Rewriting the Code
Editor’s Note
This article is personal.
My brother was diagnosed with ALS in 2012. His disease is caused by a SOD1 mutation — one of the genetic variations now being targeted by gene-based therapies. Fourteen years later, his disease has progressed relentlessly. He is now essentially quadriplegic, wheelchair-bound, and dependent on 24/7 noninvasive positive pressure ventilation. His mind remains sharp. His body no longer cooperates.
When I read about therapies like tofersen (Qalsody) — the first FDA-approved treatment to target a genetic cause of ALS — I don’t see an abstract clinical trial result. I see a therapy that might have changed my brother’s life if it had arrived a decade sooner. And I see a future where diseases like his might be stopped before they start.
That is why this article exists. Not to advocate for reckless science, but to help patients and families understand what gene editing is, what it isn’t, and why the fear surrounding these technologies — much of it fueled by misinformation — risks blocking therapies from reaching the people who need them most.
The Tragedy That Changed Everything
On September 13, 1999, an 18-year-old named Jesse Gelsinger was infused with a recombinant adenoviral vector at the University of Pennsylvania, part of a gene therapy trial for ornithine transcarbamylase (OTC) deficiency — a rare metabolic liver disorder that is usually fatal at birth. Jesse had a milder form and volunteered not to cure himself, but to help babies who were dying from the disease.
Within hours, his body mounted a catastrophic immune response. The adenovirus triggered a systemic inflammatory cascade — organ failure, disseminated intravascular coagulation, and brain death. Jesse died four days later. He became the first person publicly identified as having died in a gene therapy trial.
At the time, I was a second-year medical student at the Uniformed Services University (USUHS) in Bethesda, Maryland, right across the street from the NIH campus. The shockwave from Jesse’s death rippled through every lecture hall and research corridor in the country. Gene therapy, which had seemed like the inevitable next frontier, was suddenly radioactive.
Federal investigators found that the trial’s leader, Dr. James Wilson, had violated multiple regulations, including failing to report serious adverse events in earlier subjects. UPenn paid fines. Clinical trials across the country were halted. Companies pulled out. The entire field of gene therapy went dark for nearly a decade.
But here’s the part that often gets lost: Wilson’s lab didn’t stop working. They pivoted to a safer delivery vehicle — adeno-associated virus (AAV) — which has since become the backbone of modern gene therapy. That pivot led to more than 250 clinical trials and two FDA-approved gene therapies. Tragedy, it turns out, can be a teacher.
The Code Breaker
Walter Isaacson’s 2021 book The Code Breaker tells the story of Jennifer Doudna, the Berkeley biochemist who, alongside Emmanuelle Charpentier, discovered how to repurpose an ancient bacterial immune defense into a revolutionary gene-editing tool: CRISPR-Cas9.
The science, in simple terms: bacteria have evolved a system to remember and destroy viruses that attack them. They store fragments of viral DNA in their own genome — like a molecular mugshot — and use a protein called Cas9 as molecular scissors to cut matching DNA sequences. In 2012, Doudna and Charpentier demonstrated that this system could be programmed to cut any DNA sequence — not just viral DNA.
The implications were staggering. For the first time, scientists had a tool that was precise, programmable, and cheap enough to edit the human genome with unprecedented accuracy. In 2020, Doudna and Charpentier were awarded the Nobel Prize in Chemistry for their discovery.
But with great power came a profound question: just because we can edit the human genome, should we?
Designer Babies and the Moratorium
The answer to that question arrived with disturbing speed.
In November 2018, Chinese biophysicist He Jiankui shocked the world by announcing that he had used CRISPR-Cas9 to edit the genomes of twin girls — Lulu and Nana — while they were still embryos. His stated goal was to make them resistant to HIV by disabling the CCR5 gene, which encodes a protein that allows the virus to enter immune cells.
The scientific community was horrified. Not because the technology didn’t work — but because He Jiankui had crossed a fundamental ethical line. He had performed germline editing: changes to embryonic DNA that would be passed to every subsequent generation. The babies were not at high risk for HIV. The edits were medically unnecessary. And the long-term consequences — for the children and their future offspring — were completely unknown.
A Chinese court sentenced He Jiankui to three years in prison and fined him approximately $434,000 for illegally practicing medicine and forging ethical review documents. As CRISPR pioneer Jennifer Doudna noted at the time: “As a scientist, one does not like to see scientists going to jail, but this was an unusual case.”
In March 2019, prominent scientists and ethicists — including two of the three CRISPR pioneers — called for a global moratorium on germline editing of human embryos for clinical use. That moratorium remains in effect today. The line is clear: editing embryos that will become people is, for now, off limits.
From Germline to Somatic: Where Gene Editing Fits Today
Understanding the distinction between germline and somatic gene editing is essential for patients, families, and clinicians trying to navigate this rapidly evolving landscape.
Germline editing modifies DNA in embryos or reproductive cells. The changes are heritable — they pass to the next generation and every generation after. This is what He Jiankui did, and it is what the moratorium prohibits.
Somatic editing modifies DNA in the cells of a living person — liver cells, blood cells, muscle cells. The changes affect only that individual and are not passed to their children. This is where the revolution is happening.
Think of it this way: germline editing rewrites the master blueprint for all future copies. Somatic editing fixes a typo in one specific copy of the book. Most of the therapies discussed in this article — and the ones most likely to reach your doctor’s office — are somatic.
Several distinct approaches are now in clinical development:
CRISPR-Cas9 gene editing uses molecular scissors to cut DNA at a precise location, disabling (or occasionally repairing) a target gene. It is powerful but irreversible. The cut is permanent.
Base editing is a refined version that changes a single DNA letter (like correcting a typo) without cutting both strands of the double helix. It is more precise and carries a lower risk of unintended mutations.
Epigenetic silencing uses a disabled version of the CRISPR machinery — the scissors are deactivated — to chemically silence a gene without altering the DNA sequence itself. In theory, this could be reversible, which addresses one of the biggest concerns about permanent gene editing.
RNA interference (siRNA and ASO) doesn’t edit DNA at all. Instead, it intercepts and degrades the messenger RNA (mRNA) that carries instructions from a gene to the cell’s protein-making machinery. Drugs like inclisiran (an siRNA targeting PCSK9) and tofersen (an ASO targeting SOD1 in ALS) work this way. They require repeated dosing because the effect wears off as new mRNA is produced.
The Cardiometabolic Revolution
A comprehensive review of liver-targeted gene editing therapies for cardiovascular disease (LivGETx-CVD) published in Cells (January 2026) captures just how far this field has come. The data are remarkable — and they illustrate why gene editing is moving from laboratory curiosity to clinical reality.
VERVE-102: Base Editing for Familial Hypercholesterolemia
Verve Therapeutics is developing VERVE-102, a single-dose base editing therapy that creates a precise A-to-G DNA edit to introduce a premature stop codon in the PCSK9 gene. PCSK9 is the protein that prevents your liver from clearing LDL cholesterol from the blood. Individuals born with naturally occurring PCSK9 loss-of-function mutations have dramatically lower LDL levels and up to an 88% reduction in coronary heart disease risk.
Initial data from the Heart-2 Phase 1b trial (April 2025) showed dose-dependent reductions in LDL cholesterol — up to 69% in a single participant at the highest dose studied, with a mean reduction of 53% in the 0.6 mg/kg cohort. No treatment-related serious adverse events were reported. The FDA granted Fast Track designation in 2025, and a Phase 2 trial is planned.
The delivery system itself is innovative: VERVE-102 uses a GalNAc-LNP (lipid nanoparticle with a liver-targeting molecule) to ensure the editing machinery reaches hepatocytes specifically — minimizing off-target effects in other organs.
CTX310: CRISPR-Cas9 for ANGPTL3
CRISPR Therapeutics is developing CTX310, a one-time CRISPR-Cas9 therapy that disables the ANGPTL3 gene in hepatocytes. ANGPTL3 is a protein that regulates both triglyceride and LDL cholesterol levels. People born with natural ANGPTL3 loss-of-function mutations have lower lipids and reduced cardiovascular risk.
Phase 1 data presented at the 2025 AHA Scientific Sessions and published simultaneously in the NEJM showed a mean 73% reduction in ANGPTL3, 55% reduction in triglycerides, and 49% reduction in LDL at the highest dose — results the investigators said exceeded expectations. A single treatment produced effects lasting at least 60 days. Lead investigator Stephen J. Nicholls of Monash University called the findings “truly unprecedented.”
Critically, CTX310 works through an LDLR-independent pathway — meaning it could help patients with homozygous familial hypercholesterolemia (HoFH) whose LDL receptors are nonfunctional. For these patients, who often develop coronary artery disease in childhood, CTX310 represents a genuinely new treatment paradigm.
STX-1150: Epigenetic Silencing — Editing Without Cutting
Scribe Therapeutics is developing STX-1150, which uses their proprietary ELXR (Epigenetic Long-Term X-Repressor) technology — a disabled CasX enzyme fused to proteins that chemically silence gene expression. In preclinical studies in non-human primates, a single low-dose injection reduced PCSK9 by up to 90% and LDL cholesterol by up to 68%, with effects lasting 18 months and ongoing.
The key distinction: STX-1150 does not cut DNA. It silences the gene through epigenetic modifications — think of it as putting a “mute” button on a gene rather than deleting it. Transcriptome-wide profiling showed that their allosteric regulatory domain reduced unintended gene expression changes by 10- to 100-fold compared to conventional constructs. A Phase 1 clinical trial is planned for mid-2026.
This approach directly addresses the irreversibility concern raised in a February 2026 NEJM correspondence that cautioned against using permanent gene editing for non-life-threatening cardiometabolic conditions. If a therapy can be “unmuted,” the risk calculus changes dramatically.
The Four Targets
Current cardiometabolic gene editing programs target four proteins, each genetically and clinically validated:
| Target | Primary Effect | Clinical Significance |
|---|---|---|
| PCSK9 | LDL cholesterol | Most advanced target; VERVE-102 base editing in Phase 1b; 88% CHD risk reduction with natural loss-of-function |
| ANGPTL3 | Triglycerides + LDL | LDLR-independent pathway; critical for HoFH patients; CTX310 Phase 1 human data published (NEJM 2025): 73% ANGPTL3 reduction, 55% TG reduction, 49% LDL reduction at highest dose; no serious adverse events; Phase 2 planning underway |
| APOC3 | Triglycerides | CV benefits independent of LDL lowering; multiple programs in development |
| LPA | Lipoprotein(a) | Addresses the most intractable genetic CV risk factor; Lp(a) levels ~90% determined by genetics |
Beyond the Heart
The cardiometabolic applications are exciting, but they represent only one front of a much larger revolution.
Sickle Cell Disease: The First CRISPR Cure
On December 8, 2023, the FDA approved Casgevy (exagamglogene autotemcel) — the first-ever CRISPR-based therapy approved for clinical use. Developed by Vertex Pharmaceuticals and CRISPR Therapeutics, Casgevy treats sickle cell disease by editing patients’ own stem cells to reactivate production of fetal hemoglobin, which prevents the sickling of red blood cells.
In clinical trials, 29 of 30 patients were free of severe pain crises for at least 12 consecutive months after treatment. For a disease that affects approximately 100,000 Americans and has a median life expectancy of 45 years, this represents a potential functional cure.
ALS and the SOD1 Mutation
Tofersen (Qalsody), approved by the FDA in April 2023, is not a gene editor — it’s an antisense oligonucleotide (ASO) that targets the mRNA produced by mutated SOD1 genes to reduce production of the toxic protein. SOD1 mutations account for about 2% of ALS cases — approximately 330 people in the United States.
Long-term data show that tofersen delays symptom progression and, in about one-quarter of participants, leads to stabilization or improvement. It is administered intrathecally (via lumbar puncture) every 28 days. It is not a cure. But for a disease that has been uniformly fatal with no disease-modifying therapy for over a century, it represents a fundamental shift.
And the field is not stopping at ASOs. True gene editing approaches for ALS — including CRISPR-based strategies to permanently silence mutant SOD1 — are in preclinical development. For patients like my brother, these represent the next horizon.
Cancer, Rare Diseases, and Beyond
Gene editing is being explored for dozens of conditions: beta-thalassemia (Casgevy was also approved for this), hereditary angioedema, transthyretin amyloidosis, certain cancers (using CRISPR-edited T cells), and rare pediatric diseases. The common thread: conditions where a single gene or a small number of genes drive the disease, and where existing therapies are inadequate or nonexistent.
The COVID Shadow
In 2020, mRNA vaccines from Pfizer-BioNTech and Moderna saved millions of lives. They also inadvertently poisoned public understanding of RNA-based technology.
The misinformation that spread during the pandemic was pervasive and persistent: mRNA vaccines “alter your DNA,” they “rewrite your genetic code,” they are “gene therapy in disguise.” None of this was true. mRNA vaccines deliver a temporary instruction to your cells to produce a protein (the spike protein) that trains your immune system. The mRNA is degraded within days. It never enters the nucleus. It does not touch your DNA.
But the damage was done. The word “RNA” became associated with fear, conspiracy, and government overreach. And that fear has bled into an entirely unrelated clinical space.
Clinicians now report encountering patients who are hesitant about inclisiran — a twice-yearly injectable siRNA that lowers LDL cholesterol by about 50% — not because of its side effect profile, but because they hear “RNA” and assume it is related to the COVID vaccine. Research confirms that negative sentiment toward mRNA technologies is widespread and global, extending well beyond vaccines to all RNA-based therapeutics.
This confusion matters because these technologies are fundamentally different:
| Technology | What It Does | Touches DNA? | Permanent? |
|---|---|---|---|
| mRNA Vaccine | Delivers temporary protein instructions | No — never enters nucleus | No — degrades in days |
| siRNA (e.g., inclisiran) | Silences specific mRNA | No | No — requires re-dosing |
| ASO (e.g., tofersen) | Degrades specific mRNA | No | No — requires re-dosing |
| Base Editing (VERVE-102) | Changes single DNA letter | Yes — precise edit | Yes — one-and-done |
| CRISPR-Cas9 (CTX310) | Cuts and disables gene | Yes — double-strand break | Yes — one-and-done |
| Epigenetic (STX-1150) | Silences gene via chromatin | No — modifies histone/methyl marks | Durable; potentially reversible |
Lumping all of these together under the banner of “gene therapy” — or worse, “the same thing as the COVID vaccine” — is not just inaccurate. It is dangerous. It causes patients to refuse therapies that could save their lives.
Adding to the complexity: in early 2026, the FDA refused to review Moderna’s mRNA flu vaccine application under the new HHS leadership — a decision widely seen as politically motivated rather than scientifically driven. Whether or not one agrees with that decision, it further muddied the waters for patients trying to distinguish between technologies.
The Ethics of “One-and-Done”
The promise of a single treatment that permanently lowers your cholesterol, silences a toxic gene, or cures a blood disorder is extraordinary. But permanence is a double-edged sword.
A February 2026 correspondence in the NEJM raised an important caution: should we use irreversible gene editing to treat conditions that are not immediately life-threatening? A patient with homozygous FH who develops coronary disease in childhood has a very different risk-benefit calculus than someone with moderately elevated LDL who could be managed with existing therapies.
The ethical framework that has emerged centers on a spectrum:
At one end: lethal diseases with no adequate alternatives. Sickle cell disease. Homozygous FH. SOD1-ALS. For these patients, the calculus is clear. The disease will kill them. The therapy offers a chance at life. The risk of irreversibility is far outweighed by the certainty of progression without treatment.
In the middle: serious conditions with existing but imperfect therapies. Heterozygous FH with CAD despite maximum medical therapy. Severe hypertriglyceridemia refractory to treatment. Here, the conversation becomes nuanced. Gene editing may be appropriate, but patients and clinicians must weigh the permanence of the edit against the availability of reversible alternatives.
At the other end: enhancement. Editing genes to make someone taller, smarter, or more athletic. This is the dystopian scenario — the designer baby concern — and it is emphatically not what is being proposed by any legitimate clinical program today.
The emergence of epigenetic silencing (STX-1150) and reversible approaches may help resolve some of this tension. If we can silence a gene without permanently altering the DNA sequence, and if that silence can theoretically be reversed, the ethical threshold for treatment shifts. We move from “is this disease lethal enough to justify irreversible change?” to “what is the durable benefit relative to the manageable risk?”
Fifteen-year follow-up studies are mandated by the FDA for all CRISPR-based therapies. The field is proceeding with appropriate caution. But the ethical conversation must keep pace with the science — and patients deserve to be part of that conversation.
CardioAdvocate Checklist
If your clinician mentions a gene-based therapy — whether it’s a CRISPR treatment, a base editor, an siRNA, or an ASO — here are questions that can help you understand what’s being proposed and make an informed decision:
Deep Dive: The Science and History of Gene Editing
This section provides additional detail for clinicians and patients who want a deeper understanding of the science, the regulatory landscape, and the evolving clinical pipeline.
A Brief History of Gene Therapy
The idea of correcting genetic diseases by inserting functional genes is not new. The first approved gene therapy trial in the United States was conducted at the NIH in 1990, treating a four-year-old girl with severe combined immunodeficiency (SCID) using a retroviral vector to deliver a functional adenosine deaminase (ADA) gene. Early results were modest but promising.
The Jesse Gelsinger tragedy in 1999 halted the field’s momentum. But the subsequent pivot to safer adeno-associated virus (AAV) vectors gradually restored confidence. In 2017, the FDA approved Luxturna (voretigene neparvovec) for inherited retinal dystrophy — the first gene therapy approved for a genetic disease in the U.S. In 2019, Zolgensma (onasemnogene abeparvovec) was approved for spinal muscular atrophy, becoming one of the most expensive therapies in history but also one of the most transformative.
The approval of Casgevy in December 2023 marked the arrival of CRISPR in the clinic — a quantum leap from inserting genes to precisely editing them.
Understanding CRISPR: The Molecular Mechanism
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a natural bacterial defense system. When a bacterium survives a viral attack, it stores a snippet of the virus’s DNA in its own genome as a “memory.” If the same virus attacks again, the bacterium produces a guide RNA that matches the stored snippet and directs the Cas9 protein to find and cut the matching viral DNA, destroying it.
Doudna and Charpentier’s breakthrough was demonstrating that this system could be reprogrammed with a synthetic guide RNA to target any DNA sequence in any organism. The system has two components: a guide RNA that specifies the target and the Cas9 protein that makes the cut. By changing the guide RNA, researchers can direct the scissors to any gene they choose.
Base editing, developed by David Liu at the Broad Institute, refines this approach further. Instead of cutting DNA, base editors chemically convert one DNA letter to another (e.g., C to T, or A to G) without creating a double-strand break. This reduces the risk of insertions, deletions, and chromosomal rearrangements that can occur with standard CRISPR cuts.
The Regulatory Landscape
The FDA regulates gene therapies under the Center for Biologics Evaluation and Research (CBER). All CRISPR-based therapies require a 15-year long-term follow-up period, reflecting the novelty and permanence of the intervention. The accelerated approval pathway — used for tofersen — allows drugs to reach patients based on surrogate endpoints (like biomarker changes) while confirmatory trials continue.
Internationally, the regulatory landscape varies. The UK’s MHRA approved Casgevy before the FDA. The EMA in Europe has its own approval timeline. For gene editing of embryos (germline editing), most countries either ban it outright or lack specific regulations — a gap that He Jiankui exploited.
The Pipeline: What’s Coming
Beyond the therapies discussed above, the cardiometabolic gene editing pipeline includes programs targeting APOC3 (for triglyceride reduction) and LPA (for Lp(a) lowering). Lp(a) is a particularly compelling target because levels are approximately 90% genetically determined, largely unaffected by diet or exercise, and associated with significant cardiovascular risk. Current siRNA programs for Lp(a) (olpasiran, lepodisiran, zerlasiran) are in Phase 3 trials, with gene editing approaches in preclinical development.
The convergence of improved delivery systems (GalNAc-LNPs, tissue-specific targeting), refined editing tools (base editing, epigenetic silencing), and expanding target validation (PCSK9, ANGPTL3, APOC3, LPA) suggests that cardiometabolic gene editing will move from investigational to mainstream within the next decade.
Landmark References
Jinek M, Charpentier E, Fonfara I, et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096):816-821.
Musunuru K, Chadwick AC, Mizoguchi T, et al. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature. 2021;593:429-434.
Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. NEJM. 2021;384(3):252-260.
Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. NEJM. 2022;387(12):1099-1110.
Isaacson W. The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race. Simon & Schuster; 2021.
Nicholls SJ, et al. Phase 1 Trial of CRISPR-Cas9 Gene Editing Targeting ANGPTL3. NEJM. 2025.
The Bottom Line
- • Gene editing is not one technology — it is a spectrum of approaches ranging from temporary RNA silencing to permanent DNA modification. Understanding the differences is essential.
- • The CRISPR revolution has already delivered the first approved gene-editing cure (Casgevy for sickle cell) and is rapidly advancing toward cardiometabolic applications targeting PCSK9, ANGPTL3, APOC3, and LPA.
- • COVID-19 vaccine misinformation has created unwarranted fear of all RNA-based therapies. siRNA drugs like inclisiran do not alter DNA and are mechanistically distinct from mRNA vaccines.
- • The ethics of permanent gene editing center on a spectrum from lethal diseases (clear benefit) to enhancement (clearly inappropriate), with an important gray zone in between that requires shared decision-making.
- • Patients and clinicians must engage in these conversations now — before fear and misinformation close the door on therapies that could save lives.
