DNA hairpin therapy targets the gene behind high cholesterol

Overview

For two decades, lowering LDL cholesterol meant statins—daily pills that work for most but leave roughly one in five patients with muscle pain or liver enzyme changes severe enough to quit. On May 1, researchers from the University of Barcelona and Oregon Health & Science University reported that engineered DNA reduced LDL by nearly 50 percent in mice. A single injection of this engineered DNA molecule silences the gene controlling how the liver clears LDL.

HpE12 targets PCSK9—the same gene that Repatha, Praluent, and Leqvio go after, but upstream: it blocks the gene before any protein is made. The PCSK9 field is competitive: Eli Lilly paid $1.3 billion in July 2025 for Verve Therapeutics, whose base-editing drug cut LDL by 53 percent in a Phase 1b human trial. Merck's once-daily oral PCSK9 inhibitor enlicitide achieved 57 percent LDL reduction in three Phase 3 trials.

Merck published enlicitide's manufacturing method in Science on May 7, and Lerochol, another third-generation injectable, won FDA approval in December 2025. HpE12 has not entered human trials. The researchers say synthetic DNA strands are cheaper to synthesize than antibodies or RNA-based therapies and are not immunogenic; however, these claims haven't been tested at clinical scale.

Why it matters

A single DNA injection silencing PCSK9 for months could reach statin-intolerant patients far cheaper than antibodies or gene editors—if anyone funds human trials.

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Key Indicators

47%

LDL cholesterol drop

Reduction in plasma cholesterol three days after a single HpE12 injection in transgenic mice.

87%

PCSK9 protein silenced

How much HpE12 suppressed PCSK9 protein levels in liver cells.

74%

PCSK9 RNA suppressed

Reduction in PCSK9 messenger RNA, blocking the gene before it produces protein.

~10-25%

Statin patients with muscle symptoms

Share of statin users reporting muscle pain, weakness, or fatigue—the gap a non-statin therapy would fill.

Human trials so far

Findings remain preclinical. Phase 1 safety trials in humans have not begun.

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People Involved

Carles J. Ciudad

Co-lead author of the PCSK9 PPRH study

Verònica Noé

Co-lead author of the PCSK9 PPRH study

Nathalie Pamir

Co-author and collaborator on the PCSK9 study

Helen Hobbs

Identified the human genetic evidence underpinning all PCSK9 drugs

Organizations Involved

University of Barcelona

Research University

Lead institution on the PPRH platform and HpE12 molecule

Spanish research university whose pharmacy and nanotechnology institutes developed the polypurine reverse-Hoogsteen hairpin gene-silencing platform.

Oregon Health & Science University

Research University and Medical Center

Provided in vivo testing in transgenic mouse models

Portland-based academic medical center that ran the mouse experiments validating HpE12's cholesterol-lowering effect.

U.S. Food and Drug Administration

Federal Agency

Approved Lerochol (December 2025); evaluating enlicitide decanoate as potential first oral PCSK9 inhibitor

U.S. agency that approves new drugs, including the existing PCSK9 inhibitors and any future PPRH-based therapy.

Merck & Co.

Pharmaceutical Company

Advancing enlicitide decanoate toward FDA filing after positive Phase 3 results

U.S. pharmaceutical company developing enlicitide decanoate, an oral PCSK9 inhibitor that completed Phase 3 with 55–59% LDL reductions and published large-scale manufacturing methods in Science on May 7, 2026.

Verve Therapeutics (acquired by Eli Lilly, July 2025)

Biotech

Subsidiary of Eli Lilly; VERVE-102 in Phase 1b clinical trials targeting PCSK9

Boston-based gene editing company, now part of Eli Lilly, developing VERVE-102—a base-editing medicine that permanently silences PCSK9 in liver cells. Phase 1b Heart-2 trial data showed 53% mean LDL reduction at the highest dose tested.

Timeline

February 2003 May 2026

11 events Latest: May 7th, 2026 · 1 month ago Showing 8 of 11

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May 2026
Merck publishes large-scale synthesis method for oral PCSK9 inhibitor in Science
Latest Research

Merck scientists detailed a biocatalytic method for making enlicitide decanoate at commercial scale, cutting total synthesis steps to 43 and improving yield 1,000-fold over the first-generation route. Enlicitide completed Phase 3 trials with 57% mean LDL reduction and is advancing toward FDA filing as the potential first oral PCSK9 inhibitor.
May 7th, 2026
DNA hairpins cut LDL by nearly 50% in mice
Research

Barcelona and Oregon researchers publish in Biochemical Pharmacology that HpE12, a polypurine reverse-Hoogsteen hairpin, silences PCSK9 and lowers LDL cholesterol by 47 percent after a single injection in transgenic mice.
May 1st, 2026
December 2025
FDA approves Lerochol, a once-monthly PCSK9 inhibitor
Regulatory

The FDA approved lerodalcibep-liga (Lerochol; LIB Therapeutics), a once-monthly self-administered injection that cut LDL by at least 60% in high-risk patients. The drug was expected to reach U.S. pharmacies in spring 2026, adding a third generation of PCSK9-targeting drugs behind the existing monoclonal antibodies and inclisiran.
December 15th, 2025
July 2025
Eli Lilly closes $1.3B acquisition of Verve Therapeutics
Corporate

Lilly completed its acquisition of Verve Therapeutics, gaining VERVE-102, an in vivo PCSK9 base-editing medicine in Phase 1b trials. Earlier in 2025, Verve had reported that a single dose cut LDL by 53% and PCSK9 by 60% at the highest tested dose, with no serious adverse events in 14 patients.
July 25th, 2025
December 2021
FDA approves inclisiran in U.S.
Regulatory

After a manufacturing-related delay, Leqvio reaches U.S. patients. Twice-yearly dosing offers a longer-acting alternative to monthly antibody injections.
December 22nd, 2021
December 2020
Inclisiran approved in Europe
Regulatory

Novartis's Leqvio, a small interfering RNA that silences PCSK9 in the liver, gains EU approval—shifting the field from antibodies to RNA-based silencing.
December 9th, 2020
August 2015
Repatha approved
Regulatory

Amgen's evolocumab joins Praluent on the U.S. market, establishing monoclonal antibodies as the first generation of PCSK9 drugs.
August 27th, 2015
July 2015
FDA approves first PCSK9 inhibitor
Regulatory

Praluent (alirocumab), a monoclonal antibody from Regeneron and Sanofi, becomes the first PCSK9-targeting drug approved in the United States.
July 24th, 2015
January 2006
Healthy person with no PCSK9 identified
Discovery

Hobbs's group documents a woman with two non-functional copies of PCSK9, no detectable PCSK9 protein, and very low LDL—evidence that fully blocking the gene is safe.
January 1st, 2006
February 2005
Loss-of-function mutations protect against heart disease
Discovery

Helen Hobbs and Jonathan Cohen show that people with broken PCSK9 genes have low LDL and dramatically reduced rates of coronary heart disease.
February 1st, 2005
February 2003
PCSK9 gene first identified
Discovery

Nabil Seidah's lab in Montreal and Catherine Boileau's group in France independently identify PCSK9 and link mutations in the gene to familial hypercholesterolemia.
February 1st, 2003

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Historical Context

3 moments from history that rhyme with this story — and how they unfolded.

September 1987

First statin approved (1987)

The FDA approved lovastatin (Mevacor) from Merck, the first cholesterol-lowering statin. It worked by blocking HMG-CoA reductase, a liver enzyme central to cholesterol production, and it transformed cardiovascular medicine.

Then

Statins quickly became the dominant LDL-lowering class, with Lipitor going on to become the best-selling drug in pharmaceutical history.

Now

Decades of statin use cut heart attack and stroke rates substantially, but exposed a persistent gap: 10–25 percent of patients report muscle symptoms and many discontinue, leaving an opening for non-statin alternatives like PCSK9 inhibitors and now PPRHs.

Why this matters now

The statin era defined what the next class of cholesterol drugs has to beat: cheap, oral, daily, and effective for most—but not for the patients who can't tolerate them. HpE12 targets that gap directly.

July–August 2015

PCSK9 monoclonal antibody approvals (2015)

The FDA approved Praluent (alirocumab) from Regeneron-Sanofi and Repatha (evolocumab) from Amgen within five weeks of each other. Both were monoclonal antibodies that bound free PCSK9 protein in the bloodstream, lowering LDL by roughly 60 percent on top of statins.

Then

Initial uptake disappointed because of $14,000-per-year prices and tight insurance coverage. List prices eventually dropped roughly 60 percent.

Now

Established PCSK9 as a validated drug target and proved that a non-statin biologic can durably lower LDL. It also showed payers would resist high-priced cardiovascular drugs—an issue any PPRH product would inherit.

Why this matters now

HpE12 aims at the same gene the antibodies target but earlier in the pathway. Whether it can match their efficacy at lower cost is the central commercial question if it reaches humans.

December 2020–December 2021

Inclisiran approval (2020–2021)

Novartis's Leqvio, a small interfering RNA that silences PCSK9 production in liver cells, was approved in the EU in December 2020 and in the U.S. a year later after a manufacturing-related FDA rejection. Patients dose twice yearly instead of monthly.

Then

Leqvio's launch was hampered by COVID-era healthcare disruption and Medicare coverage debates over how clinics would administer and bill for it.

Now

Demonstrated that nucleic-acid-based gene silencing can reach the liver and produce sustained LDL reductions in humans—the closest commercial precedent for a PPRH cholesterol drug.

Why this matters now

Inclisiran is the proof of concept that a gene-silencing PCSK9 drug can win approval and reach patients. HpE12 would need to clear the same delivery and durability bars, but with a different—and potentially cheaper—chemistry.