Understanding a disease as complex as Spinal Muscular Atrophy at times can become overwhelming. SMA parents contribute the majority of their time during the day caring for their children. The research side of SMA has become my passion. So how can an SMA dad who is a construction worker by trade really understand research? Well throughout my life there were always two subjects I loved……..Math and Science. I chose to become a construction worker because it was a much better living than what computer programmers were making. I have come from a family of Steamfitters. Growing up as a child at family picnics the conversations would always switch to……..well what else…….Steamfitting. I am proud to be a Union Steamfitter, and the medical benefits are second to none. The coverage Sophia receives through our union is critical and affords her things that may not be covered under typical plans, we have a PPO which means our policy is self funded. As far as my schooling, I grew up in the New York City School System. One of the largest concentrations of students nationwide. NYC every year gave a citywide aptitude test encompassing the 5 boroughs. Every year the results of my tests were amongst the top 1 percent in the city. My mom was approached several times about skipping me years ahead. She refused …….to keep me with children my own age. I was an October baby and already one of the youngest in my classes. I skated through school never opening my books even through college. When I decided to apply myself at St. John’s University my major was Computer Science , I was working full time during the week 10 hrs a day Monday through Saturday for 60 hrs a week. I was taking 18 credits a semester at night with courses such as C++ programming and Matrix methods in Math(The language in which computers communicate utilizing The Binary Code). For the year my GPA was a 3.98. I have taken multiple IQ tests and my score has always been higher than the likes of Andrew Jackson, John Adams, and Bill Clinton. I admit my writing is better than my speaking………..sometimes my brain becomes overwhelmed with multiple thoughts simultaneously which leads to fumbling of words. When I write I can slow things down and make them more understandable. So why go into all of this? I sometimes get a kick out of people when they assume because of your chosen occupation, that you are not qualified to understand what happens behind lab doors, that research is simply out of your comprehension. That an SMA parent may not be educated enough to understand the principles of research….Well I am here to prove them wrong. To show that a parent can thoroughly understand the research!
I assume that part of my analytical thinking is due in large part to my profession. As a unionized Steamfitter in Manhattan I have worked on some of the largest construction projects in the world. The vast majority of these projects have budgets ranging from Tens to Hundreds of Millions of dollars. The collective collaboration required on projects of that magnitude is simply mind-boggling. It takes years of planning on these projects pulling together the skills of the largest managing corporations, with the best mechanical engineers and architectural firms as well as a highly skilled work force. Although the team is highly qualified and amongst the brightest professionals in the world……..more often than not I find mistakes on the mechanical blueprints and plan drawings that are used in our field. This mindset, which I use on a daily basis has enabled me to analyze research in regards to Spinal Muscular Atrophy and pick up on some of the mistakes and contradictions in this field of work.
The overall reason for writing a research blog from a parents perspective is to show that every parent is capable of understanding the research. I believe by educating other members of the community it will lead to further advancements for our children. In the past year alone we have made great strides together. The first steps in any society begin with education.
Prior to explaining SMA Mathematics it is important to state that these principles will apply to the general population. As with many things in life there are exceptions to any rule. For instance there are documented cases of Asymptomatic Type 1, a full deletion of SMN 1 with 1 or 2 copies of SMN2 yet the patient remains without symptoms. There is also an example of a woman who presented with SMA symptoms in her twenties. Further testing revealed that along with a full deletion of SMN1 there was also a full deletion of the SMN2 gene as well. The understanding of SMA suggests that this woman should not have survived much time after birth, yet she remained asymptomatic for over 20 years.
So how do we make an educated assumption of expected benefits of a particular drug or therapy? I like to look at this question mathematically. The expectation of many of the drugs being designed for SMA today are said to be able to upregulate the SMN2 gene by 5-10%. If we generously assume 10% we can formulate an expectation for the patient based on the number of SMN2 genes they have. So if a patient has 1 SMN2 copy we can assign a whole number of 1.0. If a patient has 2 SMN2 copies we will assign 2.0, for 3 SMN2 copies 3.0. Since the majority of Type 1 have 1-2 SMN2 copies and the majority of the stronger types have 3 SMN2 genes we can assume that to change a phenotype, not cure the disease but to go from a type 1 to a type 2 we would like to see an expression of 3.0.
So here is the Math: (1 SMN2 = 1.0 ; 2SMN2= 2.0 ; 3 SMN2= 3.0) also ( 1 SMN1 copy > 3 SMN2 copies)
1.0 + 10%(1.0) = 1.1 A Type 1 patient with 1 backup copy can expect an expression of 1.1 backup copies with administration of x drug
2.0 + 10%(2.0)= 2.2 A Type 1 patient with 2 backup copies can expect an expression of 2.2 backup copies with administration of x drug
As you see above for a meaningful change in condition of a given patient we would like to see an increase in expression closer to the lines of 3.0 copies. Drug x with a 10 percent upregulation of SMN2 falls short of desired impact. These low expression levels tend to correlate with lab results showing lack of life extension in the SMA Type 1 mouse model. We must continue to perform further assays on the vast majority of known drugs that have yet to be tested. We would like to see a drug increase SMN2 expression by 50 percent or more to have an impact. It would be nice to see an extension of life in the SMA Type 1 mouse model to 100 days or longer prior to investing heavily in further testing on a particular candidate. These minor changes in philosophy could greatly accelerate the number of pre-screened candidates for SMA and save millions of dollars. In closing a final question to ponder………might it be possible the only way to treat SMA is via Bio Tech, Stem Cells, Gene Therapy……….Is Spinal Muscular Atrophy a DRUGGABLE disease?
Just some thoughts of an SMA Dad after all I am just a man in a hard hat!