Plasminogen replacement therapy for the treatment of children and adults with congenital plasminogen deficiency

Abstract

Congenital plasminogen deficiency is caused by mutations in , the gene coding for production of the zymogen plasminogen, and is an ultrarare disorder associated with abnormal accumulation or growth of fibrin-rich pseudomembranous lesions on mucous membranes. Left untreated, these lesions may impair organ function and impact quality of life. Plasminogen replacement therapy should provide an effective treatment of the manifestations of congenital plasminogen deficiency. An open-label phase 2/3 study of human Glu-plasminogen administered IV at 6.6 mg/kg every 2 to 4 days in 15 patients with congenital plasminogen deficiency is ongoing. Reported here are data on 14 patients who completed at least 12 weeks of treatment. The primary end point was an increase in trough plasminogen activity levels by at least an absolute 10% above baseline. The secondary end point was clinical success, defined as ≥50% improvement in lesion number/size or functionality impact from baseline. All patients achieved at least an absolute 10% increase in trough plasminogen activity above baseline. Clinical success was observed in all patients with clinically visible (conjunctiva and gingiva), nonvisible (nasopharynx, bronchus, colon, kidney, cervix, and vagina), and wound-healing manifestations of the disease. Therapeutic effects were rapid, as all but 2 lesions resolved or improved after 4 weeks of treatment. Human Glu-plasminogen was well tolerated in both children and adults. This study provides critical first evidence of the clinical utility of ongoing replacement therapy with human Glu-plasminogen for the treatment of children and adults with congenital plasminogen deficiency. This trial was registered at www.clinicaltrials.gov as #NCT02690714.

Prophylactic protocol for dental care in ligneous gingivitis due to severe plasminogen deficiency: Case report and review of literature

“…Studies on the use of human plasminogen eye drops in patients with ligneous conjunctivitis (http://ClinicalTrials.gov Identifier: NCT01554956) and of intravenous human Glu‐plasminogen concentrates in severe plasminogen deficiency (http://ClinicalTrials.gov Identifier: NCT02690714) are still ongoing. Preliminary results of the latter trial showed an improvement or resolution of LG in three affected patients treated with intravenous Glu‐plasminogen replacement . The use of local and intravenous FFP has been recently reported in a series of 11 patients with plasminogen deficiency and ligneous conjunctivitis; the clinical response rate to FFP treatment was 72% …”

“…There is no definitive consensus on the management of LG. Several medical and surgical strategies have been used, including antibiotics, chlorhexidine rinses, topical cromoglycate, hyaluronidase, topical heparin, warfarin, systemic steroids, oral contraceptive pills, azathioprine, and gingivectomy with varying success; specific therapy with human Glu‐plasminogen concentrates is still under investigation …”

“…Several medical and surgical strategies have been used, including antibiotics, chlorhexidine rinses, topical cromoglycate, hyaluronidase, topical heparin, warfarin, systemic steroids, oral contraceptive pills, azathioprine, and gingivectomy with varying success 2,7,[12][13][14][15] ; specific therapy with human Glu-plasminogen concentrates is still under investigation. 16 We describe a prophylactic protocol for LG prevention after dental procedures and a review of pertinent literature.…”

Woody eyes, be gone!

“…Without question, the clinically most useful MRD test and targets are yet to be determined, and both will most likely depend on the individual patient's characteristics and the therapy administered. 1 Congenital plasminogen deficiency is caused by homozygous or compound-heterozygous mutations in the plasminogen (PLG) gene, located on chromosome 6q26. It is, in the words of the authors, "ultra-rare," predicted to affect ∼1 to 2 per million people.…”

“…Previous work has demonstrated using constitutive knockouts of the MLL/SET family that loss of these methyltransferases results in embryonic death. 4 Although all MLL/SET proteins are critical for development, each factor appears to have specific roles in regulating adult hematopoiesis and stem cell function, 1,4 including playing a role in white blood cell output, B-cell development, and erythropoiesis (see figure). 5,6 Waskow's group uses a series of conditional knockout mice to elucidate the function of Setd1a in the primitive hematopoietic compartment.…”