How can Zolgensma gene therapy help children with spinal muscular atrophy?

TeachableMedicalNews article 09302021

Teachable moment in classrooms:

1. cellular basis of life chapter – role of mRNA in protein synthesis
2. cellular basis of life chapter – concept of gene mutation leading to protein malfunction
3. muscular system chapter – role of nerve impulses in directing muscle contraction
4. nervous system chapter – functions of dendrites and axons of neurons

The news item:  Recently the following reporting was published by BBC news organization:

‘Gene therapy is a game changer for our son’

A five-month-old becomes the first person in England to get a drug with a list price of £1.79m.

The article describes the symptoms, such as loss of mobility in infants, of the spinal muscular atrophy.  The article also mentions the mutant SMN1 gene, and the Zolgensma treatment that replaces the mutated gene. The article states that the frequency of this disorder is 1 in 10,000 births.

So, Why Do I Care??  Most children whose symptoms begin after age 2 have a near normal life expectancy. However, newborns with the “infant-onset” form (about 400 newborns each year) have a very short life expectancy. That is devastating to parents, too, who are helpless while their child lays motionless, and not developing motor skills for movement or speech. Innovative treatments not only raise the hope for a more normal life for the affected infants, but also points to possible treatments of similar disorders.

Plain English, Please!!!  First, let’s talk about what is spinal muscular atrophy (SMA).  This disorder originates from damaged neurons in the spinal cord. The consequence of that damage is that skeletal muscles (muscles that move bones, drive breathing) don’t receive nerve impulses, and, therefore, the skeletal muscles weaken and then shrivel (atrophy). SMA was shown to be a single gene disorder, meaning that the mutation of the SMN1 gene is responsible for neuronal damage and muscle atrophy.

Second, let’s talk about what the SMN1 protein does. The mutated SMN1 gene directs the formation of a misshapen SMN1 protein. Inside neurons the SMN1 protein stabilizes the extensions (axons and dendrites) of neurons, and also helps with the processing messenger RNA to maintain the life of the neuron. Just like in a car factory robots construct and assemble a car, the SMN1 protein carries out several tasks.  The mutated SMN1 protein is like an unplugged robot. Without the SMN1 protein the neurons have unstable dendrite and axons, and a shortened the lifespan. The combination of those defects makes connections with muscle cells unstable, and prevent the normal flow of nerve impulses to muscles.

Third, let’s talk about how the Zolgensma treatment works. The Zolgensma treatment uses a specially designed virus to carry the normal form of the SMN1 gene into the neurons of the brain and spinal cord. Picture the virus as a very tiny syringe that injects the normal SMN1 DNA into the neuron. Once inside the neuron, the normal SMN1 protein will be made, and the neuron can now form the appropriate dendrites and axon, and maintain a normal lifespan. A normally functioning neuron will be able to send signals to muscles, and mobility will return to the patient.