CURE!
image by MorgueFile
What do we mean by saying we want to cure a disease? What does it mean to cure a disease? Alleviate pain, restore function, improve the quality of life of the patient? All of these things? Someone close to me once said to cure a disease means that you go on to die of something else. So what does it mean to seek a molecular cure or to use genetics to cure a disease?
Is it even possible?
We know the answer to that question is definitely yes. We have discussed some examples before; Gleevec stops some leukemias in many patients and Tarceva takes the debilitation of one type of lung cancer away. But in many patients the cancer returns and treatment ultimately fails. Before that happens though patients lead what can be considered a pretty normal life. These drugs were developed based on very fundamental scientific discoveries about the way those cancers arise.
Indeed if proteins are responsible for how our cells function and what makes our organs work then a failure of proteins to form normally or an alteration that results in loss of normal function is the root cause of disease. Understanding the specific failure and how it comes about in a given disease provides the keys to its cure.
We are entering a new phase of molecular understanding of diseases of nerves and muscle cells. Previously I described muscular dystrophy and how genetics gave us a way to think about treatment. We are now on the brink of curing one of the most heartbreaking of muscle disorders, spinal muscular atrophy or SMA.
SMA is a terrible disease of progressive weakness due to the death of muscle cells. As the cells die the body tries to regenerate them. At its worst babies with this disease cannot sit, their muscles progressively weaken and they die within a year or two unable to breathe. SMA is the leading genetic cause of death in infants and 1 in 50 Americans have a mutation that makes them genetic carriers of the disease. The muscle cells die because of a failure of the nerves connected to them. Those nerves fail and die because they lack an important protein critical to their survival. Indeed the protein is called survival motor neuron (SMN). This protein has 2 forms coded by 2 different genes, SMN1 and SMN2. The difference between these two genes is a single base pair alteration that arose in humans (it doesn’t exist in monkeys or chimps).
Neuromuscular junctions where nerves (dark purple) connect to muscle cells (pink). (image by Thomas Caceci https://doctorc.net/Labs/Lab10/lab10.htm)
Remember that our genes are DNA, comprising 3 billion individual letters (or base pairs). The DNA acts as a template for RNA, which leaves the cell’s nucleus to direct production of proteins. The result of the single base pair change is a profound alteration in the way RNA is processed and spliced (a necessary step for RNA to direct protein formation). The result is that SMN2 lacks an important part of the protein that renders it nearly non-functional. A very small amount of functional protein can be made from the SMN2 gene. If the SMN1 gene is mutated the absence of normal SMN protein causes this terrible disease. If patients have many copies of the SMN2 gene their disease is less severe in proportion to the amount of functional SMN made. At the Stanley Manne Children’s Research Institute Christine DiDonato and YongChao Ma have been pioneers in helping to understand and battle this tragic disease.
Our genes are DNA, which is used as a blueprint to make RNA and the RNA, is a template to produce protein. The DNA sequences of a gene include parts that are the blueprint for proteins and parts that help to regulate gene function but do not contribute to the protein. When RNA is produced from the gene (DNA) it must be processed so that only the parts needed to make the protein are in the final template. This is done by removing the other regulatory parts and then stitching together the bits that instruct the cell how to make the protein. This process is called RNA splicing.
By Ministry of Information Photo Division Photographer [Public domain]
“Here”…the parts of the gene that make the protein called exons. “Absent”…regulatory parts that don’t leave the nucleus called introns. The exons are stiched together or spliced to make a mature messenger RNA. From biocomicals.blogspot
An elaborate machinery resides within each of our cells to take the RNA produced from the DNA of our genes and splice together the protein coding parts. There are many parts to this machine and by studying patients with SMA scientists have learned much about how the machine works. They have learned how to make very small RNAs called antisense oligonucleotides that can block the effect of inhibitors of the machine and promote different processing of the SMN2 RNA such that it makes a functional protein. This has worked spectacularly well and by allowing splicing to proceed in the SMN2 gene more and more SMN can be made by cells particularly the nerve cells that are in the spinal cord. These antisense oligonucleotides are injected into the spinal canal by spinal tap. More SMN is produced and the nerve cells that promote muscle development and make our muscles move, survive and function.
These drugs have been in clinical trial for several years, including here at Lurie Children’s Hospital. Scientists and drug companies working with neurologist Nancy Kuntz have been testing the treatment and the results are amazing. Children that could barely move are now standing and, in some cases, walking. The results were so positive that the FDA has ruled that the treatment should be made more widely available and within the last month approved its general use in SMA patients. Unfortunately, Biogen has priced this treatment at such a high cost it is effectively unaffordable and so far insurance companies have not agreed to pay for it.
So here we are on the brink of the cure of a horrible disease (if we can figure out how to pay for it!) affecting thousands of children, the most common genetic cause of death in children under 4, because of our understanding of the most fundamental aspects of the biology involved.
Even with that so many questions remain. These questions will open new avenues of research that will impact other childhood diseases and as our knowledge increases the intersection of genetics, disease biology and clinical care will lead us to a new era of treatment and, yes, cures based on fundamental science!
