I’m playing catch-up on some reading given how busy I’ve been and this includes a groundbreaking NEJM pub on CRISPR for Sickle Cell and Thalassemia.
CRISPR for Sickle Cell
From December, here’s the key paper in the NEJM: CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. There’s a lot to like about this clinical trial paper and it gives real hope to patients with Sickle-Cell Disease and Thalassemia. It takes an interesting, indirect clinic approach to addressing Sickle Cell by turning off a repressor (BCL11a) of fetal globin expression. The reactivation of the fetal globin largely seems to rescue the Sickle Cell disease phenotype even though the patients still have the original globin mutation.
I’m still not really clear on the rationale for this indirect approach rather than directly trying to gene-edit the mutant globin gene itself. I had a discussion with some folks on Twitter about this after my tweet below.
ICYMI: NEJM paper on #CRISPR gene editing for sickle cell disease https://t.co/pugI3DTfDL Anyone know why has this indirect approach (inhibiting an inhibitor of fetal hemoglobin) has advanced more than direct approach of correcting the globin gene mutation in HSC? #sicklecell
— Paul Knoepfler (@pknoepfler) January 11, 2021
I still need to dig into the supplemental data, but I’m also not entirely clear on the actual genetic changes that this gene-editing makes in BCL11A as I didn’t see those discussed in the main body of the paper. Maybe I missed it.
Also, is it correct that they have not done whole-genome sequencing yet on actual patient samples either pre- or post-transplant to more rigorously look for potential off-targets? What about potential on-target indels in BCL11a or possible large chromosomal deletions that can sometimes occur with CRISPR?
Victoria Gray, first participant in the trial
The first participant in the clinical trial, Victoria Gray, is a real hero. It’s so brave to participate in a pioneering clinical trial.
She reports that she’s doing great since she received the CRISPR-based intervention, reporting a major reduction in Sickle Cell Disease symptoms. You can see a picture of her after receiving her own gene-edited blood stem cells back after chemo. She’s pictured with her children near the top of the post.
More data needed in coming months and years
The NEJM paper reports briefly on a small group of additional patients including some with Thalassemia who they indicate have had similar improvements in symptoms.
As a cautionary note, it’s early days for this trial and other similar studies. To be able to concretely judge efficacy and safety we need to see overall data for a much larger group of patients. It’s also crucial to see longer-term follow up data on safety and efficacy as well. For example, if there is a consistent benefit, does that last for months or years or do Sickle Cell or Thalassemia symptoms return in some patients?
Still, this is a very exciting beginning
Additional interesting pubs
BlueRock, FDA, and Parkinson’s
Cell Therapy DA01 Cleared for Phase 1 Trial in Advanced Disease Patients. This is an ES cell-based therapy for Parkinson’s Disease. From the news item:
“This trial is the culmination of a decade of arduous collaborative work … [and] an important milestone on the road towards regenerative brain repair,” said Viviane Tabar, MD, founding investigator of BlueRock and chair of the neurosurgery department at MSK.”
Long-term I think stem cell-based therapies for Parkinson’s are extremely promising. It’s one of the most hopeful areas in regenerative medicine overall. Scientists like Drs. Tabar and Lorenz Suder of BlueRock and others like Jeanne Loring and Jun Takahashi are the gifted pioneers who are going to make a transformative difference here.