This study is designed to learn about the safety and effectiveness of a new gene therapy called KB408 for Alpha-1 Antitrypsin Deficiency (AATD). AATD is an inherited condition in which a person has low blood levels of a protein known as alpha-1 protease inhibitor (called Alpha1-PI). AATD causes an increased risk of chronic obstructive pulmonary disease (COPD) in the form of emphysema (long term lung disease) and, less frequently, other diseases.
KB408 delivers copies of the genes that produce AAT to the lungs and is given by inhaling a mist (called nebulization). The genes are carried and delivered by a modified herpes simplex virus type 1 (HSV-1). This virus is not harmful and simply acts as a vehicle to deliver the genes to the lungs. The genes that are delivered by KB408 do not change a person's own DNA. This is an open-label study, meaning that the participants, the study doctor, and the sponsor all know that the participants are receiving KB408. KB408 is an investigational product, meaning it is not approved for commercial use by the FDA.
Eligible participants will receive one of three doses of KB408. Participants will have a screening visit first to make sure that they are able to participate in the study. After the screening visit, participants will need to return to the study center 6 more times over 2 months. At the second visit, participants will receive the study drug. Each visit will take between 2 and 6 hours to complete. Study procedures include medical history collection, vitals, physical exam, ECG, spirometry and DLCO, urine cotinine test, blood work, cheek swab, sputum sample, and bronchoscopy (only for participants in cohorts 3a and 3b).
Possible side effects of KB408 include temporary increases in certain cell types in the lungs and temporary increases in the breathing rate after dosing. Since this is the first time that KB408 has been given to humans, it is possible that participants may have an immune reaction to the study drug. There is also a risk with genetic testing and a risk to confidentiality. Participants may not receive any personal benefit from being in this study. There is no guarantee that the Study Drug will help. The information that is collected from the study may help other people in the future.

The purpose of this study is to evaluate the potential effectiveness, outcomes, and safety (before, during, and after study procedures) of the Inter Atrial Shunt Device (IASD) in the treatment of subjects with heart failure symptoms and relatively normal pumping of the heart. This study involves the use of an investigational medical device called the Corvia Atrial Shunt (CAS) System. The CAS is permanently implanted in the heart to reduce the increased pressure in the left side of the heart by creating a small opening between the two upper chambers of the heart. Participants will have a 50% chance of being in either group A having the CAS placed or group B and not receiving the device. Subjects will have 7 research clinic visits, and multiple telephone calls for a total of 5 years of follow-up. The research clinic visits will include medical exams, health questionnaires, ECG and echocardiogram of the heart and 6 minute hall walk tests.

The purpose of this study is to evaluate the potential effectiveness, outcomes, and safety (before, during, and after study procedures) of the Inter Atrial Shunt Device (IASD) in the treatment of subjects with heart failure symptoms and relatively normal pumping of the heart. This study involves the use of an investigational medical device called the Corvia Atrial Shunt (CAS) System. The CAS is permanently implanted in the heart to reduce the increased pressure in the left side of the heart by creating a small opening between the two upper chambers of the heart. Participants will have a 50% chance of being in either group A having the CAS placed or group B and not receiving the device. Subjects will have 7 research clinic visits, and multiple telephone calls for a total of 5 years of follow-up. The research clinic visits will include medical exams, health questionnaires, ECG and echocardiogram of the heart and 6 minute hall walk tests.

The purpose of the study is to evaluate the safety and how well the medication sotatercept works versus placebo in treating Heart Failure with a Preserved Ejection Fraction. The study will also look at information obtained from the tests performed as part of the study to see if subjects have improvement in symptoms of heart failure. Participation in this study will last approximately 26 months. During the study period subjects will be asked to attend regular study visits with the research coordinator. These visits will include such activities as blood tests, questionnaires, physical evaluation by a study doctor, a right heart catheterization with exercise, echocardiogram, and 6 minute hall walks. There will be 35 visits as part of participation in this clinical trial.

Participants will be randomized to either the treatment group (and receive the medication) or the control group (and not receive the medication). Subjects will have a 66:33 chance of receiving the study medication during their participation in the trial. The treatment assignment is determined by randomization, where a computer selects at random which treatment group you will be in (like drawing straws). Neither the subject, nor the blinded personnel will know which group subjects are in. Neither the subject nor the study doctor will decide what group subjects are assigned.

This research study aims to determine a less invasive way to assess heart function by taking measurements of the heart while subjects are performing an exercise cardiac MRI. Subjects will undergo two exercise phases and MRI measurements will be taken after each exercise phase. These measurements will be compared to available clinical data (including demographic, hemodynamic, radiologic, and functional) and future outcome data.