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New Updates in the Gene Therapy Realm for SMA



A few days ago, news about the success of prenatal gene therapy for Spinal Muscular Atrophy (SMA) was all over the internet. It brought hope to families affected by SMA and those seeking ways to prevent it in future generations. Before we dive into the current gene therapy update, let’s take a quick look at what SMA is.


What is SMA?

Spinal Muscular Atrophy (SMA) is a neurological and genetic condition that affects muscle function, causing muscle weakness and wasting. The central and peripheral nervous systems don’t function properly, weakening the nerves that connect to muscles throughout the body. This results in muscle weakness, more pronounced in muscles closer to the body than in the limbs.

SMA is one of the most common neuromuscular conditions that can appear in childhood, often leading to significant morbidity and mortality. The incidence is approximately 1 in 10,000 to 20,000 live births.


Subtypes and Symptoms of SMA:

There are five subtypes of SMA. Symptoms and age of onset vary by type. The earlier the onset, the more severe the condition tends to be.

SMA Type 0

  • Most severe form, with onset during the prenatal period

  • May cause serious respiratory issues shortly after birth

  • Symptoms: reduced fetal movement, heart defects, absent reflexes, facial weakness, joint stiffness

  • Lifespan: a few weeks to around six months

SMA Type 1

  • Most common infantile form, affecting about half of SMA cases

  • Onset: around 6 months or earlier

  • Symptoms: limited head control, can sit only with support, facial weakness, joint stiffness, trouble swallowing or sucking

  • Life expectancy: 8 to 10 months

SMA Type 2

  • Intermediate form with onset before 18 months

  • Children can sit independently but cannot stand or walk unaided

  • Symptoms: developmental delays, finger tremors, reduced or absent reflexes, weakness in shoulders, hips, and thighs

  • Around 70% live into adulthood

SMA Type 3

  • Milder form with onset after 18 months

  • Children can stand and walk independently

  • Symptoms: muscle weakness near the body’s center, fatigue, hand tremors, reduced knee reflexes, mild respiratory issues

  • Life expectancy is normal

SMA Type 4

  • Mildest and rarest form, with adult-onset (second or third decade of life)

  • Symptoms: fatigue and proximal muscle weakness

  • Normal development and life expectancy

  • Accounts for about 5% of SMA cases


Genetics of SMA:

SMA is associated with a gene called SMN1, which is responsible for producing a motor neuron protein called SMN (Survival of Motor Neuron). This protein is essential for the normal function of motor neurons. Motor neurons are special nerve cells that carry instructions from the brain and spinal cord to the muscles. They tell your muscles when to move, like when to lift your arm, blink, walk, or even smile! When the SMN1 gene doesn’t function properly due to variants (also called mutations) or deletions (partial or complete absence), the body produces little or no SMN protein. As a result, motor neurons begin to degenerate, leading to muscle weakness across the body. In about 95% of SMA cases, there is a large deletion in the SMN1 gene. Nearby lies another gene called SMN2, which is nearly identical to SMN1. SMN2 also produces SMN protein, though in smaller amounts. It can partially compensate for a nonfunctional SMN1 gene. Most people have two copies of SMN2, but some may have up to eight. The more SMN2 copies present, the milder the symptoms tend to be.


Inheritance:

SMA is inherited in an autosomal recessive pattern. Both biological parents must pass on a variant in the SMN1 gene for the child to be affected. Most parents are carriers, meaning they each carry one faulty copy but show no symptoms. When both parents are carriers, there is a 25% chance their child will inherit both non-working copies and have SMA. In rare cases (about 1%), a person may inherit one faulty copy and acquire a new faulty variant spontaneously in the other copy during early development.


Management:

There is no cure for SMA, but treatment can help ease symptoms, prevent complications, and improve quality of life. Supportive care may include physical, speech, and occupational therapy, feeding tubes, assisted ventilation, and help with bowel, nutrition, and musculoskeletal issues.


Gene Therapies:

Gene therapy medications for SMA target the underlying genetic issue. They aim to replace the faulty gene or boost SMN protein production from the SMN2 gene. The three main treatments are:

  • Nusinersen (Spinraza)

  • Onasemnogene abeparvovec-xioi (Zolgensma)

  • Risdiplam (Evrysdi)

These treatments work best when given early before symptoms fully develop. Early intervention can reduce symptom severity and improve outcomes.


Current Update:

At St. Jude Children’s Research Hospital in Memphis, scientists recently performed the first in-utero treatment for SMA using Risdiplam. Both parents were known carriers, and prenatal testing showed the fetus had no copies of the SMN1 gene, indicating SMA Type 1.

Risdiplam was administered to the mother during the last six weeks of pregnancy. The child, now 2.5 years old, is being monitored and has shown no signs of SMA so far. This breakthrough highlights the potential of prenatal intervention and the importance of genetic screening for couples. Further research is needed, but this case brings hope for treating SMA before birth in high-risk pregnancies.


Resources:



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