Shark Tooth Biotech

Developing treatments for CMT1A. Follow us to learn more about the science behind CMT1A, and potential pathways to treatments.

[David Apple @davidcapple]

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:

https://t.co/oGMyINHtus

[David Apple @davidcapple]

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).

🧵

[Shark Tooth Biotech @SharkToothBio]

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!

https://t.co/dCK5XR3HQj

[Shark Tooth Biotech @SharkToothBio]

Grateful to Effie (@OnceUponAGene) for this great episode about choosing friends as rare disease parents 👇

https://t.co/cOYI86gVT7

Highlights:
- Find your people
- Remember who you were before rare disease
- Be intentional

[Shark Tooth Biotech @SharkToothBio]

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?

https://t.co/HAswYeyEeo

[Shark Tooth Biotech @SharkToothBio]

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…

[Shark Tooth Biotech @SharkToothBio]

https://t.co/KSlAi6rATP

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.

[Shark Tooth Biotech @SharkToothBio]

https://t.co/7ulCxODypI

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.

[Shark Tooth Biotech @SharkToothBio]

The combination of these processes explains why CMT1A can present with early-onset symptoms that progressively worsen over time. The initial poor quality of myelin affects nerve function early in life, and continued damage to this already weak myelin exacerbates the condition.

[Shark Tooth Biotech @SharkToothBio]

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).

[Shark Tooth Biotech @SharkToothBio]

Note: this study was performed on CMT1 patients (both CMT1A and 1B). Unfortunately it does not differentiate between the two groups so it's unknown how many were 1A vs. 1B.

[Shark Tooth Biotech @SharkToothBio]

Interesting chart of nerve conduction velocity over time in 107 patients with CMT
(Source: https://t.co/1up3YPUrzk)

[Shark Tooth Biotech @SharkToothBio]

https://t.co/bOZtE7d76y

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.

[Shark Tooth Biotech @SharkToothBio]

Note: there are concerns with AAV (viral vectors) delivery:
1) Since CMT1A is non-lethal, the risk-reward might not be there for some patients.
2) Taking an AAV treatment now might preclude patients from taking a safer AAV treatment in the future.

[Shark Tooth Biotech @SharkToothBio]

https://t.co/1jRLSSMxqD

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.

[Shark Tooth Biotech @SharkToothBio]

Note: this is not the same delivery as LNPs.

Squalenoyl siRNA: chemical conjugation of siRNA to squalene, leading to self-assembly into nanoparticles.

LNPs: encapsulation of siRNA within a lipid matrix, without direct chemical bonding between the siRNA and lipid components.

[Shark Tooth Biotech @SharkToothBio]

https://t.co/55JTwKGl3H

This study demonstrates that squalenoyl siRNA PMP22 nanoparticles treat CMT1A in mice, offering hope for developing a similar therapeutic approach for human patients.

[Shark Tooth Biotech @SharkToothBio]

Evidence suggests that CMT1A involves developmental defects in myelination, leading to uniformly slowed nerve conduction, rather than active demyelination.

This insight challenges traditional views and impacts therapeutic approaches.

[Shark Tooth Biotech @SharkToothBio]

Is CMT1A demyelinating or dysmyelinating?
https://t.co/x4DXG4DBA5