Thread by @Biotech2k1

Looking at $CRSP:

Taking a look at the use of CRISPR CAS9 use in ex-vivo cell therapies.

1/ $CRSP is using the same CRISPR/CAS9 system as $NTLA. This is made up of the CAS9 enzyme which has 2 nuclease domains that do the cutting of the DNA into a Double Stranded Break. It also includes a guide RNA for searching the DNA for the correct site.

2/ The biggest danger of the CAS9 enzyme is that cuts both strands of the DNA at the same location. Without the use of a template strand, this will trigger Non Homologous End Joining which is a very inaccurate process.

3/ This can lead to Insertions and Deletions (Indels) of bases that could shift the reading frame of the gene. $CRSP is getting around this as they are focusing ex-vivo cell therapies.

4/ All their therapies extract cells from a patient and edit them before inserting them back into the patient. The exception to this is the Regenerative Medicines they are doing with stem cells for diabetes.

5/ CTX-001:

Their fist program is actually the most advanced of all the CRISPR programs in development. It is in an ongoing phase 1 and 2 trial for Beta Thalassemia and Sickle Cell Disease.

6/ The Beta Thalassemia indications is very small. Only a few thousand patients world wide. The Sickle Cell Disease is 90,000 in US and over 300,000 world wide.

7/ Sickle Cell Disease is a horrible disease with a defect in the normal production of Bet Globin. The Hemoglobin is made up of 2 alpha and 2 beta globin. The defect in the Beta Globin causes the Hemoglobin to polymerize into long chains in low oxygen.

8/ This causes the Red Blood Cells to sickle into a boomerang like shape. This causes blockages that can be life threatening and intense pain.

9/ The data is best in class for SCD showing follow up with no events of Vaso-Occlusive Crisis so far. All patients were into the normal hemoglobin range of 11 to 15.9 g/dl and fetal Hb level in the 39.6% to 49.6% range.

10/ This is considered a functional cure. The safety data looks consistent with what would be expected from an autologous stem cell transplant. $CRSP only owns 40% of the revenue for CTX-001. They are partnered with Vertex who gets the other 60%.

11/ CAR-T:
The next set of programs for them are their 3 CAR-T programs CTX-110, CTX-120, and CTX-130. The early efficacy data in these programs was promising, but the durability was horribly low.

12/ They showed less then 6 months durability which is actually on par with other allogeneic CAR-T programs. The error in this is not $CRSP, but the entire allogeneic space. It could be limitations in the science at this stage.

13/ The company took a huge pounding on its massively bubbly market cap last year after this data failed to impress. Its been a long and difficult road since going from over loved to value stock.

14/ This last program is their Diabetes cell therapy. This is in partnership with ViaCyte. They are using CRISPR to engineer islet cells that can produce insulin for a patient.

15/ This is placed into the ViaCyte capsule and then into the patient. The biggest risk of this system in immunogenicity of the capsule. The other big issue is the cells inside the capsule responding to levels of insulin and demand.

16/ I have been in $CRSP since October 2018, and I haven't seen the pipeline or the science change in all those years. They are still advancing the same programs.

17/ Meanwhile, other CRISPR companies are adding all kinds of cool new technologies like base editing, targeted LNP and In-vivo editing. I recently fell out of love with the company as they lack the innovation, and I don't know if they will get it back.