Thread by @Biotech2k1

@HassanAesthetic Profile for $BEAM.

1/ This is the first company to take CRISPR and modify it for base editing. It uses the CAS9 enzyme that is modified for cutting only 1 strand of the DNA. It is called a nickase. The guide is the same. They add an additional enzyme called deaminase.

2/ The guide works the same to find the right place in the DNA. It can still have off target effects like any guide RNA. That part has not been eliminated. What has been changed is only 1 strand of the DNA gets cut.

3/ This removes the possibility of indels related to the DNA double strand breaks that might cause mutations with other first generation editors. It also significantly limits its ability. It can no longer do insertions.

4/ The demainase works on either the Adenosine or the Cytosine by plucking off the Amino group. This is the main difference between them and their counter parts Guanine and Thymine.

5/ This allows for the transition of the A to a G known as the Adenosine Base Editor (ABE), or the Cytosine to a Thymine known as the Cytosine Base Editor (CBE).

6/ This further limits this technology as it can only do certain base edits. It can't make a G into an A or a T into C. It also can't exchange a purine for a pyrimadine like A to a T.

7/ The other risk of the deaminse is it has no way of telling one A or C from another. The reading window is 4 bases wide if I recall correctly. If 3 A's fall into the window, there is no way of telling which one of them gets changed. This is called a bystander edit.

8/ This can also lead to pathogenesis if they don't screen each target correctly. This will also eliminate some potential targets as they might be unable to target them due to bystander edits. In the SCD indication it creates a variant of Hemoglobulin that is still functional.

9/ This technology has some data in animal models that looks fantastic, but we just don't know if it will work in humans yet.

10/ Their lead indication is a SCD cell therapy that will compete with $CRSP and $BLUE. I think there is plenty of room for this to work as we have 90,000 a year patients in the US.

11/ I think it will take multiple companies to keep up with that population if these therapies become main stream. I think they can do 1,000 per year for $1.5 billion in line with my $CRSP estimates. They have no partner so I don't know if they can scale bigger than that.

12/ They have some early preclinical programs in the eye and liver, but using these in-vivo will be very complicated. The size of this structure is over 7kb. It would take LNP for liver, but multiple AAV vectors for anything else.

13/ If you start using multiple vectors for delivery, then you run into issues with getting enough of the right parts into the right cells in the right amounts to work. That is another major obstacle if it comes to that.

14/ They have a cell therapy program going on, but its really hard as they can't do insertions. They have to use lentivirus to insert the CAR into the T cells. That already makes them way behind everyone else.

15/ I think the valuation of this company is one of the hardest to justify. They have zero data to validate any of this will work in humans. They have a ton of challenges in the tech, and they have no big cap partners to help them.

16/ I honestly can not justify any valuation bigger than $3 billion for a company with no clinical data. Especially with the high level of limitations.