Netherton Syndrome: Investigational Therapeutic Expansion
Netherton Syndrome is a rare genetic disorder that occur in around 1 in 200,000 births with an estimated total population of 6,000 to 7,000 in North America and Europe. Inheritance is autosomal recessive with both parents needing to be carriers which may occur at rates as high as 1 in 100 in the general population.
Neterton Syndrome is caused via a SPINK5 mutation which in turn causes a LETKI mutation that impairs its activity to multiple targets downstream such as KLK 5, KLK7, and KLK14. The KLK family regulate desquamation of dead skin, KLK5 can start the cycle on its own, so without LEKTI to inhibit KLK the skin can tart to shed continuously. Altered LETKI can impact the digestion of proteins (via Trypsin), clot breakdown (Plasmin), and inflammation (Cathepsin G). The severity of the dysfunction depends on the extent of the SPINK5 mutation so symptoms can vary significantly between patients.
Dermatological symptoms include but are not limited to white scaly irritated skin (Ichthyosiform erythoderma), thickening of the skin with double edge scales at the edge of the plaques (Ichthyosis linearis circumflexa), recurrent skin infection, and enlarged skin tags at the body folds and joints (Hypertrophic papilomas). Generalized cohesion of the skin is impacted with notable breaks overall and itching being major patient impact factors.
Hair of the patients are also impacted with some hallmark presentations being ‘Bamboo hair” where visible ball and socket nodules are seen on the shaft of the hair, also appearing as looking like matchstick heads on the eyebrows. Other hair symptoms are Pili Torti which is there the hair flattens and twists at random sections and Trichorhexis Nodosa where the shaft of hair may fray in the middle and appear like two brushes pressed into each other. In addition to being visually distinctive, Netherton Syndrome patients’ hair also results in irregular growth, thickness, spacing, difficulty irritating the already irritated skin by growth. This is a compounding factor along with the physical presentation of irritated skin that negatively impacts younger patients social and emotional health.
Some less typical manifestations are elevated IgE levels resulting in severe and multiple food/environmental allergies that can increase in intensity over time. Others can be Growth hormone deficiency, general immunodeficiency, and multiple metabolic dysregulations have been reported in the literature.
Primarily symptom treatment for Netherton Syndrome revolves around maintaining and assisting dermatologic integrity. This is focused on an overall treatment goal to restore the outer dermis barrier and decreasing itching or inflammation. The skin barrier protection is via frequent application of topical emollients or moisturizers, some use of Ultraviolet Phototherapy has been successful in some cases. Topical steroids (of various strengths) have been historically used to treat the inflammation and itching portion of symptoms, but its use generally should be limited in duration due to the impaired barrier promoting systemic absorption and increasing rates of Cushing Syndrome especially in pediatric patients. This limited treatment recommendation is also true for topical calcineurin inhibitors such as tacrolimus where again the dermal impairment increases the rate of systemic absorption which in the case of the calcineurin inhibitors can negatively affect renal function.
Advanced treatments are centered around immune and inflammation symptom response. Most commonly reported is Intravenous Immune Globulins (IVIG), focused on decreasing the rate of serious infections which is the most common mortality among patients. Various immunotherapies have been studied and trialed for use in Netherton Syndrome such Anakinra (Kineret), Dupilumab (Dupixent), Infliximab (Remicade), Ixekizumab (Taltz), Secukinumab (Cosentyx), and Ustekinumab (Stelara). The treatment cohort numbers and reports for immunotherapy use has been limited in scale due to multiple factors such as disease rarity and splintered treatment groups between so many agents. True efficacy data is unclear and may suggest only temporary response or agent resistance.
Investigational data for Netherton Syndrome historically has been quite low. Within recent years there has been a noticeable uptake in both pharmaceutical industry as well as treatment center interest in sponsoring studies, both for already commercially available and investigational agents. Pre-clinical interest has been shown for direct KLK agents such as GSK951 (KLK5-) and Sunflower Trypsin (KLK5/7/14-) or direct gene therapy. Below are two separate charts that overview recently completed phase I/II studies and active I-III studies.
Due to the rarity of the disease an internationally focused treatment site program is especially helpful to obtain more robust and effective data. For example, Quoin Pharmaceutical’s QRX003 (NCT05789056 and NCT05521438) has went for a more widespread net of sites. With 5 active clinical trial sites in the United States, One in Saudi Arabia, two planned for the United Kingdom, One in Ireland, and additional patients eligibility being investigated in Spain, New Zealand, Canada, France, Germany, and Japan. QRX003 for example is a topical serine protease inhibitor which would downstream regulate KLK activity to better control the skin shedding mechanism. Treatment length of 12 weeks with a patient population of 14yo or older, although a pediatric patient was reported as enrolled recently.
As there is no cure or FDA approved treatment for Netherton Syndrome, developing new therapies or pivoting existing ones should be the highest priority for patient quality of life and long-term survival. Unfortunately, due to the current FDA study design and safety factors it is much more difficult to directly study pediatric patients versus adults. This complicates the intended need as the highest mortality for Netherton Syndrome is early in life with up to a 9% mortality in infants from systemic infection or dehydration. Although optimal treatment protocols for all Netherton Syndrome patients is needed, a deeper push for efficient and effective treatment in pediatric and neonatal patients is an area of paramount need.
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Li H, Wang J. Upadacitinib shows efficacy in Netherton syndrome with poor response to Dupilumab. J Dermatol. 2024 Sep 20. doi: 10.1111/1346-8138.17461. Epub ahead of print. PMID: 39301863.
Liu T, Tang M, Liu J, Kong T, Tian Y, Yang S, Zhang J, Ji S, Lin Z, Xue R, Ding Y, Yang B, Liang Y. A combination therapy with secukinumab and dupilumab in Netherton syndrome: A prospective pilot study. J Am Acad Dermatol. 2024 Dec;91(6):1258-1260. doi: 10.1016/j.jaad.2024.07.1513. Epub 2024 Sep 7. PMID: 39182676.
Salici NS, Ozcanli A, Rasulova G, Basak AN, Tekgul S, Vural S. Successful infliximab treatment in siblings with Netherton syndrome: Unveiling a novel SPINK5 gene variant and literature review. Australas J Dermatol. 2024 May;65(3):e45-e49. doi: 10.1111/ajd.14234. Epub 2024 Feb 28. PMID: 38419182.
Bellon N, Hadj-Rabia S, Moulin F, Lambe C, Lezmi G, Charbit-Henrion F, Alby C, Le Saché-de Peufeilhoux L, Leclerc-Mercier S, Hadchouel A, Steffann J, Hovnanian A, Lapillonne A, Bodemer C. The challenging management of a series of 43 infants with Netherton syndrome: unexpected complications and novel mutations. Br J Dermatol. 2021 Mar;184(3):532-537. doi: 10.1111/bjd.19265. Epub 2020 Sep 10. PMID: 32479644.