Developing treatments for CMT1A. Follow us to learn more about the science behind CMT1A, and potential pathways to treatments.
San Francisco
Joined July 2024
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Shark Tooth Biotech retweeted
Big thanks to @fishmanaf for inviting me to join him on the Startup Dad podcast. This conversation was deeply personal and a good forcing function to organize my thoughts on topics that are important to me.
I hope you enjoy our conversation in which we covered:
- The decision to leave my tech career
- Navigating the difficult and painful diagnostic journey
- The importance of being an advocate > an expert
- Fatherhood, family, and marriage frameworks that work for me
- Launching Shark Tooth Biotech
- What is wrong with the common advice to "pursue your passion"
- Why we should be less obsessed with our legacy
- Turning life's obstacles into personal growth
- And a few more hot takes and one embarrassing story :)
I’m incredibly grateful to Adam for providing his platform to share my journey, and to Haesun Brooks for the thoughtful introduction that made this possible.
Attached is a brief excerpt from our conversation. For the full episode, you can listen here:
open.spotify.com/episode/71w…
Shark Tooth Biotech retweeted
𝗜𝗻𝘁𝗿𝗼𝗱𝘂𝗰𝗶𝗻𝗴 @SharkToothBio: 𝗔 𝗣𝗲𝗿𝘀𝗼𝗻𝗮𝗹 𝗠𝗶𝘀𝘀𝗶𝗼𝗻 𝘁𝗼 𝗖𝗼𝗺𝗯𝗮𝘁 𝗖𝗠𝗧𝟭𝗔
2 years ago, my world was flipped upside down. My 2-year-old son, Ari, was diagnosed with Charcot-Marie-Tooth Disease Type 1A (CMT1A).
🧵
This 2024 study reveals that boosting cGMP with drugs like tadalafil or CYR119 improves proteostasis, myelination, and nerve conduction in mouse models of #CMT1A & #CMT1B. Promising steps toward potential treatments!
link.springer.com/article/10…
Grateful to Effie (@OnceUponAGene) for this great episode about choosing friends as rare disease parents 👇
effieparks.com/podcast/episo…
Highlights:
- Find your people
- Remember who you were before rare disease
- Be intentional
Interesting targeting approach: Antibody-targeted chromatin delivers CRISPR/Cas9 efficiently into cells. High precision, low toxicity, and no viral components. Could this be applicable to CMT1A?
academic.oup.com/nar/article…
Fascinating treatment for SMA 👇
EVRYSDI is a small molecule taken daily. It modifies SMN2 gene splicing by binding to SMN2 mRNA and results in increasing the production of the life-saving SMN protein.
Wondering if it could be engineered to bind to PMP22 mRNA…
academic.oup.com/brain/artic…
Boosting cGMP levels with sildenafil restores proteasome function, reduces proteotoxic stress, & improves myelination in a mouse model of CMT1B. This could also work for CMT1A.
onlinelibrary.wiley.com/doi/…
This paper shows that we can measure a 1.55x increase in PMP22 from CMT1A skin biopsies. This implies that skin biopsies can be used to accurately measure a (future) treatment's ability to downregulate the body's production of PMP22.
Demyelinating vs. Dysmyelinating? From our reading so far it appears that CMT1A is a combination of both.
Initially, myelin is improperly formed (dysmyelination). Over time, this already defective myelin becomes further damaged and degraded (demyelination).
Interesting chart of nerve conduction velocity over time in 107 patients with CMT
(Source: pubmed.ncbi.nlm.nih.gov/6314…)
ncbi.nlm.nih.gov/pmc/article…
Excessive PMP22 disrupts the delicate balance of lipid-to-protein ratio required for proper myelin structure. This imbalance leads to the formation of disordered myelin-like assemblies, contributing to the defective myelin in CMT1A.
nature.com/articles/s41467-0…
This study concludes that AAV2/9 gene therapy is an effective approach for treating CMT1A by reducing PMP22 overexpression in Schwann cells. This approach maintained motor and sensory functions in animal models over an extended period.
nature.com/articles/s42003-0…
This study demonstrates that squalenoyl siRNA PMP22 nanoparticles treat CMT1A in mice, offering hope for developing a similar therapeutic approach for human patients.
Is CMT1A demyelinating or dysmyelinating?
ncbi.nlm.nih.gov/pmc/article…
