So often this site, and our community in general, is a place of extreme sorrow, pessimism, regret, despair and horror. Understandably so. I have my periods of intense lamentation and despair. However, things are changing in and outside of our community which should provide everyone with a sense of hope and optimism provided we continue being intelligent and proactive.
In 2023, thanks to the hard work of Mitch, Axo et al, we will begin what is the most rigorous and important scientific investigation into our condition thus far. There is also a second study that is in the works, as well as other important initiatives on the awareness and fundraising fronts, which will likely bear fruit. Every week I speak to new patients who are eager to get involved and who recognise the importance of intelligent proactivity to support fundraising and awareness raising. There are new members of our community, myself included, who will be appearing in the second season of the PFSN podcast (if this is something you are interested in please reach out). Parents are coming together and planning events aimed at securing more resources from outside of our community for our important research. For more details on the progress made by the PFS Network, you can refer to the year end address from Mitch.
Our brothers and sisters in the PSSD community are now starting to speak out and make their voices heard in a way that hasn’t occurred over the decades their disease has existed. Some of their videos on TikTok have received over 700,000 views in the matter of a couple weeks. Their very large community has the potential to make a significant impact in this fight.
Outside of our community, CRISPR, regenerative medicine, and base editing is continuing to advance at a breakneck speed. In September 2022, the FDA gave Vertex the green light to submit rolling application for review of CRISPR based therapy to treat sickle cell disease and beta thalassemia. In November, clinical trial results showed CRISPR was a promising tool for editing immune cells to enhance their capacity to destroy cancer cells. In the same month, new CRISPR gene editing tools were found in thousands of phages.
Multiple epigenomic editing companies launched this year including Chroma medicine, Tune therapeutics, and Epic Bio. In the case of Epic Bio, their “GEMS therapies” can precisely modulate gene expression both in vivo and ex vivo. They are mutation-agnostic, meaning that one GEMS construct can address most or all genetic subtypes of a disease. And they are modular, allowing an effectively infinite range of combinations that can be tailored to specific therapeutic needs. Additionally, Epic Bio are using advanced data science, genetic and protein engineering, and functional genomics to expand their toolkit of GEMS components and to optimize the combination of all components into epigenetic therapies. Similarly, Chroma’s modular, flexible platform enables them to develop medicines that address a wide range of diseases, whether they require silencing, activation, or more complex targeting of multiple genes at once.
The advent of multiple epigenetic editing companies working on the ability to treat a wide range of diseases with an epigenetic origin, a mere 10 years since the advent of CRISPR, bodes extremely well for us.
“These short 10 years were marked by stunningly swift development and a great promise to cure thousands of genetic diseases with relative ease—with a single treatment dose that specifically corrects disease-causing DNA mutations in the body’s cells. Sickle cell anemia and muscular dystrophy are two such diseases. And indeed, a decade later, we are now delivering on that promise in the form of many therapies currently being tested in human clinical trials.”
In a 2021 paper in Nature, scientists at Verve and the University of Pennsylvania found that in monkeys, base editing was able to disable a gene called PCSK9 in the liver, shutting down the production of low-density lipoprotein, or LDL. High levels of LDL, also known as “bad” cholesterol, raise the risk of heart disease and stroke. An infusion of the base-editing lowered the PCSK9 protein by 90 percent and LDL levels by 60 percent. The effect lasted throughout the 10-month study—as well as over the two and a half years the company has followed the monkey since then, Kathiresan says.
Kathiresan sees a future in which base editing becomes a routine treatment for people at risk of repeated heart attacks. In the US, about one in five people who have a first heart attack are readmitted to a hospital for a second one within five years. After a heart attack, it’s common for people to get a stent—a small mesh tube that props open an artery—to improve blood flow. Kathiresan imagines that they might one day receive a second preventative procedure: a one-time base-editing treatment to permanently lower their LDL levels.
In terms of regenerative medicine, scientists from the USC Stem Cell laboratory of Neil Segil have identified a natural barrier to the regeneration of the inner ear’s sensory cells, which are lost in hearing and balance disorders. Overcoming this barrier may be a first step in returning inner ear cells to a newborn-like state that’s primed for regeneration, as described in a new study published in Developmental Cell. “Our study raises the possibility of using therapeutic drugs, gene editing, or other strategies to make epigenetic modifications that tap into the latent regenerative capacity of inner ear cells as a way to restore hearing,” said Segil. “Similar epigenetic modifications may also prove useful in other non-regenerating tissues, such as the retina, kidney, lung, and heart.”
Scientists at the University of California, San Francisco (UCSF) have engineered molecules that act like “cellular glue,” allowing them to direct in precise fashion how cells bond with each other. The discovery represents a major step toward building tissues and organs, a long-sought goal of regenerative medicine. “We were able to engineer cells in a manner that allows us to control which cells they interact with, and also to control the nature of that interaction,“ said senior author Wendell Lim, PhD, the Byers Distinguished Professor of Cellular and Molecular Pharmacology and director of UCSF’s Cell Design Institute. “This opens the door to building novel structures like tissues and organs.”
“It’s very exciting that we now understand much more about how evolution may have started building bodies,” he said. “Our work reveals a flexible molecular adhesion code that determines which cells will interact, and in what way. Now that we are starting to understand it, we can harness this code to direct how cells assemble into tissues and organs. These tools could be really transformative.”
AI is now being used in an effective and precise manner. A promising avenue for treatment is drug repurposing, where FDA-approved drugs are repositioned as novel treatments. However, linking disease mechanisms to drug action can be extraordinarily difficult and requires a depth of knowledge across multiple fields, which is complicated by the rapid pace of biomedical knowledge discovery. To address these challenges, The Hugh Kaul Precision Medicine Institute developed an artificial intelligence tool, mediKanren, that leverages the mechanistic insight of genetic disorders to identify therapeutic options. Using knowledge graphs, mediKanren enables an efficient way to link all relevant literature and databases. This tool has allowed for a scalable process that has been used to help over 500 rare disease families. As biomedical discoveries continue to contribute vast datasets and knowledge, an opportunity emerges for AI to assist in translating this biomedical knowledge into a format that can be searched by clinicians and researchers to better understand these diseases and identify therapeutic strategies for patients.
Small rare disease communities are making enormous strides which we can look draw inspiration and hope from. This year, scientists at the UC Davis MIND Institute, in the US, are set to commence a research programme to develop transformative gene therapies for activity dependent neuroprotective protein (ADNP) syndrome. The team will analyse three therapies, including a standard gene therapy, ASO, and a CRISPR-developed one, simultaneously. Incidentally, the ADNP community have also utilised mediKanren.
After three-plus years of intense fundraising and equally laborious work to develop a possible cure, four-year-old Michael Pirovolakis recently became the first person in the world to receive individual gene therapy for spastic paraplegia type 50, SPG50 for short. This complex neurogenerative condition is caused by a missing protein in the brain and results in severe developmental delays, progressive weakness and stiffness of the legs, and paralysis by the age of 10. Roughly 80 children around the world have SPG50. However, Michael is believed to be the only one with the disease in Canada. Their community consists of less than 100, is neurogenerative and complex, and yet they have tangible hope from an individualised gene therapy. Remember this the next time someone in the community tries to make you feel hopeless and pessimistic.
I’ll conclude with what I am working on now, and will continue to work on when the bell strikes midnight and 2023 begins. I am in the initial stages of working on a documentary with a team consisting of a creative producer, assistant researcher, director, line producer, and writing team with an award winning Netherlands production company quite interested in the documentary. They have previously obtained funding from the Netherlands Film Funds for other projects. Needless to say, such a production can make a big difference in demonstrating the harrowing reality of PFS and will be accurately informed.
I will continue to recruit patients for the monthly donation group we launched this year, to support the work of the PFS Network. Since launching the group, we have welcomed 46 members including some friends and family. We have raised 20,000 euros from this community. All donations go directly to fund research. If this is something you are interested in joining, please DM me.
I did the PFS Network podcast this year, and next year I will find other ways to raise awareness about what this drug has done to me personally. I encourage you all to discard the undue stigma and shame you might feel about this issue and raise your voice so that the outside world can more easily care about this issue.
I will continue reaching out to organisations, such as Movember, to see if they can support our community. We are due a response from Movember soon. I thank the 27 patients who shared their personal video testimony with Movember, to highlight the level of destruction caused by PFS. The mothers of Marc Turner and Connall Gould (Rest in Peace) provided heart-wrenching testimony as well.
We have real momentum for, perhaps, the first time in the history of our community. Let’s stop prioritising dead end broscience self-experimentation which has consistently failed for over 20 years. Let us now push like we never have before so we can uncover the mechanism, link the drug to the disease, and thereby enable us to win class action lawsuits against the manufacturers, secure large grant funding, and trial therapeutics with an animal model. All of this is within reach. There are, of course, innate time constraints not in our control. But fundraising and awareness is in our control and will have a direct tangible impact on the trajectory of this disease.
Please ask yourself, what will you do to secure a better future in the new year?
Happy new year, everyone. Here is to a brighter future for all.
