A New Era in the Treatment of Rare Neurological Disorders with Gene Transfer Therapy

AUTHORS:

Bailey Hamner, MD¹; Emma Johnson, MD²; Maria Gieron-Korthals, MD^3
1Department of Internal Medicine (Internal Medicine-Pediatrics), University of Michigan, Ann Arbor, Michigan
²Department of Pediatric Neurology, Johns Hopkins University, Baltimore, Maryland
³Department of Pediatric Neurology, University of South Florida Morsani College of Medicine, Tampa, Florida

REVIEW ARTICLE | PUBLISHED SPRING 2025 | Volume 45, Issue 2

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Abstract

In this review article, we discuss important developments in the diagnosis and treatment of spinal muscular atrophy that dramatically altered the course of the disease, which is historically fatal by age two. The addition of spinal muscular atrophy to Florida’s Newborn Screening Program in 2020 significantly impacted outcomes in infants with spinal muscular atrophy, as they now attain earlier diagnosis (often before symptom onset) and, thus, earlier treatment. Until 2016, the mainstay of treatment was supportive care. Since then, three gene therapies have been FDA-approved, the newest of which is a one-time gene transfer that shows great promise in reducing morbidity and mortality for infants with spinal muscular atrophy. Today, patients with spinal muscular atrophy are living longer and reaching motor milestones rarely, if ever, achieved in historical patients. We discuss the results of clinical trials, spinal muscular atrophy gene therapy mechanisms, safety profiles, and post-infusion monitoring. We include two cases from our spinal muscular atrophy treatment program that describe the process from abnormal newborn screening to gene therapy to developmental outcomes following therapy.

Introduction

Spinal muscular atrophy (SMA) is an autosomal recessive disorder that results in severe, progressive degeneration of anterior horn cells in the spinal cord and brain stem nuclei. This leads to symmetric, proximal muscle weakness, a defining phenotypical feature. Five phenotypes of SMA (types 0-4) are characterized by age of onset and disease course. This article focuses on the most common phenotype—SMA type 1, also known as Werdnig-Hoffman disease—and disease-modifying treatment with gene therapy.

SMA type 0 presents prenatally and has the worst prognosis, with survival of weeks to 6 months without treatment. Type 1, often identified on newborn screens, typically presents before six months; median survival is 8-10 months of age. SMA type 2 presents at 6-18 months of age; 70% of patients survive to age 25 years. SMA types 3 and 4 present at >18 months of age and in adulthood, respectively, and patients have normal lifeh3s.^1,2

Most cases of SMA are caused by a homozygous exon-7 deletion of the survival motor neuron 1 (SMN1) gene.^2,3 The SMN2 gene can, to an extent, compensate for the lost SMN1 gene by producing the same functional protein. However, only 10-20% of SMN2 transcripts produce this protein.¹ Thus, the number of SMN2 copies is closely tied to prognosis and phenotype, with the mildest form of SMA seen in patients with at least four SMN2 copies.¹

Historically, treatment of SMA has been primarily supportive. Recent advancements in gene therapies have significantly altered the management and prognosis of SMA. These include nusinersen (Spinraza®), risdiplam (Evrysdi®), and onasemnogene abeparvovec (Zolgensma®), discussed in detail below. Supportive care typically addresses multiple domains, focusing on the pulmonary, gastrointestinal, and musculoskeletal systems.

Patients with SMA type 1 often require early respiratory and nutritional support. Bulbar and truncal weakness can make clearing secretions, maintaining respirations, swallowing safely, and positioning difficult.⁴ This causes early respiratory failure and increases the risk of aspiration and GERD.⁴ It should be emphasized that supportive care benefits all patients with SMA, regardless of newer treatments. A multidisciplinary approach and early enrollment in therapies (including physical, occupational, and speech therapies) are pivotal to maximizing quality of life and the benefit of medical treatments.

Disease-Modifying Treatments for SMA

The increasing availability of disease-modifying therapy (DMT) for SMA has significantly altered the course of the disease. Currently, there are three FDA-approved therapies for SMA, each acting through distinct mechanisms. DMT for SMA is most effective when initiated before symptom onset.⁵ Thus, early diagnosis and intervention are key, and advocacy groups have been major advocates in recent years for the inclusion of SMA in routine universal newborn screening (NBS).⁶

In May 2020, SMA was added to Florida’s NBS program. The SMA NBS uses the standard dried blood spot sample to test for homozygous SMN1 deletions, found in 95% of patients with SMA.³ Patients with a positive SMA NBS test are referred to an NBS Genetic Center for additional confirmatory testing, including measuring the number of SMN2 copies. Once a diagnosis of SMA has been confirmed, infants are referred to an NBS SMA Treatment Center for ongoing care and treatment management. Management is guided by the patient’s number of SMN2 copies⁶:

• Those with two to three copies (seen in SMA types 1, 2, or 3) should proceed to immediate treatment (assuming they meet eligibility criteria).
• Those with one copy (SMA type 0) are typically symptomatic at birth. Depending on the severity of symptoms at the time of diagnosis, the patient may not benefit from treatment. Whether to initiate treatment should be a shared decision-making process between the caregiver(s) and the physician.
• There is less consensus on whether those with > four copies (SMA type 4) should be treated immediately or monitored for symptom onset (which does not typically occur until the third decade of life³).

Our cohort includes 18 patients with SMA identified via Florida’s NBS Program, two of whom transferred to different programs. Ten had 2 SMN2 copies, two had between 1 and 2 copies, four had three, and two had four copies.

Nusinersen and Risdiplam

In 2016, intrathecal nusinersen (Spinraza®) became the first FDA-approved DMT for SMA.⁷ Risdiplam (Evrysdi®), approved in 2020, is an oral drug with a similar net effect to nusinersen.⁸ Both therapies increase exon-7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts—nusinersen via antisense oligonucleotides and risdiplam via splicing modifications.³ This enables each SMN2 copy to produce additional functional SMN protein, compensating for the loss of SMN1. Both therapies require repeated administration throughout the lifeh3 and associated life-long monitoring.³

Onasemnogene Abeparvovec

Mechanism of Action

In 2019, the FDA approved onasemnogene abeparvovec (Zolgensma®)—the first, and thus far only, gene addition therapy for SMA.⁹ A viral vector, adeno-associated viral vector (AAV) 9, carries a functional copy of the SMN1 gene (Figure 1).¹⁰ AAV9 has a high affinity for the central nervous system and crosses the blood-brain barrier, effectively targeting motor neuron cells.^3,11

One dose of onasemnogene abeparvovec (OA) administers 1.1×10¹⁴ vector genomes (vg) in a single infusion, and it is intended as a one-time treatment.¹¹ This single-dose approach has utility in both efficacy and safety, as patients develop anti-AAV antibodies after their first treatment and would thus be ineligible for a second.³

Several studies demonstrate the efficacy of one-time OA therapy. In clinical trials, pre- and post-symptomatic patients who took OA had significantly better clinical outcomes than historical controls (HCs).^12-18 Higher doses of OA and administration before symptom onset were correlated with better outcomes.^3,15,16 Patients not only lived longer with significantly lower mechanical ventilation needs but also reached and maintained motor milestones that were rarely, if ever, achieved in historical SMA patients.

Clinical Trials

Notable clinical trials of OA use in patients with SMA Type 1 include:

START Trial

This was a Phase 1 trial, which included 15 symptomatic patients <6 months of age who received either low-dose (6.7×10¹³ vg per kilogram [kg]) or high-dose (2.0×10¹⁴ vg/kg) OA.

• At 20 months of age, 100% of patients were alive without permanent mechanical ventilation (versus 8% in HCs). Those who received high-dose OA significantly increased motor function and achieved new motor milestones, which were achieved by 0% of HCs.¹¹
• At around five years after dosing, all 10 patients in the high-dose group maintained motor milestones and were alive without permanent ventilation. Two high-dose patients achieved new milestones of “standing with assistance.”¹⁵
• At around seven years after dosing, 100% of patients in the high-dose group were alive without permanent ventilation and continued to maintain motor milestones. Three additional patients gained the ability to stand without assistance.¹⁴

STR1VE-US Trial

This was a Phase 3 trial that included 22 symptomatic patients <6 months of age who received therapeutic high-dose OA. Similar Phase 3 trials were performed in Europe (STR1VE-EU) and Asia (STR1VE-AP).

• At 14 months of age¹⁷: 91% survived without mechanical ventilation (compared to 26% of HCs). At 18 months, 60% could sit without support (compared to 0% of HCs).

SPR1NT Trial

This was a Phase 3 trial of 30 pre-symptomatic patients < 6 weeks of age who had 2 (n=14) or 3 (n=16) copies of SMN2 and were treated with therapeutic doses of OA.

• In those with 2 SMN2 copies, at 18 months of age, 100% were alive, did not require respiratory support, and achieved the primary endpoint of sitting without support, and 71% were able to stand and walk unsupported.¹³
• In those with 3 SMN2 copies, at 24 months of age, 100% were alive, did not require nutritional or respiratory support, and achieved the primary endpoint of standing without support. Their gross motor skills were similar to other children their age.¹²

LT002: Long-Term Follow-Up Study of OA

The ongoing Phase 4 of this study will follow the safety and efficacy of OA for 15 years post-infusion. It includes 81 patients previously treated in the phase 3 studies (STR1VE -US, STR1VE-EU, STR1VE-AP, SPR1NT).

• At around 3.4 years after dosing, all patients maintained previously achieved motor milestones. The majority never received add-on therapy with another DMT; of those who did, only half achieved a new motor milestone after initiation of add-on therapy. There were no deaths and no adverse events significant enough to discontinue therapy.¹⁸
  • • SPR1NT (pre-symptomatic patients): Of those who had not yet achieved motor milestones measured in the initial study, 100% achieved these milestones by the time of follow-up (including walking independently).
    • STR1VE (symptomatic patients): At the time of follow-up, 42% of patients achieved new developmental milestones, and 89% could sit without support.

Safety Profile

The most common adverse reaction described after transfer therapy of OA is hepatotoxicity; less commonly, patients experienced vomiting, transient thrombocytopenia, immune-related thrombotic microangiopathy, and elevated troponin levels.¹⁹

Most often, hepatotoxicity will manifest as asymptomatic transaminitis, though acute liver failure has occurred in rare cases.^19,20 For this reason, OA carries a “black box” warning for serious liver injury.

The precise mechanism of hepatotoxicity is unknown but is thought to be secondary to AAV9 used to deliver the transgene rather than the transgene itself.²⁰ Similar hepatotoxicity has been seen in patients receiving other therapies via AAVs, perhaps due to increased hepatocellular uptake of AAV.^3,20 This is consistent with post-mortem analyses showing the “highest levels of vector DNA were found in the liver” in patients who received OA therapy.¹⁹

A retrospective study of patients who received OA showed that 90% had elevated liver enzymes post-infusion and that these elevations responded to oral steroids.²⁰ For most, liver enzymes peaked at one-week post-infusion and normalized at about two weeks post-infusion. Patients with severe elevations and/or acute liver injuries took longer to recover, though levels still normalized by the end of the observation period. Most patients also experienced a second peak when steroids were tapered, which again normalized within 30 days. Thus, all patients begin steroid prophylaxis before infusion and continued for at least 30 days post-infusion. An extended course of steroids is given for evidence of hepatotoxicity.

One patient with SMA presented with a spinal cord neoplasm 14 months after OA infusion; however, tissue analysis did not detect OA integration.²¹ Though this was the first reported case of an epithelioid spinal cord neoplasm associated with SMA, prior cases have documented malignancies occurring in adolescent and adult patients with SMA, including ependymoma, neuroblastoma, and alveolar rhabdomyosarcoma. The potential association between SMA and malignancy is poorly understood, theorized by some to be related to abnormal DNA repair pathways seen in patients with SMA.^21,22

Eligibility Criteria

Patients with SMA are eligible for OA if they are under the age of two years, were born full-term, and have AAV antibody titers < 1:50 (Table 1).¹⁹ They should be otherwise clinically stable without signs/symptoms of infection.

Patients with high levels of anti-AAV9 antibodies or liver impairment should be given careful consideration. Patients with titers > 1:50 or abnormal liver function should be retested until results normalize. There is no consensus on the timing of re-testing AAV9 titers, but based on patient data from clinical trials, every 3-4 weeks may be appropriate.²³

Pre-Infusion

Before OA treatment, eligible patients should¹⁹:

• Undergo testing to assess baseline:
  • • Liver function (via aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, albumin, prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR))
    • Creatinine
    • Complete blood count
    • Serum troponin-I level
• Get vaccinated:
  • • Vaccination status should be current before OA administration, including seasonal prophylaxis against influenza and respiratory syncytial virus.
• Initiate steroids:
  • • One day before treatment, patients are started on steroids (equivalent to oral prednisolone at 1 mg/kg of body weight per day). After treatment, they will continue this dose for at least 30 days, then taper as indicated.

Post-Infusion

Patients are closely monitored for at least 3 months after OA infusion (Table 2).¹⁹ Caregivers are given a management and monitoring sheet with a plan and specific dates for follow-up.

The purpose of monitoring is to screen for rare but serious adverse effects, including¹⁹:

Thrombotic microangiopathy

• Signs and symptoms (S/S): Thrombocytopenia, hemolytic anemia, hypertension, increased bruising or bleeding, seizures, or decreased urine output in the setting of acute kidney injury.
• Consult a pediatric hematologist and/or nephrologist immediately to manage as clinically indicated.

Hepatotoxicity

• S/S: Vomiting, jaundice, abnormal PT/INR, elevated bilirubin, ALT, and AST levels > 2 × ULN, or gamma-glutamyltransferase (GGT) elevations.
• If liver function abnormalities ≥ 2 × ULN (upper limit of normal) persist after the 30 days of systemic corticosteroids, promptly consult a pediatric gastroenterologist or hepatologist.

Cardiac injury

• S/S: Troponin elevations, heart rate changes, cyanosis, tachypnea, or respiratory distress.
• Consider consultation with a cardiologist if clinical signs or symptoms accompany troponin elevations.

Case Presentations

Our cases demonstrate the step-by-step evolution and management of newborns after abnormal NBS results and the different outcomes of gene therapy for SMA.

Patient A:

Patient A was born at 40 weeks (w) and 3 days (d). Her NBS returned positive for SMA on day-of-life (DOL) 5. This infant had a homozygous exon-7 deletion of the SMN1 gene and three copies of SMN2, consistent with SMA type 1 or 2.

Two maternal relatives had SMA (type unknown), and one was treated with OA.

The family met with Genetics and Pediatric Neurology on DOL 6 and 7, respectively. At the initial neurology evaluation, the patient was minimally symptomatic with only mild axial hypotonia. Treatment options were discussed, and the parents opted for OA. OA was administered on DOL 35, followed by standard post-dosing labs and prednisolone treatment. At 13 months, the patient was walking, running, saying single words, feeding themselves with utensils, reaching for objects, and using a pincer grasp. Patellar deep tendon reflexes were 1+, and the patient had no abnormal movements.

Patient B:

Patient B was born at 39w4d and had a positive NBS on DOL 4. The patient had a homozygous exon 7 deletion of the SMN1 gene and two copies of SMN2, consistent with SMA Type 1.

A paternal first cousin has SMA and was treated with OA.

The infant was seen by Pediatric Neurology on DOL 10 and found to have tongue fasciculations and hypotonia of the trunk and hip girdle. The family decided on treatment with OA, which was given on DOL 47. AST and troponin were elevated one week after administration, with AST 2 x ULN. Six weeks after infusion, the patient continued to display truncal and hip girdle hypotonia and significant head lag. At this time, it was decided to add risdiplam. After six weeks of risdiplam, there was minimal improvement in motor function. At 18 months of age, the infant remained hypotonic. He occasionally sat unassisted for 30-45 seconds and required a wheelchair. Due to scoliosis, the patient was referred to an orthopedist and more intense therapies.

Conclusion

In the last decade, the development of novel gene therapies has changed the natural course of SMA. When administered early after abnormal NBS results, gene therapy for SMA can lead to normal motor development and prevent disease progression. Although the results of the studies and our own experiences with OA are promising, we acknowledge these are very recent developments, and research is still ongoing. Limited follow-up data exists regarding the long-term efficacy and safety of OA.

Limitations

Oncogenesis is a commonly encountered concern regarding gene therapies. AAVs are considered non-integrating, meaning they do not insert DNA into the host genome.²⁴ Instead, the DNA is delivered via vector forms episomes that produce the desired gene. This significantly lowers the risk of insertional mutagenesis or off-target effects, including malignancy. To date, there have been no reported cases of AAV-mediated oncogenesis. Still, spontaneous integration remains a theoretical risk. One case study describes a patient with SMA who developed a spinal cord neoplasm 14 months after receiving OA therapy.²¹ The question remains: Was this a side effect of AAV therapy or a yet-unknown complication of SMA? Prior case reports document malignancies occurring in adolescent and adult patients with SMA, and some theorize that oncogenesis is related to abnormal DNA repair pathways in SMA.²² New complications may emerge as these patients’ lifeh3s continue to increase beyond their historical expectations.

It is not known if patients will require re-administration of OA. As discussed above, AAVs are non-integrating. Non-integration also means non-replication; thus, the desired gene will not be copied to new cells and will “die” when its host cell dies. While this is a limitation in other contexts, it is less problematic in SMA treatment, as the target cells (i.e., motor neurons) are non-dividing. Indeed, re-administration of OA would prove difficult, as patients would have existing AAV-antibodies from their initial treatment course.

Finally, more research is needed regarding the multiple modalities of SMA gene therapy. To date, no head-to-head trials have compared the efficacy of nusinersen, risdiplam, and OA. The utility of combining therapies must also be explored. In the ongoing phase 4 OA study (LT002), some patients developed new motor milestones with the addition of another DMT, though this is not always the case, as seen in Patient B.

Next steps

Further research may provide methods to improve the efficacy, safety, and longevity of treatment for SMA and broaden the range of diseases treated by gene therapies. One recent example is the 2023 FDA approval of delandistrogene moxeparvovec (Elevidys®) – the first AAV-based gene therapy for treating Duchenne muscular dystrophy (DMD).²⁵ Similarly to SMA, DMD is a rare and progressive genetic disease causing early-onset morbidity and mortality. Prior gene therapies for DMD existed, though they were only effective for those with specific mutations and required repeated administration. Delandistrogene moxeparvovec is administered as a single infusion and delivers the micro-dystrophin gene, a shortened protein that includes specific domains of the normal dystrophin protein.²⁵ Its accelerated approval has already improved function and quality of life for patients with DMD.²⁶

These novel therapies represent essential advancements in the treatment of two devastating, progressive childhood conditions with high morbidity and mortality.

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