Attenuating disease progression in
Pulmonary Arterial Hypertension

Long Story Short

  • For an unknown reason, arteries between the heart and the lungs become narrow or blocked, making it difficult for blood to flow through them, cutting supply to lungs. As a result stress on the right side of the heart increases to facilitate higher blood flow to the lungs leading to weakened heart muscle and eventual heart failure. 

  • MPO, a neutrophil protein has been implicated as culprit in causing long term structural damages to the arteries and heart, eventually leading to end stage PAH.

  • By removing the MPO from the immune system, we are able to create a disease modifying effect, without compromising the immune system strength.

 
  • Pulmonary Arterial Hypertension (PAH) is a rare, progressive disorder with no cure and poor life expectancy. With a prevalence rate of 10-52 cases / million worldwide, it can affect people of all ages, predominantly young women with a female to male ratio of 67% to 33%, respectively.

  • PAH is defined as ‘Group 1’ in the World Health Organization (WHO) clinical classification of pulmonary hypertension (PH) and is characterized by progressively increased blood pressure in the pulmonary arteries, increased vascular resistance and right ventricular dysfunction. 

  • Even with substantial pharmacologic advances in the modern treatment era, existing treatments provide only symptomatic relief and survival remains unacceptably poor. Patients who fail to respond to medications usually have the worst prognosis and patients with persistently elevated pulmonary pressure and right heart failure usually die within 5 years.

  • The trigger causing this disease is not entirely known.

  • The underlying pathological hallmarks of PAH include pulmonary arterial endothelial cell (EC) dysfunction, pulmonary artery EC and smooth muscle cell (SMC) proliferation, excessive vasoconstriction, RV hypertrophy, fibrosis & inflammation and in-situ thrombosis.

Unknown Cause 

  • MPO is a peroxidase enzyme residing almost solely in neutrophils, encoded by the MPO gene on chromosome 17 in humans.

  • Dubbed as a “powerful chemical bomb", it is the most abundantly expressed protein in neutrophil - 5% of its net weight and is the most toxic enzyme found in the azurophilic granules of neutrophils acting as a primary mediator of the neutrophils oxidative burst, producing hypochlorous acid (HOCl) and other strong oxidants in response to pathogens.

MPO Protein – Myeloperoxidase 

  • Neutrophils are the most abundant type of granulocytes and make up to 70% of all white blood cells in humans.

  • They form an essential part of the innate immune system acting as first responders against pathogens.

  • Neutrophils are formed from stem cells in the bone marrow and differentiated into subpopulations of neutrophil-killers and neutrophil-cagers. They are short-lived and highly mobile, as they can enter parts of tissue where other cells/molecules cannot.

Neutrophils

MPO is a Culprit in PAH Progression

   MPO has been implicated in aggravating PAH via 3 main pathways:

  • NETs creation (Intracellular activity)
    MPO is required for regulating the formation of Neutrophil Extracellular Traps (NETosis), a neutrophil cell death characterized by secretion of large web-like structures. NET formation is associated with the severity of aortic stenosis, trigger of angiogenesis and creation of blood clots.

  • Oxidative damage (Extracellular enzymatic activity)
    By production of reactive oxygen species (ROS), activation of vascular Rho-kinase and consumption of nitric oxide (NO) causing smooth muscles vasoconstriction and hypoxia-induced vascular remodeling.

  • Physical damage (Cationic charge dependent)

    Being of a high cationic charge, MPO is attracted to the inner layer of the artery wall (Endothelial Glycocalyx -EG), leading to its collapse and damaging its integrity.

MP-001 - Removing the MPO Protein Off the Immune System

AHSCT + CRISPR
  • MP-001, our treatment, is based on a knockout of the MPO gene using CRISPR/Cas9 in CD34+ stem cells.

  • It is a one-time treatment and does not require follow-on treatment. MP-001 is delivered by an autologous Hematopoietic Stem Cell Transplantation, using the following procedure:

1. At the hospital

  • Stem cells collected from the patient via mobilization and apheresis

  • Backup cells kept at site as a safety measure

  • Cells shipped to manufacturing facility

2. At Lempo's manufacturing facility

  • CD34+ cells isolated

  • Ribonucleoprotein (RNP)-mediated CRISPR genome editing delivered via electroporation

3. At Lempo's manufacturing facility

  • MPO knocked out stem cells cryopreserved and tested

  • Once approved, cells are released back to the hospital

4. At the hospital

  • Cryopreserved cells received and stored until infusion

  • Patient goes through myeloablative conditioning

  • MPO-001 thawed and infused

  • Patient monitored for engraftment and immune reconstitution

Much evidence show the value of MPO Deficiency in attenuating PAH progression. Lempo studies and others, done in mice, rats and pigs revealed the following benefits:

  • Protects from hyper-proliferation.

  • Preserves endothelial functions.

  • Prevents reduction of endothelial glycocalyx (EG) thickness (and allows recovery)

  • Inhibits excessive vasoconstriction and smooth muscle damage.

  • Attenuates pulmonary vascular remodeling.

  • Reduces inflammation angiogenesis and fibrosis.

A Disease Modifying Effect on PAH 

  • Immune system strength is not compromised by the removal of MPO and MPO bacterial killing activity is compensated by other mechanisms.

  • This is the case for every 1:2000-1:4000 people that are naturally born with MPO deficiency and are generally healthy with no meaningful clinical issues.

  • in 2005, the International Union of Immunological Societies omitted MPO deficiency from the immunodeficiency classification because of its “marginal clinical relevance”

MPO Deficiency is Not Classified as an Immune Deficiency