Is Spinraza a Gene Therapy or an Antisense Oligonucleotide?

Spinraza (nusinersen) is a treatment for spinal muscular atrophy (SMA), a genetic disorder that affects muscle strength and movement. Since its approval, there has been confusion about how to categorize it—particularly whether it qualifies as a gene therapy.

What Defines Gene Therapy

Gene therapy involves modifying or replacing genetic material within a patient’s cells to treat or prevent disease. This typically includes delivering functional genes, silencing defective ones, or altering gene expression. The defining characteristic is its direct interaction with DNA or RNA to induce lasting molecular changes. Regulatory agencies like the FDA and EMA classify gene therapies based on their mechanism of action, often involving viral or non-viral vectors to introduce genetic material.

A common form of gene therapy uses viral vectors, such as adeno-associated viruses (AAV) or lentiviruses, to deliver functional genes into cells. This approach has been used in treatments for SMA and inherited retinal diseases, aiming for a long-term therapeutic effect. Gene editing technologies like CRISPR-Cas9 offer precise genetic corrections, further expanding the potential of gene therapy.

Non-viral delivery methods, such as lipid nanoparticles and electroporation, also facilitate genetic modifications. These approaches are being explored for conditions like sickle cell disease and certain cancers. Regardless of the method, gene therapy addresses the root cause of genetic disorders rather than just alleviating symptoms, distinguishing it from other treatments.

Antisense Oligonucleotides

Antisense oligonucleotides (ASOs) are short, synthetic nucleotide strands that bind to complementary RNA sequences to regulate gene expression. They work by mechanisms such as exon skipping, RNA degradation, or translation inhibition. Unlike gene therapies that introduce or edit genetic material, ASOs function at the RNA level, providing a reversible approach to gene modulation.

Chemical modifications enhance ASO stability and efficacy, protecting them from enzymatic degradation. Modifications like phosphorothioate backbones and locked nucleic acids improve binding affinity and prolong half-life. Intrathecal injections are often used for neurological disorders, allowing ASOs to bypass the blood-brain barrier and reach the central nervous system.

Several ASO therapies have been approved for genetic conditions. For example, eteplirsen treats Duchenne muscular dystrophy (DMD) by promoting exon skipping to restore partial dystrophin production. Similarly, tominersen for Huntington’s disease reduces toxic huntingtin mRNA levels. These examples illustrate ASOs’ ability to modulate gene expression for therapeutic benefit.

Spinraza’s Mechanism

Spinraza (nusinersen) targets the genetic deficiency in SMA, a disorder caused by insufficient survival motor neuron (SMN) protein. The SMN1 gene, responsible for producing this protein, is mutated or deleted in SMA patients. Although a backup gene, SMN2, exists, it primarily generates a truncated, unstable version of the SMN protein due to a splicing error that excludes exon 7. Spinraza corrects this defect, increasing functional SMN protein production to support motor neuron survival.

As an antisense oligonucleotide, Spinraza binds to SMN2 pre-mRNA, preventing exon 7 exclusion. This enables the SMN2 gene to produce more full-length SMN protein, compensating for the loss of SMN1-derived protein. Increased SMN protein helps maintain motor neuron integrity, slowing disease progression and, in some cases, improving motor function. Clinical trials, such as ENDEAR, have shown significant motor milestone improvements in treated infants.

Spinraza is administered via intrathecal injection to ensure delivery to motor neurons in the spinal cord. This method bypasses systemic degradation, allowing the drug to reach its target effectively. Treatment involves an initial loading phase followed by maintenance doses every four months to sustain therapeutic levels. Long-term data indicate that continued treatment leads to sustained benefits in many patients.

Classification Status

Determining whether Spinraza qualifies as a gene therapy requires examining its mechanism and regulatory classification. Gene therapy typically involves introducing, replacing, or editing genetic material, often using viral or non-viral vectors for long-term effects. Spinraza does not introduce new genetic material or alter DNA; instead, it modulates RNA splicing to enhance protein production.

Regulatory agencies classify Spinraza as an antisense oligonucleotide therapy rather than gene therapy. The FDA approved it as an RNA-targeted treatment, recognizing that it influences gene expression at the mRNA level without modifying the genome. Unlike gene therapies that typically require a single administration for lasting effects, Spinraza requires repeated dosing to maintain its benefits, further distinguishing it from permanent genetic interventions.