Gene Therapy: Spinal Muscular Atrophy

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You’re looking at a short reference article from Explain Medicine (one of four distinct learning formats available in Clinical Odyssey). Try it out, and have fun improving your clinical skills.

Cell Therapy

Last updated on:
November 3^rd, 2023

Cell Therapy

Last updated on:
November 3^rd, 2023

Hi there!

You’re looking at a short reference article from Explain Medicine (one of four distinct learning formats available in Clinical Odyssey). Try it out, and have fun improving your clinical skills.

Background

Fact	Explanation
Spinal muscular atrophy (SMA)	Spinal muscular atrophy (SMA) refers to a group of rare genetic diseases, many of which are caused by deletions or mutations in both copies of the survival motor neuron 1 (SMN1) gene. SMN1 is the main gene responsible for the production of the survival motor neuron (SMN) protein. Loss of function of SMN1 results in a lack of the SMN protein. This results in impaired motor neuron function by degeneration of the spinal anterior horn cells (alpha motor neurons). Loss of functional motor neurons causes severe, progressive muscle atrophy and weakness, followed by death due to respiratory failure secondary to infection or other respiratory events. SMA is a major inherited cause of death in early childhood. It has an estimated prevalence of 1:10000 births, considering all of its clinical types.
Genetic cause of SMA	Early-onset SMA is inherited in an autosomal recessive fashion. It is due to either a homozygous deletion of the SMN1 gene or a heterozygous deletion together with a point mutation of the gene, resulting in a shortened, nonfunctioning SMN protein. This stems from the deletion of exon 7 from SMN1's messenger RNA. Humans also carry a similar gene to SMN1, called SMN2. Both contain nine exons. SMN2 differs from SMN1 in only one DNA nucleotide. This minor difference causes the deletion of exon 7 from most of the messenger RNA (mRNA) molecules produced by SMN2. In some SMA patients, this deletion can also affect exon 8. SMA has been diagnosed through the detection of exon 7 deletion in mRNA produced from SMN1. Nevertheless, routine methods fail to distinguish between this deletion event and the potential replacement of the SMN1 gene by one of the SMN2 gene copies (because this deletion event occurs naturally in the mRNA from the SMN2 gene). The SMN protein produced from mRNA lacking exon 7 (and sometimes 8) is highly unstable and rapidly degrades in cells, leading to the failure of the protein to perform its function. In patients with SMA, genetic defects in SMN1 impede the production of SMN protein. The copy number of the SMN2 gene is variable in humans (between 0 and 5 copies). Since there is a small amount of residual mRNA containing exon 7 in SMN2 genes, the higher the copy number, the larger the amount of SMN protein produced from SMN2. Nevertheless, these amounts are never sufficient to fully compensate for the lack of SMN produced from deleted/mutated SMN1. This failure to compensate for the lack of SMN production brings devastating consequences for muscular function.
Disease severity	The severity of SMA is higher in patients with a lower number of SMN2 copies. Patients with a single copy may show a prenatal onset of disease (described by some authors as type 0 or prenatal SMA) and die during the first month of age. Patients with two copies of the SMN2 gene typically (known as type 1 or infantile SMA, or Werdnig-Hoffman disease) show disease onset within the first six months of life and die before the age of two. Individuals with a higher number of SMN2 gene copies generally have a later age of onset and a milder presentation. More specifically, type II or juvenile SMA (Dubowitz disease) first manifests between 6 and 18 months; type III or juvenile SMA (Kugelberg-Welander disease), from 18 months through adolescence; and type IV or late-onset SMA, in adulthood, most frequently after the age of 35. In every case, muscular dysfunction will impact the physical autonomy of the patient, although patients with milder, later-onset forms tend to have only minor impairment and have normal life expectancies.
Gene therapy approach for SMA	The gene therapy approach for SMA consists of the delivery to the patient of an exogenous SMN1 gene. The gene is stored in viral particles, which are injected into the patient’s blood. After reaching motor neurons, this exogenous gene will induce the production of a functional SMN protein. Effective treatment must be performed before the critical stages of neuron maturation, ideally as soon as possible after diagnosis, in order to avoid permanent neuronal damage.
Adeno-associated virus	In the gene therapy approach for the treatment of SMA, the exogenous SMN1 gene is stored in an adeno-associated virus (AAV9). This class of viruses is non-pathogenic to humans, causes a reduced immune response, and is able to cross the blood-brain barrier to deliver genetic material to neurons.
FDA approval	Only one gene therapy modality for the treatment of SMA is currently approved by the Food and Drug Administration (FDA) of the United States: onasemnogene abeparvovec. This consists of a single intravenous injection of adeno-associated viral particles containing an SMN1 gene. There are also two non-gene therapy, FDA-approved treatments for SMA: nusinersen and risdiplam. Both enhance the inclusion of exon 7 in the SMN2 gene. Therapies involving more than one of the three treatments have been tested in clinical trials.

Spinal muscular atrophy (SMA)

Spinal muscular atrophy (SMA) refers to a group of rare genetic diseases, many of which are caused by deletions or mutations in both copies of the survival motor neuron 1 (SMN1) gene. SMN1 is the main gene responsible for the production of the survival motor neuron (SMN) protein. Loss of function of SMN1 results in a lack of the SMN protein. This results in impaired motor neuron function by degeneration of the spinal anterior horn cells (alpha motor neurons). Loss of functional motor neurons causes severe, progressive muscle atrophy and weakness, followed by death due to respiratory failure secondary to infection or other respiratory events.

SMA is a major inherited cause of death in early childhood. It has an estimated prevalence of 1:10000 births, considering all of its clinical types.

Genetic cause of SMA

Early-onset SMA is inherited in an autosomal recessive fashion. It is due to either a homozygous deletion of the SMN1 gene or a heterozygous deletion together with a point mutation of the gene, resulting in a shortened, nonfunctioning SMN protein. This stems from the deletion of exon 7 from SMN1's messenger RNA.

Humans also carry a similar gene to SMN1, called SMN2. Both contain nine exons. SMN2 differs from SMN1 in only one DNA nucleotide. This minor difference causes the deletion of exon 7 from most of the messenger RNA (mRNA) molecules produced by SMN2. In some SMA patients, this deletion can also affect exon 8. SMA has been diagnosed through the detection of exon 7 deletion in mRNA produced from SMN1. Nevertheless, routine methods fail to distinguish between this deletion event and the potential replacement of the SMN1 gene by one of the SMN2 gene copies (because this deletion event occurs naturally in the mRNA from the SMN2 gene).

The SMN protein produced from mRNA lacking exon 7 (and sometimes 8) is highly unstable and rapidly degrades in cells, leading to the failure of the protein to perform its function. In patients with SMA, genetic defects in SMN1 impede the production of SMN protein.

The copy number of the SMN2 gene is variable in humans (between 0 and 5 copies). Since there is a small amount of residual mRNA containing exon 7 in SMN2 genes, the higher the copy number, the larger the amount of SMN protein produced from SMN2. Nevertheless, these amounts are never sufficient to fully compensate for the lack of SMN produced from deleted/mutated SMN1. This failure to compensate for the lack of SMN production brings devastating consequences for muscular function.

Disease severity

The severity of SMA is higher in patients with a lower number of SMN2 copies. Patients with a single copy may show a prenatal onset of disease (described by some authors as type 0 or prenatal SMA) and die during the first month of age. Patients with two copies of the SMN2 gene typically (known as type 1 or infantile SMA, or Werdnig-Hoffman disease) show disease onset within the first six months of life and die before the age of two.

Individuals with a higher number of SMN2 gene copies generally have a later age of onset and a milder presentation. More specifically, type II or juvenile SMA (Dubowitz disease) first manifests between 6 and 18 months; type III or juvenile SMA (Kugelberg-Welander disease), from 18 months through adolescence; and type IV or late-onset SMA, in adulthood, most frequently after the age of 35. In every case, muscular dysfunction will impact the physical autonomy of the patient, although patients with milder, later-onset forms tend to have only minor impairment and have normal life expectancies.

Gene therapy approach for SMA

The gene therapy approach for SMA consists of the delivery to the patient of an exogenous SMN1 gene. The gene is stored in viral particles, which are injected into the patient’s blood. After reaching motor neurons, this exogenous gene will induce the production of a functional SMN protein. Effective treatment must be performed before the critical stages of neuron maturation, ideally as soon as possible after diagnosis, in order to avoid permanent neuronal damage.

Adeno-associated virus

In the gene therapy approach for the treatment of SMA, the exogenous SMN1 gene is stored in an adeno-associated virus (AAV9). This class of viruses is non-pathogenic to humans, causes a reduced immune response, and is able to cross the blood-brain barrier to deliver genetic material to neurons.

FDA approval

Only one gene therapy modality for the treatment of SMA is currently approved by the Food and Drug Administration (FDA) of the United States: onasemnogene abeparvovec. This consists of a single intravenous injection of adeno-associated viral particles containing an SMN1 gene. There are also two non-gene therapy, FDA-approved treatments for SMA: nusinersen and risdiplam. Both enhance the inclusion of exon 7 in the SMN2 gene. Therapies involving more than one of the three treatments have been tested in clinical trials.

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