Emmery’s Story Part 2
A huge thank you to Dr. Dylan Verden for helping me edit this post
I ended my last blog post talking about how the first two months after Emmery’s diagnosis were the darkest days of my life. Let me just start off by saying that this blog post is much more positive. It’s about our uphill climb out of that low place. It’s going to be full of hope, anticipation, and growth. Oh, and I’m also going to do my best to explain the science behind KIF1A Associated Neurological Disorder (KAND), genetics, and all the research that is being done, not just for KIF1A, but for all genetic diseases in the world.
On April 2, 2022, almost 2 months after we got Emmery’s diagnosis of KIF1A Associated Neurological Disorder (KAND), KIF1A.org had a “Community Call” where all of us that were interested got on a Zoom meeting with Dr. Dylan Verden, one of the researchers that works for KIF1A.org. The call was about something called CRISPR. It was something that I had never heard of before. But if there is one thing that pulled me fast and hard out of my depression, it was Dylan telling me (and all of us) about CRISPR. I am beyond thankful that he decided to have that community call that day, and at the KIF1A conference this year, I had the privilege of meeting him and letting him know how much his work means to me.
Before I get into explaining CRISPR, let me back up a little bit and explain a little more about genes and Emmery’s specific diagnosis. The human body has 23 pairs of chromosomes (46 total). Chromosomes then hold our DNA. The DNA in each person’s body contains about 3 billion bases. These bases are Adenine, Thymine, Cytosine, and Guanine. Genes are then segments of this DNA. Genes also vary in size, meaning some have a few hundred bases and some might have 2 million bases. We all have approximately 20,000 genes in our body. Your genes contain instructions that tell your cells to make proteins. Proteins are made up of 20 amino acids. Each person has 2 copies of each gene, one from each parent. Emmery has a mutation on one of her genes (the gene with a mutation is called KIF1A.) Gene mutations can either be inherited from one or both of your parents (meaning that they have the mutation also) or it can be a de novo mutation, meaning it was a spontaneous mutation. De novo mutations can occur when the egg or sperm are made, after the sperm fertilizes the egg, or when cells begin to divide after fertilization. Emmery’s mutation is de novo. Here is a picture of Emmery’s specific genetic results:
So where it says “c.946 C>T”, this means that at nucleotide (a nucleotide is a location on that gene that contains all 4 bases, A, T, C, and G) 946 on the KIF1A gene, she should have a Cytosine base, but she has a Thymine base. And then where it says “p.(R316W)” that means because of the incorrect base at position 946, her gene then gave the incorrect instructions when it came to making protein. So when there should have been Arginine (R) amino acid, she has Tryptophan (W) amino acids.
Another thing that I wanted to point out (that I just learned at the KIF1A conference in August) is that every single one of us has mutations on our genes. However, most of them are not significant enough to impact our lives. So what makes Emmery’s mutation so significant?
Genes all have different functions throughout the body. The KIF1A gene is large, meaning that it contains a large strand of DNA.
Emmery’s KIF1A variant changes the DNA sequence which also changes the function of the protein made from the gene. Some genetic variants change the DNA without changing the protein made by the gene.
Some amino acids are positively charged, some are negatively charged, and some are neutral. Emmery’s “R” (positive charge) was replaced with a “W” which is uncharged. If the amino acid is replaced by one with the same charge, the symptoms might not be as severe. This also explains why among all the people with KIF1A variants, the severity of the disease has a very wide range.
Gene Therapy
Gene therapy is a general term that means the manipulation or modification of a gene. There are many different types of gene therapy, and they can go into 2 different categories: genetic treatments and gene editing (cures).
Genetic Treatments
Genetic treatments are medications or drugs that can change expression of the mutated gene. These treatments help with symptoms and have the potential to drastically improve quality of life. They can help manage symptoms and prevent progression of the disorder. Treatments are not permanent, which make them less risky.
Antisense Oligonucleotide (ASO) therapy is basically where a medication is designed for a specific genetic variant. After the medication is administered, it “blocks” expression of the mutant copy of the gene (remember we have 2 copies- one from each parent) so only the healthy version of KIF1A protein is made. Working with Dr. Wendy Chung’s team, N-Lorem has already successfully developed and administered ASO therapy to one child with KAND. For KAND specifically, the medication would be administered intrathecally (through the spinal canal) so that it can cross the blood brain barrier, and treatment is administered roughly once every two months. Overall, it looks very promising. For example, she wasn’t able to walk or stand on her own, but now that she has been receiving ASO therapy, she can! This “n-of-1” trial is still ongoing but we’re all hopeful and excited about this advance.
These treatments all rely on “finding” mutant KIF1A, but each patient’s mutant KIF1A looks different. As I mentioned earlier, all of us have gene mutations, and not all of them are harmful. When a mutation affects one DNA base, we call it a Single Nucleotide Polymorphism (literally, one base that can have multiple shapes), or SNP for short. SNPs are more common than KAND-related mutations. If multiple patients have the same SNP on their mutant copy of KIF1A, we can use that SNP as a “handle” to stop expression of mutants in more patients. We have already had bloodwork drawn for Emmery to see if she has one of these “handles”. If she does, then she may qualify to receive the ASO treatment that has already been developed for the other KAND patient that I mentioned above.
Gene Editing
Gene editing is replacing or changing a gene. This is permanent and could possibly be considered a “cure.”
CRISPR (Also called CRISPR Cas-9) is a gene editing technology. It precisely cuts out the incorrect DNA and lets the natural DNA process takeover. This basically replaces the mutated DNA with correct DNA. CRISPR has been used in many human clinical trials already with success. At this point it, it is used for terminal diseases such as Spinal Muscular Atrophy and Duchenne Muscular Dystrophy. CRISPR can also have off-target effects if it interacts with the wrong gene.
Base Editing is a new technique in gene editingthat changes the incorrect base into the correct one. For Emmery, it would change her Thymine to a Cystine. This can fix the exact mutation and is more precise than CRISPR. We were told at the KIF1A conference in August that Base Editing is one of the best options for a cure for KAND.
Viral Vectors are able to carry genetic material into genes,. The disease-causing genes are removed by the virus, replacing them with genes needed to stop the disease.
Prime editing is a gene editing technique that can replace larger chunks of DNA; instead of fixing one mutation at a time, prime editing could replace a region of the KIF1A gene that contains multiple KAND mutations, helping more of our community with each treatment.
Curing KIF1A mutations by editing them back to normal is more complicated than getting rid of the mutant copy because we need the treatment to make very specific changes to the DNA it’s targeted. Because there are so many kinds of KIF1A mutations, making a cure that edits each specific mutation is a slow process.
I wanted to share a little bit of the science behind Emmery’s disease because I am hoping that this will help everyone understand why we have gotten so involved with KIF1A.org and also with fundraising. This is also why we take her once per year to NYC to be involved in KIF1A.org’s research study. I never in a million years thought that this is what I would be spending all my time on, but treatments and a CURE for Emmery are very possibly going to be here in the next 2-10 years. We are so lucky! And hopefully this helps explain why Dylan’s CRISPR discussion helped pull me into a better place of HOPE and encouragement. It gave me the motivation to take a leap of faith and do my first fundraiser. We have had many of Emmery’s specialty doctors at Vanderbilt tell us that there are so many amazing things being developed in the world of genetics and that there are going to be all kids of genetic diseases cured in the next decade.
I also just want to thank everyone from the bottom of my heart for every single word of encouragement, prayer, act of service, and dollar donated to help our sweet Emmery. We are beyond blessed to be surrounded by such an amazing community that chooses to help us in so many different ways. We couldn’t do this without you. Please don’t hesitate to reach out to me if you have any questions about KIF1A. I can’t wait for the day when I post videos of Emmery being a living miracle, and I get to tell each and every one of you that YOU are the reason she’s been cured.
