Putting an end to the damages caused in
MPO-ANCA associated Glomerulonephritis
Long Story Short
-
By mistake, the immune system recognizes its own MPO protein as an invader and produces antibodies against it.
-
These antibodies attack the immune system neutrophils, triggering immune response eventually leading to increased risk of kidney failure and death.
-
By removing the MPO from the immune system, we terminate this vicious cycle, without compromising the immune system strength.
-
Myeloperoxidase (MPO) Anti-Neutrophil Cytoplasmic Antibody (ANCA) associated Glomerulonephritis (AAGN) is a form of ANCA associated Vasculitis (AAV) with severe kidney involvement.
-
It is a severe and often fatal autoimmune disease with anti-neutrophil cytoplasmic autoantibodies against MPO (MPO-ANCA) involved in the pathogenesis, characterized by inflammation of small blood vessels affecting a patient’s kidneys.
-
It is a rare disease, with an annual incidence rate of 1.5-14 per 100,000 population.
-
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
MP-001 - Removing the MPO protein off the immune system
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
Termination of this vicious cycle by the removal of the MPO protein has been clearly demonstrated in the following glomerulonephritis (GN) mice model experiment testing MPO-KO bone marrow transplant (BMT) effect on GN (Schreiber A, et al. J Am Soc Nephrol. 2006):
A) Therapeutic effect - Healthy MPO-KO mice immunized with MPO protein to create MPO-ANCAs and then went through BMT. Results:
- Following WT BMT (with MPO) severe GN developed in all mice
- Following MPO-KO BMT (no MPO) no GN developed in all mice
B) Relapse therapeutic effect - Injection of MPO-antibodies and then went through BMT. Results:
-
All mice with WT BM (with MPO) developed GN following injection
-
All mice with MPO-KO BM (no MPO) did not develop GN following injection
Terminating AAGN Vicious Cycle
The biological mechanisms underpinning this autoimmune disease are not entirely known, but research points to a combination of genetics and environmental factors, such as exposure to pollutants, drugs, and microbial infections.
Nature's Mistake
-
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
-
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.