Landon’s Story

Meet Our Son, Landon

Landon was born on January 4th, 2017 in St. Louis, Missouri. Prior to birth, ultrasound imaging revealed brain abnormalities which were confirmed with an intrauterine MRI. The day after Landon was born, a second MRI was performed of his brain and noted rare brain structure malformations including lissencephaly (“smooth brain”), agenesis of the corpus callosum (missing the midline structure of the brain), and a small cerebellum. At about 4 months of age, Landon began to demonstrate atypical movements. Initially his pediatrician contributed his behaviors to episodic acid reflux. These movements began happening more often and his neurologist subsequently ordered an EEG that confirmed these movements were happening due to seizure activity. Despite a trial run of a common anti-seizure medication known as Keppra, the seizures seemed to be getting worse and were prolongated. Landon was then hospitalized at Children’s Hospital in St. Louis, MO in late June 2017 and diagnosed with an even more rare seizure disorder known as infantile spasms. He was prescribed a month long treatment of a steroid called prednisolone. Following that treatment, he was transitioned to an anti-epileptic medication called Sabril (Vigabatrin). This medication alone did not keep the seizures away so a second medication, Onfi (clobazam), was added. After 2 months of dual therapy, we began slowly weaning Sabril over the course of 12 months, and dual therapy eventually ended in October 2018 – he was on both medications for 14 months.

Additional challenges for Landon include global developmental delay, dystonia – a mix of hypotonia (low core and neck muscle tone) and hypertonia (rigid and guarded arms and legs), cortical vision impairment, and feeding difficulties. He continues making great strides due to the countless hours of home as well as outpatient physical, occupational, vision, and speech therapy.

With no known cause despite x3 unremarkable genetic panel tests, whole exome sequencing (WES) was performed which analyzed/compared Landon’s genetic makeup to his parents. On February 8th, 2018, during a car ride home from therapy, we received the WES results that found single “candidate” gene mutation from his genetics team – a gene known as “CAMSAP1”. However, it was conveyed that Landon was the only one in the world known with this mutation. Subsequently, the genetics office conveyed “there had not been any research regarding that gene” and that “there wasn’t anything that we could do, we’ll revisit this in two years…try to have a good rest of your day”. The mutated gene that Landon inherited is autosomal recessive, meaning his parents are unaffected carriers and had a 25% chance of passing the gene to future offspring.

HOWEVER…

Landon’s father Joe, a medical practitioner in his own-right, would not take this information as gospel. For the next 3 months he would spend countless hours researching and piecing together seemingly unrelated research about CAMSAP1, similar genes (PTRN-1 and patronin), and proteins that it interacted with. On May 2, 2018, it seemed to have all come together! A study was published by Dr. Jana Marcette et. al., identifying a CAMSAP1 gene rescue study that was completed at Washington University in St. Louis, MO (WUSTL) whereby a small nematode demonstrated Landon-like movements until the gene was corrected and it SWAM AWAY! Joe contacted Dr. Marcette who was astonished that her post-doctoral research may have such profound implications on potentially curing a child in her own community.

On May 23, 2018, Dr. Marcette, Randy Ray (future MD), and Joe secured a meeting with Dr. David Curiel, also at Washington University in St. Louis, and presented the findings of the research to him.  Dr. Curiel was amazed at the research, and the BEST scenario happened as he agreed to advance the research of CAMSAP1 in hopes of finding a safe gene therapy/cure for Landon in his lab!  The plan involved furthering the research of this gene by creating a mouse knockout model with a CAMSAP1 mutation.

Dr. Curiel reached out to The Jackson Laboratory, a company that creates rodent models demonstrating rare conditions. After a few months of careful planning, four “founder mice” were born ironically on November 3rd, 2018 (Landon’s parents’ 6th wedding anniversary). These mice are essentially unaffected carriers of the gene mutation as they had one normal and one abnormal copy of the gene.

In December 2018, these four founder mice were bred with normal mice.  Provided that the laws of genetics would hold true, 25% of the offspring would then be true CAMSAP1 mutants.  Further irony ensued, and in January 2019, the second generation mice were born with 1/2 of the litters being born on Landon’s original due date.

On March 4, 2019, Joe sent a brief email to many of the lead authors of previously published CAMSAP1 research simply thanking them for their work, notifying them of the research we were endeavoring through The Jackson Laboratory and WUSTL, and to inquire about their knowledge of other possibly ongoing CAMSAP1 research. A few email exchanges ensued thereafter but there did not seem to be any knowledge of other active CAMSAP1 research from the replies received.

After several attempts to breed the so-called “founder mice” and their offspring, it was discovered that our attempt to create a CAMSAP1 knockout model was unsuccessful in May 2019. Despite this brief setback, we assumed a certain aspect of the CAMSAP1 gene would be necessary for any organism to survive birth but we could not prove as much. Although we were unsuccessful in creating a CAMSAP1 mouse model, research had been published by Dr. Takeichi from Japan that indicated that the two other CAMSAP genes, CAMSAP2 and CAMSAP3, did have successful knockout mouse models.

Joe was tasked to discover where the genes were modified for the two other CAMSAP knockout models. Amazingly, after only five hours of sending an email to the Dr. Takeichi, a reply was received with the answers to the question. Furthermore, much to the surprise of all involved, Dr. Takeichi conveyed that his colleague in China, Dr. Meng, was actively researching a CAMSAP1 mouse model that was indeed successfully created! As Dr. Meng continued his research, Joe reached out to another lab at WUSTL in St. Louis, MO whose interest(s) include neuronal genetics, cell-to-cell communication, intracellular structures and genes associated with axon outgrowth – exactly what CAMSAP1 had been implicated to do!

After contacting the new lab, it was decided and agreed upon to create induced pluripotent stem cells (iPSCs) from a simple blood draw from Landon and his parents. This process was accomplished by adding four genes called “Yamanaka Factors” to these cells to reengineer them back to their pluripotent stem cell state. Further engineering of these new iPSCs can differentiate them into whatever tissue type that could be needed or desired (ie nerve cells, muscle cells, skin cells, etc.). These cells would be analyzed to see if/how much CAMSAP1 exists in each cell type, respectively, and they would be compared to a normal cell with a normal functional CAMSAP1 gene – this process was anticipated to take approximately 6-8 weeks and be completed by end of October 2019.

Much to the surprise of the researchers at Washington University working on iPSC induction, the initial attempt to create the iPSCs was unsuccessful. However, the lab successfully created iPSCs from a second blood sample. To this point, Landon was still the only one recognized internationally with this unnamed ultra-rare condition.

It may seem cliché, but the adage “a thank you can go a long way”, never proved to be more true. At 5:52AM on 10/11/2019, we woke up to an email from one of the lead authors and thought leaders regarding the CAMSAP1 gene, Dr. Anna Akhmanova of Utrecht University (Netherlands), who Joe had reached out to earlier in the year via email to thank her for her work. Dr. Akhmanova sent this email as a means of introducing Dr. Andrew Crosby and Dr. Emma Baple from The University of Exeter School of Medicine (United Kingdom) to Joe as they were actively studying CAMSAP1 and had discovered 3 other children from Palestine with “strikingly similar clinical features” as Landon who also inherited two abnormal copies of the CAMSAP1 gene. About 1-2 weeks after this introduction, a 5th affected child was discovered from Turkey. A few months later, a 6th affected child from the USA was discovered with the help of social media.

Unfortunately, the momentum of our endeavor was slowed and the research progress came to a stop secondary to the uncertainties surrounding the COVID19 worldwide pandemic. As the world began to open back up several months later, so-to-speak, our research progress slowly resumed but was again halted in the Fall/Winter of 2021 due to a surge in COVID19 cases. In early 2022, our research endeavor resumed and much to our amazement, a lab in Ohio successfully created the CAMSAP1 mouse model with the help of The Jackson Laboratory, and it ended up ironically being created from the attempt we previously funded and did not have success with! Over the next few months, the mouse model and the iPSCs were meticulously analyzed and studied. Clinical imaging studies, EEG(s), laboratory results, and medical notes from the affected children were compared, contrasted, and reviewed by experts from the international medical community. While this continued throughout the Spring 2022, a 7th child was discovered with the condition from Saudi Arabia and an 8th affected child from the USA was discovered soon thereafter.

Despite encountering numerous hurdles along the way, our efforts finally paid off in August 2022 as we submitted our research manuscript for international publication consideration in the “American Journal of Human Genetics”. After making a few corrections, we were notified by the journal that our research manuscript was formally accepted and would be published within the following few weeks. And, in perfect serendipitous fashion, our manuscript recognizing CAMSAP1 as a “disease gene” was formally published and printed on 11/03/2022 – Lauren and Joe’s 10th wedding anniversary.

Establishing CAMSAP1 as a disease gene allows researchers access to grants for further research of the gene/condition. Although our manuscript and other CAMSAP1 research studies demonstrated a lot of information, there is still much work to be done.

Most recently, (04/21/2023) our team discussed plans for future research plans geared toward ultimately developing a gene therapy, and we are currently testing the iPSCs to validate whether or not there is partial CAMSAP1 protein function.

We thank you for your support and welcome you to continue following our journey!