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March 2006

Topical Recombinant Alpha1-Antitrypsin: A Potential Treatment for Netherton Syndrome?

Arch Dermatol. 2006;142(3):393-403. doi:10.1001/archderm.142.3.396

Netherton syndrome is a severe autosomal recessive disorder characterized by generalized scaly erythroderma, specific hair shaft defects, and atopic manifestations. Netherton syndrome is caused by mutations in SPINK5, which cause loss of expression of LEKTI (lymphoepithelial Kazal-type–related inhibitor), a serine protease inhibitor.1LEKTI could be involved in skin desquamation by its inhibitory effect on stratum corneum trypsin enzyme and stratum corneum chymotryptic enzyme. LEKTI itself would be the preferred option for replacement therapy, but it is not as yet available. Alpha1-antitrypsin (AAT) is an endogenous serine protease inhibitor used as replacement therapy in congenital AAT deficiency.2 It is a good candidate for LEKTI replacement because it inhibits pancreatic trypsin that demonstrates considerable similarities to stratum corneum trypsin enzyme and stratum corneum chymotryptic enzyme.3 To our knowledge, this is the first study to evaluate the use of topical recombinant human AAT (rAAT) gel for Netherton syndrome. The objective of the study was to evaluate the short-term efficacy and tolerability of this drug in patients with Netherton syndrome.

Methods

The study was designed as a double-blind, randomized, placebo-controlled trial using 2% rAAT gel vs placebo (gel base: aqueous hydroxyethylcellulose 250HHX; Arriva-Prometic Inc, Alameda, Calif [Arriva], and Mont-Royal, Quebec, Ontario [Prometic]) twice daily for 21 days, applied to 2 symmetrical areas of 50 cm2 on the limbs. Patients were informed of the study procedures and gave written informed consent. The study was approved by the local medical ethics committee. For assessment of the skin, erythema, and scaling were scored on 2 separate 10-point analogue scales by the same blinded investigator. Zero corresponded to the absence of skin lesions and 10 to the most severe skin involvement. Exclusion criteria included all topical or systemic therapy except emollients. Statistical differences between the rAAT-treated lesions and the placebo-treated lesions were assessed by the Mann-Whitney test using Epi Info 6.0 software (Centers for Disease Control and Prevention, Atlanta, Ga). All results were considered statistically significant at P<.05.

Results

Five patients with Netherton syndrome were recruited, and their characteristics are detailed in the Table. After 3 weeks of treatment, all had partial clearance on both sides, but none showed a statistically significant difference between drug and placebo-treated sites at the different stages of the study (Figure). No adverse events were reported by the patients.

Figure.
Scoring of erythema and scaling for each patient, separately on each side and for each visit using 2 separate 10-point analogue scales (0 corresponded to the absence of lesions and 10 to the most severe skin involvement). AAT indicates alpha1-antitrypsin.

Scoring of erythema and scaling for each patient, separately on each side and for each visit using 2 separate 10-point analogue scales (0 corresponded to the absence of lesions and 10 to the most severe skin involvement). AAT indicates alpha1-antitrypsin.

Table. 
Characteristics of 5 Patients With Netherton Syndrome
Characteristics of 5 Patients With Netherton Syndrome
Comment

Replacement therapy for Netherton syndrome is a novel therapy of great promise. In this study we failed to demonstrate any statistically significant difference between rAAT and placebo-treated sites. Several hypotheses could account for the lack of stronger efficacy: first, despite the fact that AAT is active against pancreatic trypsin and that a marked increase of trypsinlike hydrolytic activity in stratum corneum samples from Netherton syndrome has been demonstrated,4 the activity of AAT against stratum corneum trypsin enzyme is currently unknown; second, the penetration of the rAAT formulation may not be adequate; and third, the duration of the study may have been too short or the concentration of the drug too low. All these hypotheses could be tested by in vitro studies or using recently available knockout mice.5 Further studies are warranted to fully investigate the potential of rAAT as a new therapy for Netherton syndrome.

Correspondence: Dr Mazereeuw-Hautier, Department of Dermatology, CHU Rangueil, 1 avenue J Poulhès, TSA 50032, 31059 Toulouse CEDEX 9, France (mazereeuw-hautier.j@chu-toulouse.fr).

Financial Disclosure: None.

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Article Information

Acknowledgment: We thank Pierre Laurin from Prometic, Quebec, Ontario, and David Sundin from Arriva, Alameda, Calif, for supplying the rAAT gel and for their support of this study.

References
1.
Bitoun  EChavanas  SIrvine  AD  et al.  Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families. J Invest Dermatol 2002;118352- 361
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Carrell  RWLomas  DA Alpha1-antitrypsin deficiency-a model for conformational diseases. N Engl J Med 2002;34645- 53
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Franzke  CWBaici  ABartels  J  et al.  Antileukoprotease inhibits stratum corneum chymotryptic enzyme: evidence for a regulative function in desquamation. J Biol Chem 1996;27121886- 21890
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4.
Komatsu  NTakata  MOtsuki  N  et al.  Elevated stratum corneum hydrolytic activity in Netherton syndrome suggests an inhibitory regulation of desquamation by SPINK5-derived peptides. J Invest Dermatol 2002;118436- 443
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5.
Descargues  PDeraison  CBonnart  C  et al.  Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity. Nat Genet 2005;3756- 65
PubMed
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