SMA in 2026: From Newborn Screening to Gene Therapy
Three Approved Therapies, Emerging Pipelines, and How Presymptomatic Treatment Is Rewriting the Natural History
- Describe the genetics, pathophysiology, and historical classification of spinal muscular atrophy including the role of SMN1 and SMN2 copy number
- Explain how newborn screening identifies presymptomatic infants and compare developmental outcomes of presymptomatic versus symptomatic treatment
- Compare the three approved SMN-enhancing therapies — nusinersen, onasemnogene abeparvovec, and risdiplam — by mechanism, efficacy, and safety
- Evaluate the evidence supporting combination and sequential treatment strategies using data from ICISS, SAPPHIRE, and real-world registries
- Identify emerging SMN-independent therapies including apitegromab, next-generation gene therapies, and investigational ASOs entering clinical trials
- Apply a multidisciplinary care framework for SMA patients in the treatment era, addressing new phenotypes and long-term monitoring needs
SMA in 2026
From Newborn Screening to Gene Therapy
Medaptly · Pediatric Neurology Series · April 2026
Agenda
Genetics & Pathophysiology
The molecular basis of disease and therapeutic targets
SMA at a Glance
SMN1 vs SMN2: The Molecular Basis
SMN1 Gene
- Produces ~100% full-length SMN protein
- Homozygous deletion/mutation → SMA
- Gene replacement therapy targets this deficit
SMN2 Gene
- C→T transition causes exon 7 skipping
- Produces ~10–15% full-length SMN protein
- Splicing modifiers increase functional output
| SMN2 Copies | Typical SMA Type |
|---|---|
| 1 copy | Type 0/1 (most severe) |
| 2 copies | Type 1 |
| 3 copies | Type 2 or 3 |
| 4+ copies | Type 3, 4, or asymptomatic |
Historical SMA Classification
| Type | Onset | Max Motor Function | SMN2 Copies | Natural History Survival |
|---|---|---|---|---|
| Type 0 | Prenatal | None | 1 | <6 months |
| Type 1 | <6 months | Never sits | 2 | <2 years |
| Type 2 | 6–18 months | Sits, never walks | 3 | Into adulthood |
| Type 3 | >18 months | Walks independently | 3–4 | Normal lifespan |
| Type 4 | Adult | Walks | 4+ | Normal lifespan |
In 2026: This classification is increasingly inadequate. Treated patients routinely exceed their predicted motor milestones, creating “new phenotypes” that do not fit these historical categories.
Newborn Screening
The game-changer for SMA outcomes
How NBS Works & Global Implementation
Screening Methodology
- PCR on dried blood spot: Detects homozygous SMN1 exon 7 deletion
- Sensitivity >95%, Specificity >99.99%
- SMN2 copy number: Separate quantitative test needed after positive screen
2026 Implementation Status
- USA: All 50 states screening
- Europe: 25+ countries implemented
- Asia-Pacific: Australia, Japan, Taiwan, others
- Middle East: Several countries active
- Global total: 40+ countries
Presymptomatic vs Symptomatic Treatment
Presymptomatic (via NBS)
- 100% with 3 SMN2 copies achieved walking (NURTURE)
- 88% with 2 SMN2 copies achieved walking
- Motor milestones near age-appropriate
- Minimal or no respiratory support needed
- Normal or near-normal development
Symptomatic Treatment
- Significant motor gains but persistent limitations
- Many Type 1 patients still require respiratory support
- Scoliosis, contractures still develop
- Outcomes highly dependent on baseline function
- Irreversible motor neuron loss already occurred
The window between NBS result and symptom onset is the most consequential therapeutic interval in SMA — every day counts.
The 4-Copy Dilemma
Clinical Challenge: Infants with 4+ SMN2 copies may develop SMA type 3/4 or remain asymptomatic. When to treat remains unclear.
Current Approach
- Serial motor assessments (every 3–6 months)
- CMAP monitoring for subclinical denervation
- Neurofilament light chain (NfL) monitoring (investigational)
- Family counseling about uncertain prognosis
Treatment Trigger Considerations
- Declining CMAP values
- Rising neurofilament levels
- Any clinical signs of weakness
- No consensus on prophylactic treatment
Approved SMN-Enhancing Therapies
Three mechanisms, one goal: more functional SMN protein
Three Therapies Head-to-Head
| Feature | Nusinersen (Spinraza) | Onasemnogene (Zolgensma) | Risdiplam (Evrysdi) |
|---|---|---|---|
| Mechanism | ASO — SMN2 splicing modifier | AAV9 gene replacement | Small molecule splicing modifier |
| Route | Intrathecal | IV (<2 yr) or IT (2–18 yr) | Oral (daily liquid/tablet) |
| Dosing | Loading + q4 month maintenance | One-time | Daily, continuous |
| FDA Approval | 2016 | 2019 | 2020 |
| Age Range | All ages (including adults) | <2 yr (IV), 2–18 yr (IT) | ≥2 months |
Nusinersen (Spinraza) — Deep Dive
Pivotal Evidence
- ENDEAR (Type 1): 47% motor response vs 0% sham
- CHERISH (Type 2/3): +3.9 HFMSE points at 15 months
- NURTURE (Presymptomatic): 100% sitting, 88–100% walking
- SHINE: Sustained benefit >5 years
2025–2026 Updates
- Higher-dose regimen (28 mg) under FDA/EMA review
- BIIB115 (next-gen ASO): Phase 1 data reported mid-2025 — potentially longer dosing intervals
- Real-world registries confirm sustained benefit across ages
Key Limitation: Intrathecal delivery — requires sedation in young children, can be challenging with scoliosis/spinal fusion.
Onasemnogene Abeparvovec (Zolgensma)
Pivotal Evidence
- STR1VE (Type 1): 59% independent sitting, 91% event-free survival
- SPR1NT (Presymptomatic): Age-appropriate milestones in majority
- STEER (IT, age 2–18): +2.39 HFMSE vs +0.51 sham
Safety Monitoring
- Hepatotoxicity (LFTs weekly ×3 months)
- Thrombocytopenia, TMA risk
- Prednisolone taper required
2025–2026 Milestone: Intrathecal formulation (OAV101 IT) approved for patients aged 2–18 years, expanding gene therapy access beyond the under-2 IV age limit.
Next-Gen: GB221 (Gemma Bio) — next-generation gene therapy for SMA1 via intracisterna magna injection. Phase 1/2 CHARISMA trial initiated February 2026.
Risdiplam (Evrysdi)
Pivotal Evidence
- FIREFISH (Type 1): 29% sitting, 81% event-free survival
- SUNFISH (Type 2/3): +1.36 MFM-32 points at 12 months
- RAINBOWFISH (Presymptomatic): Majority achieved milestones
Practical Advantages
- Oral daily administration (home-based)
- Systemic distribution (CNS + peripheral)
- No sedation or procedures required
- New 5 mg tablet formulation (2025)
Unique Benefit: Risdiplam’s systemic distribution may address peripheral organ manifestations of SMN deficiency (cardiac, hepatic, metabolic) that CNS-targeted therapies do not reach.
Combination & Sequential Therapy
When one therapy isn’t enough
Combination Therapy Landscape
Gene Therapy + Splicing Modifier
Most common combination. Gene therapy provides baseline SMN; splicing modifier augments endogenous production.
Nusinersen → Risdiplam Switch
IT to oral transition. Data show maintained or improved function. Reduces procedural burden.
SMN Therapy + Muscle-Targeted
Adding apitegromab (anti-myostatin) to SMN-enhancing therapy. SAPPHIRE trial positive. Pending FDA approval.
Triple Combination?
Gene therapy + splicing modifier + muscle-targeted agent. Under investigation. No formal trial data yet.
Emerging Pipeline
SMN-independent targets and next-generation therapies
Apitegromab — Muscle-Targeted Therapy
Mechanism & Evidence
- Target: Selectively inhibits myostatin activation in skeletal muscle
- SAPPHIRE Phase 3: Met primary endpoint — significant HFMSE improvement as add-on to SMN therapy
- OPAL Phase 2: Enrolling infants/toddlers with SMA <2 years
- Route: IV infusion every 4 weeks; SC formulation in development
Regulatory Status (April 2026): BLA resubmitted March 2026. PDUFA target: late September 2026. If approved, first SMN-independent SMA therapy.
Next-Generation Pipeline
| Agent | Mechanism | Phase | Key Update |
|---|---|---|---|
| GB221 (Gemma Bio) | Next-gen AAV gene therapy (ICM) | Phase 1/2 | CHARISMA trial dosing began Feb 2026 |
| BIIB115 / Salanersen | Next-gen ASO (longer intervals) | Phase 1 | Topline data reported mid-2025 |
| Apitegromab | Anti-myostatin (muscle-targeted) | BLA submitted | PDUFA target: Sept 2026 |
| Talditercept alfa | Myostatin pathway modulation | Clinical | In development for NMD |
| Spinal cord stimulation | Reactivate dormant motor neurons | Pilot | Improved 6MWT in 3 patients (UPitt) |
Multidisciplinary Care in 2026
New phenotypes, new challenges, integrated management
Emerging Treatment-Era Phenotypes
- Walking Type 1 patients: Presymptomatic-treated 2-copy infants achieving walking — unprecedented in natural history
- Discordant limb function: Lower limb gains may exceed upper limb, creating atypical weakness patterns
- Fatigue as dominant symptom: Increasingly active patients report significant fatigability as a limiting factor
- Multisystem manifestations: Cardiac, hepatic, metabolic, and autonomic features of SMN deficiency persist despite motor gains
- Scoliosis progression: Continues in many treated patients, especially those with early-onset disease
Multidisciplinary Monitoring Framework
Motor Function
CHOP INTEND, HFMSE, RULM every 3–6 months. Track trajectory, not just absolute scores.
Respiratory
Polysomnography, spirometry, cough peak flow annually. NIV titration as needed.
Nutrition & Growth
Weight, BMI, feeding assessment. Screen for metabolic abnormalities. Bone density.
Orthopedic
Scoliosis screening (Cobb angle), hip surveillance, contracture assessment annually.
Biomarkers for Treatment Monitoring
| Biomarker | What It Measures | Clinical Utility |
|---|---|---|
| CMAP amplitude | Functional motor unit number | Validated; declines predict motor loss |
| Neurofilament light (NfL) | Axonal damage / motor neuron loss | Promising; decreases with treatment |
| Phospho-NfH (pNfH) | Axonal damage | Research stage; correlates with severity |
| SMN protein (blood) | Treatment pharmacodynamics | Confirms splicing modifier effect |
Clinical Application: Declining CMAP or rising NfL in a treated patient should prompt reassessment of treatment adequacy and consideration of therapy intensification or switching.
Family Communication & Shared Decision-Making
Set Realistic Expectations
Treatment improves outcomes dramatically but may not normalize function in all patients. Discuss the spectrum of possible outcomes honestly.
Present All Options
Each therapy has distinct advantages. IV gene therapy (one-time), IT nusinersen (proven long-term), oral risdiplam (convenience). No single “best” choice for all patients.
Address Access & Cost
Navigate insurance, patient assistance programs, and advocacy organizations. Cost should not prevent access to life-changing therapy.
Emphasize Urgency for NBS-Positive Infants
Every day before treatment = motor neuron loss. Target treatment initiation within 2–4 weeks of positive NBS result.
Key Takeaways
NBS + Presymptomatic Treatment = Best Outcomes
Treating before symptoms onset produces near-normal motor development. Every day of delay costs motor neurons that cannot be replaced.
Three Therapies, Distinct Profiles
Nusinersen (IT ASO, long-term data), onasemnogene (one-time gene therapy, now IV + IT), risdiplam (oral, systemic). Choice depends on age, type, and family preference.
Muscle-Targeted Therapy Is Coming
Apitegromab (anti-myostatin) demonstrated additive benefit on top of SMN therapy. FDA decision anticipated September 2026.
New Phenotypes Require New Care Models
Walking Type 1 patients, persistent fatigue, metabolic complications — the treatment era is redefining SMA clinical practice.
SMA Is Systemic, Not Just Motor Neurons
Cardiac, hepatic, metabolic, and bone manifestations persist. Multidisciplinary care is essential across the lifespan.
References
- Schroth MK, et al. Spinal Muscular Atrophy Update in Best Practices: Recommendations for Treatment Considerations. Neurol Clin Pract. 2025;15:e200374. DOI
- Yu F, et al. Spinal Muscular Atrophy: Advances in Diagnosis, Treatment, and Emerging Therapies. Curr Treat Options Neurol. 2026;28:2. DOI
- Matesanz SE, Finkel RS. Real-world evidence on nusinersen treatment of persons with SMA: a focused review. Ther Adv Rare Dis. 2026. DOI
- Finkel RS, et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017;377(18):1723-1732. DOI
- Mendell JR, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017;377(18):1713-1722. DOI
- Darras BT, et al. Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls. N Engl J Med. 2021;385(5):427-435. DOI
- De Vivo DC, et al. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study. Neuromuscul Disord. 2019;29(11):842-856. DOI
- Vrščaj E, et al. Newborn Screening Programs for Spinal Muscular Atrophy Worldwide in 2023. J Neuromuscul Dis. 2024;11:1180-1189. DOI
Thank You
Questions & Discussion