Safety and Efficacy of PMT Therapy of hPAP

The major goal of this study is to evaluate a new type of cell transplantation therapy for individuals with hereditary PAP, study a new treatment that may be useful for treatment of other diseases, and research mechanisms that drive the development and function of lung macrophages.

Hereditary pulmonary alveolar proteinosis (hPAP) is a rare lung disease characterized by the progressive accumulation of pulmonary surfactant in alveoli resulting in progressive hypoxemic respiratory failure, and in some patients, secondary infections and/or pulmonary fibrosis. While hPAP affects men, women, and children, most patients present as children. The lung structure appears well-preserved in many cases with pathogenesis being driven by the consequences of the filling of alveoli with surfactant sediment; however, some patients develop respiratory failure caused by pulmonary fibrosis requiring therapeutic lung transplantation.

Hereditary PAP is caused by homozygous or compound heterozygous mutations in the genes (CSF2RA or CSF2RB) encoding the GM-CSF receptor alpha or beta chains, respectively. Mutations in these genes disrupt GM-CSF receptor function, blocking GM-CSF signaling and impairing the removal of excess surfactant from alveoli by alveolar macrophages (AMs).

This study is an open-label, non-randomized, single center clinical treatment study to evaluate the feasibility of manufacturing CSF2RA gene-corrected macrophages, as well as the safety, tolerability, efficacy, and durability of CSF2RA gene correction/pulmonary macrophage transplantation (PMT) therapy in three patients with hPAP caused by recessive homozygous or compound heterozygous CSF2RA mutations. In addition to safety and tolerability, the clinical trial will evaluate outcome measures related to clinical efficacy and biologic signature of CSF2RA gene-correction/PMT therapy, as well as pharmacokinetics, pharmacodynamics, and the mechanism of action.

The clinical trial design includes a 2-month observation period, a Baseline visit, 5-month treatment period, and Short-, Medium-, and Long-Term follow-up periods of 1, 4, and 10 years, respectively. Each patient will serve as their own self-control and receive a split-dose comprising three administrations of autologous, bone marrow cluster of differentiation 34+ (CD34+) cell-derived, lentiviral CSF2RA gene-corrected macrophages at a minimum of 2-month intervals, delivered by direct bronchoscopic instillation of cells into individual lung segments (5.8x105 cells/segment); an increasing number of cells at each administration will be achieved by sequentially increasing the number of segments treated. Current standard medical care (whole lung lavage and supplemental oxygen) will be continuously available to all enrolled patients.

Assessments will include safety (adverse events and serious adverse events), tolerability (short-term, treatment-emergent pulmonary symptoms), efficacy (beneficial effects on clinical, physiological, and radiological manifestations of hPAP), durability (persistence of beneficial effects), and mechanism of action (persistence, CSF2RA-expression, and function of alveolar macrophages (AMs)).

Expected results will inform the feasibility, safety, tolerability, efficacy, durability, and mechanism of action of gene transfer/PMT as therapy of hPAP. These results will impact the field because it departs markedly from the current inefficient, highly invasive method of physically removing surfactant by whole lung lavage (WLL) and instead uses a novel approach to restore AM function. This study is expected to establish the feasibility of a novel, specific therapy for children with hPAP and a new type of cell transplantation therapy (PMT) that may be useful for other diseases.

Eligibility Criteria:
Inclusion Criteria:

Patients must meet all of the following conditions to be eligible for participation in this study:

1. Male or female with a confirmed diagnosis of hPAP defined as:

   * Homozygous or compound heterozygous CSF2RA mutations - AND -
   * A normal GM-CSF autoantibody test result - AND -
   * An abnormal STAT5-PI test result - OR -
   * An abnormal GM-CSF 50% effective concentration (EC50) test result
2. Diffuse ground glass opacification of the lungs visualized on a chest computed tomogram (CT)
3. History of prior receipt of WLL therapy or moderate hPAP lung disease severity requiring therapy in the opinion of the Clinical Site Investigator and/or Sponsor
4. Able to undergo bone marrow collection by routine clinical aspiration
5. 18 years of age or older on the date the Informed consent form (ICF) is signed
6. Females who have been post-menopausal for \>2 years or females of child-bearing potential after a confirmed menstrual period using a highly efficient method of contraception (as described in Section 11.4.2) for the period from 3 months prior to the first administration of gene-corrected macrophages until 12 months after the last administration of gene-corrected macrophages. Females of child-bearing potential must have a negative serum pregnancy test at Screening (Visit 1), at bone marrow collection (Visit 2), and immediately before each administration of gene-corrected macrophages (Visits 3, 5, 7), and must not be lactating.
7. Males of reproductive potential must agree to use condoms for the period from the 1st administration of gene-corrected macrophages until 12 months after the last dose of gene-corrected macrophages, have a partner who is not of child-bearing potential (i.e. men or females who have been post-menopausal for \>2 years), or have a female partner who is using adequate contraception as described in Section 11.4.2.
8. Signed written informed consent form (ICF)

Exclusion Criteria:

Patients who meet any of the following conditions will not be eligible for participation in this study:

1. History of a confirmed diagnosis of any other PAP-causing disease defined as:

   1. PAP caused by function-altering mutations in CSF2RB, adenosine triphosphate (ATP)-binding cassette subfamily A member 3 (ABCA3), SFTPB, SFTPC, Thyroid Transcription Factor 1 (TTF-1), GATA-binding factor 2 (GATA2), SLC7A7, and methionyl-transfer RNA (tRNA) synthetase (MARS), or other genes demonstrated to cause PAP other than CSF2RA
   2. PAP associated with an abnormal GM-CSF autoantibody test
   3. PAP associated with hematologic disorders including but not limited to myelodysplasia, aplastic anemia, leukemia, multiple myeloma, lymphoma
   4. PAP associated with non-hematologic malignancies
   5. PAP associated with immune deficiency syndromes
   6. PAP associated with chronic inflammatory syndromes
   7. PAP associated with chronic infections including but not limited to human immunodeficiency virus, Mycobacteria tuberculosis or other Mycobacterial species, or other organisms
   8. PAP associated with inhaled materials including but not limited to inorganic dusts (e.g., silica, titanium, indium, aluminum), organic dusts (e.g., sawdust, fertilizer); or gases/vapors (e.g., cleaning products, paints, and welding-related fumes)
2. Pulmonary fibrosis that is clinically significant in the opinion of Clinical Site Investigator and/or Sponsor
3. A confirmed (i.e., repeated) positive serum anti-GM-CSF receptor antibody test and/or a confirmed positive anti-lentiviral antibody test at the time of screening and prior to each administration of gene-corrected macrophages
4. History of receipt of any investigational agent within 3 months of Study Visit 3
5. History of active chronic infection (e.g., HIV, Hepatitis, others) at the time of Screening
6. History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to Study Visit 3, defined as more than 14 drinks/week for females or 21 drinks/week for males (1 drink - 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer, or 1.5 ounces (45 ml) of hard liquor)
7. History of medication or illicit drug abuse within 1 year prior to Study Visit 3, including but not limited to cocaine, heroin, or other opioids
8. Currently or planning to become pregnant between the Screening visit and Visit 14 and/or currently breast-feeding
9. Any other medical, behavioral, or psychiatric condition that would interfere with the completion of Study Visits or assessments in the opinion of the Clinical Site Investigator and/or Sponsor