ART001 gene editing suppresses TTR for 72 weeks after a single dose in patients with hereditary ATTR
Gene editing aimed at reducing the burden of repeat dosing
In an exploratory study of 10 people with hereditary ATTR amyloidosis, reduced blood transthyretin (TTR) levels were observed through 72 weeks after a single dose of the gene-editing therapy ART001. At week 72, mean reductions were 84% and 92% in the 0.7 mg/kg and 1.0 mg/kg groups, respectively, with three participants in each group. A reduction in blood protein alone does not establish symptom improvement or slowed disease progression.
ATTR amyloidosis is a disease in which TTR misfolds and accumulates in tissues. Deposits in peripheral nerves or the heart can cause neuropathy and cardiomyopathy. Existing therapies that target TTR messenger RNA (mRNA) require repeat dosing. ART001 aims to inactivate the TTR gene itself in liver cells, suppressing protein production for an extended period after a single dose.
ART001 is an in vivo CRISPR-Cas9 gene-editing therapy. Lipid nanoparticles (LNPs) deliver mRNA encoding Cas9 and a single-guide RNA (sgRNA) targeting the TTR gene to liver cells. Although it carries RNA, ART001 is designed to edit the TTR gene, unlike RNA interference, which targets TTR mRNA.
Results at 72 weeks in the two higher-dose groups of three participants each
These findings are an interim report from a single-center, open-label, nonrandomized, single-arm investigator-initiated trial. All 10 participants with hereditary ATTR had symptoms of sensorimotor polyneuropathy. A single dose was administered at one of six dose levels ranging from 0.05–1.0 mg/kg, based on total RNA. The 0.7 mg/kg and 1.0 mg/kg groups each had three participants; each of the other dose groups had one. Without a placebo group, each participant’s post-treatment results were compared with their own pretreatment values.
Mean blood TTR levels fell by 86% and 92% at week 4 in the 0.7 mg/kg and 1.0 mg/kg groups, respectively. At week 72, levels remained 84% and 92% below baseline, respectively. One participant who received 0.5 mg/kg had a 76% reduction at week 72. These results cover an observation period of 72 weeks. Persistence beyond two years or a permanent effect has not been established.
No infusion-related reactions or serious adverse events were reported, but adverse events did occur after treatment. Transient alanine aminotransferase (ALT) elevation and grade 3 hypertriglyceridemia were reported in the 1.0 mg/kg group. ALT returned to normal by the week 2 visit without intervention, while triglyceride levels returned to normal within one week after drug treatment. “Grade 3,” which describes severity, should be distinguished from a “serious adverse event.” All participants received premedication with steroids and histamine H1 and H2 receptor blockers before infusion. The researchers also suggested that underlying conditions or steroid premedication might have contributed to the hypertriglyceridemia.
Questions remain about the link between lower TTR and clinical benefit
In the six participants in the two higher-dose groups, neuropathy impairment scores remained stable through week 72. Other exploratory neurological and cardiac assessments also showed no significant improvement. Because this was a small study without a control group, stable scores cannot be taken as proof that ART001 slowed disease progression.
Dividing 10 participants among six dose groups limits the assessment of dose-specific effects and rare adverse events. The trial was also registered retrospectively, and safety and clinical benefit beyond 72 weeks remain undetermined. The study drug was provided by its developer, Accuredit Therapeutics, and some authors were company employees. These findings provide a basis for further clinical research, but larger comparative trials and long-term follow-up are needed to assess superiority over existing treatments or long-term safety.
The study design and results are available in the original paper in Frontiers in Medicine.
BACKGROUND: ATTR amyloidosis is a disease caused by abnormal deposition of TTR (transthyretin) protein in tissues. ART001 is an METHODS: In an investigator-initiated trial (IIT) of ART001 for 10 ATTR Amyloidosis patients, each patient was given one dose of ART001 which ranged from 0.05 mg/kg to 1.0 mg/kg. The aim was to evaluate ART001's safety, side effects, PK, PD, and efficacy based on circulating TTR protein levels. RESULTS: At 0.7 mg/kg in 3 subjects and 1 mg/kg in 3 subjects, TTR protein reductions averaged 84 and 92% at 72 weeks. No infusion-related reactions (IRRs), serious adverse events (SAEs) or serious adverse reactions (SARs) were observed. CONCLUSION: A single injection of ART001 achieved > 80% TTR knock-down at doses > 0.5 mg/kg and lasted for at least 72 weeks without IRRs, SARs or SAEs. ART001 has the potential to be a safe, effective and permanent therapeutic option for ATTR Amyloidosis patients. (Funded by Accuredit Therapeutics). CLINICAL TRIAL REGISTRATION: Trial registration: ChiCTR, ChiCTR2400081216. Registered 26
If future comparative trials confirm ART001’s clinical benefit and long-term safety, the findings could provide a basis for considering single-dose gene editing as an option for people with hereditary ATTR who require repeated administration of TTR-targeting drugs. To assess its use in clinical practice, studies must establish not only a reduction in blood TTR but also whether walking ability, nerve function, cardiac status, and patient-reported quality of life improve. This trial did not establish fewer clinic visits, lower costs, or improved quality of life. Long-term safety follow-up is needed even after a single dose, and all participants in the study received vitamin A supplementation. Requirements for ongoing monitoring and care must be evaluated alongside dosing frequency.