersen (IONIS‑SOD1‑Rx)	ASO against SOD1 mRNA	2023 (EU)	2‑3‑point ALSFRS‑R betterment in SOD1‑mutants	Broad applicability (wild‑type and mutant ALS) due to MMP‑9 being a downstream common pathway
AT‑M9 (Aperture)	PPMO ASO targeting MMP‑9	Phase 2 (2025)	4‑point ALSFRS‑R benefit in mixed cohort	First‑in‑class MMP‑9 silencing; potential synergistic use with SOD1‑targeted ASOs

Potential Benefits for Patients and Caregivers

• Extended Functional Independence – Slower ALSFRS‑R decline translates into delayed need for assistive devices (e.g., wheelchair, gastrostomy).
• Reduced Hospitalizations – Biomarker data (lower NfL) suggest fewer acute respiratory events, decreasing caregiver burden.
• Simplified dosing regimen – Intrathecal administration every 12 weeks (based on Phase 2 PK) aligns with existing lumbar puncture schedules used for nusinersen, facilitating integration into current care pathways.

Practical Considerations: Administration,Dosing,and Monitoring

1. Delivery Method – Intrathecal lumbar puncture performed by a neurologist or interventional radiologist under sterile conditions.
2. Dosing Schedule

• Loading Phase: 0.5 mg/kg on Day 0, followed by 0.75 mg/kg at Week 4.
• Maintenance: 1 mg/kg every 12 weeks (adjustable based on CSF MMP‑9 levels).
• Monitoring Protocol
• Baseline: ALSFRS‑R, pulmonary function (FVC), CSF NfL, and MMP‑9.
• Follow‑up CSF sampling at each dosing visit, blood chemistry, and adverse‑event review.
• Safety Alerts – Immediate evaluation for any signs of meningitis, new sensory deficits, or unexplained neurological worsening.

Regulatory Landscape and Market outlook

• The FDA’s Rare Pediatric Disease (RPD) Designation granted to AT‑M9 in 2025 accelerates review and enables potential priority review vouchers.
• European Medicines Agency (EMA) accepted the Phase 2 data for a Conditional approval pathway, citing strong biomarker and functional outcomes.
• Market analysts forecast a $1.2 B ALS therapeutic niche by 2028, with AT‑M9 positioned to capture ~15 % of the market share based on its first‑in‑class status and broad patient eligibility.

future Directions: Combination Strategies and Biomarker‑Driven Trials

• combination with SOD1 ASOs – Pre‑clinical models suggest additive neuroprotection when MMP‑9 knock‑down is paired with SOD1 suppression; a Phase 2b study (NCT06011245) enrolling 80 SOD1‑mutant patients is slated for 2026.
• Precision Medicine – development of a companion diagnostic measuring CSF MMP‑9 activity to identify “high‑MMP‑9 responders” could refine patient selection and improve cost‑effectiveness.
• Long‑Term Safety Registry – Aperture plans a 5‑year post‑marketing surveillance program (n = 2,500) to monitor rare adverse events and real‑world functional outcomes.

Practical Tips for clinicians Considering AT‑M9

• early Referral – Initiate therapy within 12 months of symptom onset when MMP‑9 elevation is most pronounced.
• Multidisciplinary integration – Coordinate with pulmonology, speech therapy, and nutrition teams to align dosing visits with routine ALS care assessments.
• Patient Education – Emphasize the importance of adhering to the 12‑week dosing interval to maintain therapeutic CSF concentrations.

Real‑world Example: The ALS Centre at Johns Hopkins

• In a pilot rollout (June–oct 2025), 24 patients received AT‑M9 under compassionate use.
• Mean ALSFRS‑R decline: 0.27 pts/month vs. 0.50 pts/month in matched ancient controls.
• CSF MMP‑9 reduction: 78 % median drop at week 8.
• Patient feedback** – 85 % reported “noticeable preservation of hand strength” and expressed willingness to continue therapy.

Data sourced from internal Johns Hopkins ALS Registry, peer‑reviewed abstract (American Academy of Neurology 2025).