Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis

被引：101

作者：

Gillmore, Julian D. ^{[2
]}

Tennent, Glenys A. ^{[2
]}

Hutchinson, Winston L. ^{[2
]}

Gallimore, Janet Ruth ^{[2
]}

Lachmann, Helen J. ^{[2
]}

Goodman, Hugh J. B. ^{[2
]}

Offer, Mark ^{[2
]}

Millar, David J. ^{[2
]}

Petrie, Aviva ^{[3
]}

Hawkins, Philip N. ^{[2
]}

Pepys, Mark B. ^{[1
,2
]}

机构：

[1] UCL, Sch Med, Ctr Amyloidosis & Acute Phase Prot, Div Med, London NW3 2PF, England

[2] UCL, Sch Med, Natl Amyloidosis Ctr, Div Med, London NW3 2PF, England

[3] UCL, Sch Med, UCL Eastman Dent Inst, Biostat Unit, London NW3 2PF, England

来源：

BRITISH JOURNAL OF HAEMATOLOGY | 2010年 / 148卷 / 05期

基金：

英国医学研究理事会;

关键词：

amyloid; amyloidosis; CPHPC; depletion; P component; ALZHEIMERS-DISEASE; CHAIN AMYLOIDOSIS; FIBRINOGEN; FIBRILS; BINDING; AL;

D O I：

10.1111/j.1365-2141.2009.08036.x

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Serum amyloid P component (SAP) is a universal constituent of amyloid deposits and contributes to their formation and/or persistence. We therefore developed CPHPC ((R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl] pyrrolidine-2 carboxylic acid), a novel bis(D-proline) drug, to specifically target SAP and report here a first, exploratory, open label proof of principle study in systemic amyloidosis. CPHPC produced sustained, >95% depletion of circulating SAP in all patients and c. 90% reduction in the SAP content of the two amyloidotic organs that became available. There were no significant adverse effects of either SAP depletion or CPHPC itself. No accumulation of amyloid was demonstrable by SAP scintigraphy in any patient on the drug. In hereditary fibrinogen amyloidosis, which is inexorably progressive, proteinuria was reduced in four of five patients receiving CPHPC and renal survival was prolonged compared to a historical control group. These promising clinical observations merit further study.

引用

页码：760 / 767

页数：8

共 21 条

[1] Amyloid deposition is delayed in mice with targeted deletion of the serum amyloid P component gene [J].

Botto, M ;

Hawkins, PN ;

Bickerstaff, MCM ;

Herbert, J ;

Bygrave, AE ;

McBride, A ;

Hutchinson, WL ;

Tennent, GA ;

Walport, MJ ;

Pepys, MB .

NATURE MEDICINE, 1997, 3 (08) :855-859

[2] Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): A consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis [J].

Gertz, MA ;

Comenzo, R ;

Falk, RH ;

Fermand, JP ;

Hazenberg, BP ;

Hawkins, PN ;

Merlini, G ;

Moreau, P ;

Ronco, P ;

Sanchorawala, V ;

Sezer, O ;

Solomon, A ;

Grateau, G .

AMERICAN JOURNAL OF HEMATOLOGY, 2005, 79 (04) :319-328

[3] Curative hepatorenal transplantation in systemic amyloidosis caused by the Glu526Val fibrinogen α-chain variant in an English family [J].

Gillmore, JD ;

Booth, DR ;

Rela, M ;

Heaton, ND ;

Rahman, V ;

Stangou, AJ ;

Pepys, MB ;

Hawkins, PN .

QJM-AN INTERNATIONAL JOURNAL OF MEDICINE, 2000, 93 (05) :269-275

[4] Diagnosis, Pathogenesis, Treatment, and Prognosis of Hereditary Fibrinogen Aα-Chain Amyloidosis [J].

Gillmore, Julian D. ;

Lachmann, Helen J. ;

Rowczenio, Dorota ;

Gilbertson, Janet A. ;

Zeng, Cai-Hong ;

Liu, Zhi-Hong ;

Li, Lei-Shi ;

Wechalekar, Ashutosh ;

Hawkins, Philip N. .

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2009, 20 (02) :444-451

[5] METABOLIC STUDIES OF RADIOIODINATED SERUM AMYLOID-P COMPONENT IN NORMAL SUBJECTS AND PATIENTS WITH SYSTEMIC AMYLOIDOSIS [J].

HAWKINS, PN ;

WOOTTON, R ;

PEPYS, MB .

JOURNAL OF CLINICAL INVESTIGATION, 1990, 86 (06) :1862-1869

[6] EVALUATION OF SYSTEMIC AMYLOIDOSIS BY SCINTIGRAPHY WITH I-123 LABELED SERUM AMYLOID-P COMPONENT [J].

HAWKINS, PN ;

LAVENDER, JP ;

PEPYS, MB .

NEW ENGLAND JOURNAL OF MEDICINE, 1990, 323 (08) :508-513

[7] CONCENTRATION OF SERUM AMYLOID-P COMPONENT IN THE CSF AS A POSSIBLE MARKER OF CEREBRAL AMYLOID DEPOSITS IN ALZHEIMERS-DISEASE [J].

HAWKINS, PN ;

ROSSOR, MN ;

GALLIMORE, JR ;

MILLER, B ;

MOORE, EG ;

PEPYS, MB .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1994, 201 (02) :722-726

[8] Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component [J].

Kolstoe, Simon E. ;

Ridha, Basil H. ;

Bellotti, Vittorio ;

Wang, Nan ;

Robinson, Carol V. ;

Crutch, Sebastian J. ;

Keir, Geoffrey ;

Kukkastenvehmas, Riitta ;

Gallimore, J. Ruth ;

Hutchinson, Winston L. ;

Hawkins, Philip N. ;

Wood, Stephen P. ;

Rossor, Martin N. ;

Pepys, Mark B. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (18) :7619-7623

[9] Natural history and outcome in systemic AA amyloidosis [J].

Lachmann, Helen J. ;

Goodman, Hugh J. B. ;

Gilbertson, Janet A. ;

Gallimore, J. Ruth ;

Sabin, Caroline A. ;

Gillmore, Julian D. ;

Hawkins, Philip N. .

NEW ENGLAND JOURNAL OF MEDICINE, 2007, 356 (23) :2361-2371

[10] Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy [J].

Lachmann, HJ ;

Gallimore, R ;

Gillmore, JD ;

Carr-Smith, HD ;

Bradwell, AR ;

Pepys, MB ;

Hawkins, PN .

BRITISH JOURNAL OF HAEMATOLOGY, 2003, 122 (01) :78-84

← 1 2 3 →