Therapy goals
- Alleviation of symptomatology and discomfort
- Slowing of the progression
- Healing
Therapy recommendations
- Nusinersen (Spinraza; drug from the antisense oligonucleotide class; available in Germany since July 2017): This is a single-stranded nucleic acid that binds to the complementary intron (noncoding region of a pre-RNA transcript) 7 of SMN2 pre-mRNA (mRNA subject to processing), preventing removal of exon 7 by the spliceosome (structure in the eukaryotic nucleus that is involved in gene expression). The result is an upregulation (i.e., increased synthesis) of the SMN2 protein. Motor milestones can be achieved in 51% of children up to 12 years of age as a result. It is administered intrathecally* via lumbar puncture to allow crossing of the blood–brain barrier and thus entry into motor neurons. Treatment is approved for all ages and all types of SMA. * Injection into the fluid-filled space between the arachnoid (cobweb) and pia mater (hard meninges), the subarachnoid space.
- Zolgensma (gene therapy; approved only in the United States, since May 2019): this involves the introduction of an intact SMN1 gene into the nucleus of alpha-motoneurons with the help of a vector (a plasmid (ring-shaped DNA molecule) extracted from an adenovirus). The actual viral DNA was modified in such a way that neither replication nor transcription (synthesis of RNA using a DNA as a template) of the viral genes occurs. This replacement gene remains in a stable state for a long time. In children aged 2 years or younger, Zolgensma crosses the blood–brain barrier after intravenous administration and ultimately reaches the alpha-motoneurons of the spinal cord and brainstem. It is thus primarily suitable for the treatment of type 1 SMA. After therapy, independent sitting and walking, as well as normal language development, are observed in more than 90% of affected individuals.
- See under “Further therapy”
Active ingredients
- Mode of action of nusinersen (spinraza; antisense oligonucleotide class drug, ASO): alteration of how pre-mRNAs are spliced by SMN2 → formation of complete and functional SMN protein in larger amounts.
- Dosage: 4 administrations within 2 months (= saturation phase), each intrathecally via lumbar puncture; maintenance phase: re-administration every 4 months.
- Side effects: Coagulation disorders, thrombocytopenias (lack of platelets / platelets in the blood) and liver and kidney dysfunction.
- Mode of action of Zolgensma: gene replacement therapy (see above for description ); insertion of an intact SMN1 gene into the α-motoneurons using an adeno-associated viral vector. The α-motoneurons innervate the muscle cells responsible for executing movement.
- Indication: treatment of babies and children with spinal muscular atrophy (SMA) weighing up to 21 kilograms.
- Side effects: acute liver injury or transient (temporary) increase in transaminases (special liver values).
Other therapy alternative
- Risdiplam: this is single-stranded oligonucleotide, with the same effect as nusinersen. However, it is capable of crossing the blood-brain barrier, allowing oral absorption. Over a 12-month treatment period, a doubling of SMN2 protein serum levels was observed.Phase III SUNFISH Part 2 study: 180 children and young adults (two to 25 years) with SMA type 2 and type 3 over 12 months received either risdiplam (1 x daily orally) or placebo. This resulted in an increase in motor skills [Part 1: 3]Indication: Treatment of spinal muscular atrophy in adult children aged at least 2 months.This is the first time that the US Food and Drug Administration has approved an oral drug for the treatment of spinal muscular atrophy in 2020.
