Join me as we explore the progression of Spinal Muscular Atrophy and understand the mechanisms behind our current treatment: ASO therapy.
What’s up people and welcome to Biotech Breakdown, a platform, dedicated to simplifying cutting-edge biomedical innovations and fostering a passion for biotechnology within all. I’m your host Raghav and if you haven’t already smashed that follow button, go ahead and do that now to show your support. Anyways, if you’re ready, I’m ready let’s break down Spinal Muscular Atrophy and ASO therapy.
Alright, so what exactly is Spinal Muscular Atrophy, or SMA as I’m gonna call it. Well, it’s a genetic neuromuscular disorder characterized by muscle weakness and atrophy - aka the decrease in size of muscle tissues. It occurs due to the loss of motor neurons in the spinal cord.
Okay, so let’s take a look at it from a genetic perspective. SMA is caused by mutations in the SMN1 gene which produces the survival motor neuron protein. This protein is essential for motor neuron function and survival. However, we do have a second gene known as SMN2, which is capable of producing these proteins but at very low levels.
Next, let’s take a look at the disease progression. Typically it starts in the proximal muscles which are essentially muscles that are closer to the body’s center and then progresses to the distal muscles.
Afterward, a key symptom is the loss of motor function as well as a decline in respiratory function. Lastly, there are other orthopedic complications. Conditions such as Scoliosis and joint contractures develop often.
Lastly, let’s take a look at the different types of SMA. Type 0 or prenatal SMA is extremely rare and symptoms are usually present before birth. There’s reduced fetal movement and severe motor weakness at birth. Usually, it leads to a very short life expectancy.
Type 1 or Werdnig-Hoffman disease is the most common and severe form. It onsets between the age of 0 - 6 months. Patients wouldn’t be able to sit without support and life expectancy is typically less than 2 years without treatment.
Type 2 or Dubowitz disease onsets between 6 - 18 months of birth. Patients are unable to walk but can sit independently which leads to common respiratory issues.
Type 3 or Kugelberg-Welander disease onsets after 18 months and patients can independently walk. It leads to the gradual loss of motor function and patients can have a normal lifespan.
Type 4 is the Adult-onset SMA - It usually happens after age 21 and leads to mild motor impairment. Again, the patients can have a normal lifespan.
So, now that we have a basic understanding of what SMA is and how it progresses, let’s take a look at the current treatment we have for this condition - Antisense Oligonucleotides or ASOs.
ASO therapy’s main purpose is to basically modulate gene expression used for treating genetic diseases. But let’s focus on how it works in the context of SMA.
Well as we know, in SMA patients, the SMN1 gene is either missing or mutated. So, this therapy instead focuses on our second gene, SMN2. The main goal is to essentially boost the expression of this gene.
Typically what happens is that SMN2 produces a shortened and nonfunctional protein since it skips exon 7 during splicing. Only rarely does exon 7 actually get included. What I mean by this is that a certain part of that gene isn’t expressed which leads to a useless protein.
What ASO does is that it modifies the splicing to include the exon 7 much more frequently, leading to the expression of a healthy SMN protein. So, how exactly does it do it?
AMOs are essentially short synthetic single-stranded molecules. They can be DNA or RNA molecules. And they’re designed to be complementary to a specific pre-mRNA sequence.
Let me explain what I mean by this. Basically, the pre-mRNA sequence is the sequence right after the DNA is turned into RNA. So, it consists of both exons and introns. By the way, introns are parts of the genome that don’t go outside the nucleus while exons are the parts that leave the nucleus and get expressed.
This binding of the complementary sequences alters the splicing process which promotes the inclusion of exon 7 in the mature mRNA.
Remember that this is the application of ASOs only for SMA. Like the way it was used to include an exon in SMA, it could be utilized to alter the splicing process such that an exon is skipped instead. It’s often used as a treatment for diseases such as DMD, Hereditary Transthyretin-mediated amyloidosis, and FCS.
However, it has the potential to treat many other genetic diseases such as Huntington’s disease, cystic fibrosis, and ALS.
Alright, folks, that’s it for today. If you enjoyed this episode go ahead and smash that follow button for more premium content. This is Biotech Breakdown signing out.
