Gov.Capital’s analysis spotlights four pioneering biotech firms leveraging CRISPR-Cas9 and base-editing platforms to develop therapies aimed at molecular drivers of aging, such as PCSK9 and transthyretin. It examines in vivo lipid nanoparticle delivery, ex vivo edited stem cells, and key clinical programs for cardiovascular disease, amyloidosis, and immuno-oncology to guide investment decisions.
Key points
In vivo base editing of PCSK9 and ANGPTL3 via lipid nanoparticles achieves durable lipid reduction in early trials.
Ex vivo CRISPR-Cas9 editing of hematopoietic stem cells induces fetal hemoglobin to treat sickle cell and beta-thalassemia.
Phase 3 in vivo Cas9 therapy for transthyretin amyloidosis demonstrates clinical proof-of-concept with significant TTR protein knockdown.
Why it matters:
CRISPR-based gene therapies promise to transform treatment paradigms by offering single-dose cures for cardiovascular and degenerative age-related diseases, boosting healthspan.
Q&A
What is base editing?
How do lipid nanoparticles deliver gene editors?
What qualifies as a longevity stock?
Why target PCSK9 for healthspan?
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Academy
CRISPR-Cas9 Technology
Definition: CRISPR-Cas9 is a gene editing system originally found in bacteria, now used to precisely modify DNA in living cells for research and medical purposes. It works like a pair of molecular scissors guided by a small RNA sequence called guide RNA (gRNA), which directs the Cas9 enzyme to a specific DNA location. Once bound, Cas9 cuts the DNA, and the cell’s natural repair mechanisms can insert, delete, or replace genetic material at the cut site.
Functionally, CRISPR-Cas9 allows scientists to target any gene by designing a matching guide RNA. After the cut, two main repair paths occur:
- Non-Homologous End Joining (NHEJ): A quick repair that often leads to small insertions or deletions, disabling the gene.
- Homology-Directed Repair (HDR): A precise repair that uses a provided DNA template to correct or insert a specific sequence.
This versatility has made CRISPR-Cas9 the foundation for many research studies and emerging gene therapies.
Base Editing
Overview: Base editing is an advanced version of gene editing that allows scientists to change single letters in the DNA code without creating breaks on both strands. Imagine editing a document by changing individual characters instead of cutting the entire page. Base editors combine a modified dead Cas9 (dCas9) or nickase Cas9 (nCas9) with a chemical enzyme that can convert one DNA base into another.
Key features of base editing:
- High Precision: Direct conversion of one base to another (e.g., C→T or A→G) without introducing double-strand breaks.
- Reduced Unintended Changes: By avoiding full breaks, base editing lowers the risk of large insertions, deletions, or rearrangements.
- Therapeutic Potential: Base editing is well suited for correcting point mutations responsible for many genetic diseases, making it promising for treating age-related conditions.
Lipid Nanoparticle Delivery
What Are Lipid Nanoparticles? Lipid nanoparticles (LNPs) are tiny, ball-shaped structures made of fats that can safely carry gene-editing components such as RNA and proteins through the bloodstream. They protect the payload from degradation and help it enter target cells.
How LNPs Work:
- Encapsulation: CRISPR components (Cas9 or base editor mRNA, guide RNA) are enclosed within the lipid particle.
- Circulation: LNPs travel through the blood, avoiding rapid clearing by the immune system.
- Cellular Uptake: LNPs fuse with target cell membranes, releasing the gene-editing tools inside.
- Action: Once inside, the gene-editing machinery locates the target DNA and makes precise modifications.
LNPs have been crucial for recent mRNA vaccines and are now at the forefront of delivering gene therapies to the liver, muscle, and other tissues implicated in aging.
Applications in Longevity Science
Longevity science studies how biological processes influence aging and seeks ways to extend healthy years of life, called healthspan. Gene editing plays a key role by targeting the root causes of age-related diseases. Examples include:
- Cardiovascular Health: Inactivating the PCSK9 gene in the liver to lower cholesterol levels with a single treatment, reducing heart attack risk.
- Protein Misfolding Disorders: Editing the TTR gene to prevent harmful protein build-up in amyloidosis, a condition affecting older adults.
- Senescence: Research into editing pathways that clear “zombie” senescent cells, which drive inflammation and tissue breakdown during aging.
By correcting or disabling genes that contribute to chronic diseases, gene editing tools like CRISPR-Cas9 and base editors offer the potential for one-time treatments that can significantly boost healthy lifespan.