Phase 1/2 Study of rnaivt9315 and rnacs24757 in Adults with PiZZ Alpha‑1 Antitrypsin Deficiency Lung or Liver Disease

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What is this study about?

The study looks at adults with the PiZZ genotype of Alpha-1 Antitrypsin Deficiency, a rare condition that can cause problems in the lungs and liver. The condition means the body makes too little of a protein that protects the lungs and liver from damage, leading to breathing difficulties or liver disease. The medicine being tested is called TSRA-196, which is given as a intravenous infusion (a fluid placed into a vein).

The purpose of the study is to find out whether a single dose of the medicine is safe and can increase the amount of protective protein in the blood of people with this condition.

In the study, participants receive one dose of the medicine and are checked regularly for several months to see how they feel and to measure blood levels of the protective protein. After the first follow‑up period, a second dose may be given and the same type of monitoring continues for up to a year. Visits include simple blood tests and basic health checks, without any complex procedures.

1 baseline visit

after enrollment, you will attend a baseline visit at the study site.

during this visit a complete medical history and physical examination are performed.

blood samples are taken to measure your current total aat (alpha‑1 antitrypsin) level and to assess other laboratory values.

a lung function test called post‑bronchodilator ppfev1 (the amount of air you can forcefully exhale in one second after using medication that opens the airways) is done to evaluate lung health.

2 first dose administration

you receive a single intravenous infusion of tsra‑196, a solution for infusion that contains the active substances rnaivt9315 and rnacs24757.

the infusion is given through a vein over a short period of time as directed by the study staff.

the exact amount of medication is determined by the study protocol, but it is administered as a single dose.

3 immediate post‑infusion monitoring

after the infusion you remain at the clinic for several hours while staff check your vital signs (blood pressure, heart rate, temperature) and watch for any immediate side effects.

any symptoms you experience are recorded.

4 month 3 follow‑up after first dose

approximately three months after the first infusion you return for a follow‑up visit.

a blood draw is performed to measure total aat level and functional aat activity (how well the protein works).

the same lung function test (post‑bronchodilator ppfev1) is repeated.

the study team records any adverse events that have occurred since the last visit.

5 month 6 follow‑up after first dose

around six months after the first infusion you attend another visit.

blood samples are taken again to assess total and functional aat levels.

lung function testing is repeated.

safety assessments, including laboratory tests and vital signs, are performed.

6 extended monitoring through month 12 after first dose

from month 6 through month 12 you may have periodic clinic visits (as scheduled by the study) to check laboratory values, vital signs, and any new symptoms.

additional blood draws may be done to track aat levels over time.

7 second dose administration (part 3)

after completing the follow‑up period for the first dose, you receive a second single intravenous infusion of tsra‑196.

the procedure is the same as the first infusion: the medication is given through a vein over a short period.

8 immediate post‑second‑dose monitoring

following the second infusion you remain at the clinic for several hours while staff monitor vital signs and watch for side effects.

any symptoms are documented.

9 month 3 follow‑up after second dose

approximately three months after the second infusion you attend a follow‑up visit.

blood is drawn to measure total and functional aat levels.

lung function testing (post‑bronchodilator ppfev1) is repeated.

the study team records any adverse events that have occurred.

10 month 6 follow‑up after second dose

around six months after the second infusion you have another visit.

blood samples are taken to evaluate total and functional aat levels.

lung function testing is performed again.

safety assessments, including laboratory tests and vital signs, are completed.

11 extended monitoring through month 12 after second dose

from month 6 through month 12 after the second dose you may have additional scheduled visits to monitor laboratory values, vital signs, and any new symptoms.

further blood draws may be done to track the durability of the aat response.

Who Can Join the Study?

Must be a man or woman who is between 18 and 70 years old when signing the consent form.
If you have lung disease related to Alpha‑1 Antitrypsin Deficiency (AATD) with little or no liver scarring, you need to have noticeable lung problems that are not extremely severe and only minimal liver scarring, shown by a liver biopsy or a non‑invasive test.
If you have liver disease related to AATD with moderate‑to‑severe scarring (with or without lung disease), you must have that level of liver scarring confirmed by a liver biopsy.
Your body mass index (BMI) must be between 18 and 37 kg/m². (BMI is a number that relates your weight to your height.)
You must have a confirmed diagnosis of Alpha‑1 Antitrypsin Deficiency and the specific PiZZ genetic type.
You need at least one blood test showing a total AAT (Alpha‑1 Antitrypsin) level lower than 11 μmol/L.
You must be a nonsmoker for at least 6 months before screening and must stay smoke‑free for the entire study.
You must agree not to drink alcohol for 14 days before receiving the study drug and for 30 days after, and you must avoid significant alcohol use for the whole study.
Your total bilirubin level (a measure of liver function) must meet the study’s requirements, whether or not you have Gilbert’s syndrome (a mild condition that can affect bilirubin).
All other laboratory and hematology (blood cell) values must be within the ranges defined by the study.
You must either have never received AAT therapy before or have stopped any treatments that change AAT levels for the required wash‑out period before joining the study.

Who Cannot Join the Study?

Having a genetic change near the PiZ variant that could affect the study drug, found by a DNA test (genotyping).
Having serious lung disease that is not caused by Alpha‑1 Antitrypsin Deficiency, as decided by the doctor.
Being hospitalized one or more times for a severe exacerbation (flare‑up) of lung disease in the past year, or having received IV (intravenous) antibiotics for a lung infection within the last 6 months.
Having unstable COPD caused by AATD, or having severe bronchiectasis (damage that makes the airways permanently widened and scarred).
Having had lung‑volume‑reduction surgery in the past year or planning to have this surgery during the study.
Needing continuous positive airway pressure therapy (such as CPAP) beyond normal nighttime use.
Having received an organ transplant or being on a waiting list for one.
Being dependent on continuous supplemental oxygen.
Receiving any vaccine within 30 days before the dose if it is a weakened live vaccine, or within 14 days if it is any other vaccine.
Having previously received gene therapy that uses viruses to change DNA, or planning to permanently alter DNA (RNA‑based treatments are allowed).
Testing positive for HIV, active hepatitis B (positive blood markers indicating infection) or hepatitis C (positive RNA test or antibody).
Having had a blood clot (thromboembolic disease), heart attack (myocardial infarction), or stroke within the last 6 months.
Having high blood pressure that is not controlled (uncontrolled hypertension) as defined by the study rules.
Having had a severe allergic reaction to the lipid nanoparticle (LNP) delivery system that was graded 3 or higher (CTCAE Grade 3 or higher).
Having an active cancer diagnosed within the past 5 years, except for certain skin cancers (basal cell carcinoma, fully removed squamous cell carcinoma), treated cervical pre‑cancer (cervical carcinoma in situ), or low‑grade prostate cancer that is only being watched.
Having a “null” or loss‑of‑function mutation in the SERPINA1 gene, identified by DNA testing.
Having liver disease that is not related to AATD.
Having signs of cirrhosis (such as swollen veins in the esophagus varices or fluid buildup in the abdomen ascites).

Where you can join this trial?

Verified and Recommended Sites

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Verified Sites

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Other Sites

Site Name	City	Country
Beaumont Hospital	Dublin	Ireland
Karolinska University Hospital	Solna	Sweden
Queen Silvia Childrens Hospital – Sahlgrenska University Hospital – Vaestra Goetalandsregionen	Gothenburg	Sweden
Lfinl Ugrqeignxdia Muhxdmx Ckyihrl (qrnze	Leiden	The Netherlands

Trial status

Country	Status	Recruitment Start
Ireland	Not yet recruiting	30.04.2026
Sweden	Not yet recruiting	30.04.2026
The Netherlands	Not yet recruiting	30.04.2026

Trial locations

TSRA-196 is an experimental treatment being studied for adults who have severe alpha‑1 antitrypsin deficiency (AATD) with lung and/or liver problems. It is given by a one‑time intravenous infusion (a liquid that is slowly dripped into a vein). The product contains two specially designed RNA molecules, called RNAIVT9315 and RNACS24757, which are intended to help the body make more of the missing protective protein or to reduce disease activity. In the trial, participants receive a single dose to see how safe it is and whether it improves their condition, and some participants later receive a second dose to further evaluate its effectiveness. Patients are closely monitored for any side effects and for changes in lung and liver health.

Investigated diseases:

Alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin deficiency – A genetic condition that reduces the amount of a protein protecting lung tissue and liver cells. In the lungs, the lack of protection allows enzymes to damage the airways, leading to gradually worsening shortness of breath and coughing. Over time, the airways become less elastic, making breathing increasingly difficult. In the liver, the missing protein can accumulate, causing the organ to become enlarged and scarred. This scarring may develop slowly, often without obvious symptoms at first, but can progress to noticeable changes in liver function. The disease can affect one organ, both organs, or vary in severity between individuals.

Trial ID:

2025-523497-16-00

Protocol code:

TSRA196-AAT-201

NCT ID:

NCT07227207

Trial Phase:

Phase I and Phase II (Integrated) – First administration to humans

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Phase 1/2 Study of rnaivt9315 and rnacs24757 in Adults with PiZZ Alpha‑1 Antitrypsin Deficiency Lung or Liver Disease

What is this study about?

Who Can Join the Study?

Who Cannot Join the Study?