DNA Repair Enzyme Containing Lip Balm for the Treatment of Actinic Cheilitis: A Pilot Study

Background: DNA repair enzymes have been shown to reduce actinic keratoses and non-melanoma skin cancers, but their use for the treatment of actinic cheilitis has not been studied. Objective: The purpose of this pilot study was to examine the efficacy of a DNA repair enzyme lip balm containing T4 endonuclease in reducing the severity of actinic cheilitis in patients who applied the lip balm twice daily for 3 months. Methods: We performed a prospective study in which 29 patients with a diagnosis of actinic cheilitis underwent a 3-month trial using a topical DNA repair enzyme lip balm containing T4 endonuclease applied to the lips twice daily. The primary, objective outcome was percent of actinic lip involvement, measured using computer software by dividing the calculated affected surface area by the calculated total surface area. Additional outcomes included pre- and post-intervention determination of an actinic cheilitis score on the Actinic Cheilitis Scale, which visually and tactilely quantifies the percentage of lip involvement, amount of roughness, erythema, and tenderness as well as a physician assessment using the Global Aesthetic Improvement Scale. Results: Twenty-five of the 29 enrolled patients completed the trial. The lip balm significantly decreased the percentage of affected lip surface area (P<0.0001). According to the Actinic Cheilitis Scale, data demonstrate that the lip balm significantly decreased the percentage of lip involvement (P=0.002), amount of roughness (P=0.0012)), erythema (P=0.0020), and tenderness (P=0.0175). The total Actinic Cheilitis Scale score also significantly improved after the 3-month treatment period (P<0.0001). According to the Global Aesthetic Improvement Scale, the average score for all 26 patients was 1.04. Conclusion: This study suggests that topical DNA repair enzyme lip balm containing T4 Endonuclease could potentially be a safe and efficacious way to improve and treat actinic cheilitis. J Drugs Dermatol. 2019;18(6):576-579

Reduced number of actinic keratoses with topical application of DNA repair enzyme creams.

BACKGROUND: Actinic keratosis is regarded as a carcinoma in situ by some dermatologists and its incidence continues to rise. Exposure to ultraviolet (UV) radiation is considered to be an important risk factor for developing these pre-malignant lesions. DNA repair enzymes have been shown to reverse sun-damage, resulting in reduced rates of actinic keratoses and non-melanoma skin cancers in specific patient populations. METHODS: Seventeen patients were evaluated for differences in actinic keratoses following topical application of T4N5 liposome lotion over 48 weeks. RESULTS: Compared to baseline, a statistically significant reduction in the number of actinic keratoses was seen following the treatment period. DISCUSSION: This study suggests that DNA repair enzyme creams effectively reduce the number of actinic keratoses in normal individuals with moderate-to-severe photodamaged skin.

Repairing DNA damage in xeroderma pigmentosum: T4N5 lotion and gene therapy.

Patients with xeroderma pigmentosum (XP) have defective DNA repair and are at a high risk for cutaneous malignancies. Standard treatments for XP are limited in scope and effectiveness. Understanding the molecular etiology of XP has led to the development of novel therapeutic approaches, including enzyme and gene therapies. One new topical treatment utilizing bacteriophage T4 endonuclease 5 (T4N5) in a liposomal lotion is currently in clinical trials and has received a Fast Track designation from the FDA. Gene therapy for XP, while making leaps in preclinical studies, has been slower to develop due to tactical hurdles, but seems to have much potential for future treatment. If these treatments prove effective in lowering the risk of cancer in patients with XP, they may also be found useful in reducing skin cancers in other at-risk patient populations.

T4 endonuclease V: review and application to dermatology.

BACKGROUND: T4 endonuclease V was originally isolated from Escherichia coli infected with T4 bacteriophage. It has been shown to repair ultraviolet (UV)-induced cyclobutane pyrimidine dimers in DNA, which, when unrepaired, contribute to mutations that result in actinic keratoses and non-melanoma skin cancers (NMSC). This is a particular concern in patients with genetic defects in their DNA repair systems, especially those with xeroderma pigmentosum (XP). When packaged in liposomes and applied topically, T4 endonuclease V can traverse the stratum corneum and become incorporated within the cytoplasm and nucleus of epidermal keratinocytes and Langerhans cells. OBJECTIVE: To review all major studies evaluating the efficacy of T4 endonuclease V in animals and humans, the toxicity and safety profile of the topical medication and its potential clinical uses. METHODS: A literature search was performed through PubMed/Medline, using the keywords 'T4N5', 'T4 endonuclease V' and 'dimericine'. Papers found in the bibliographies of those identified in the initial search and deemed relevant were also included. CONCLUSION: This enzyme increases the repair of UV-damaged DNA and produces other beneficial effects on UV-damaged cells. In clinical trials in XP patients, topical application of liposome-encapsulated T4 endonuclease V reduced the incidence of basal cell carcinomas by 30% and of actinic keratoses by > 68%. Adverse effects were minimal, and there was no evidence of allergic or irritant contact dermatitis. Although the photoprotective effect of T4N5 has been investigated only in XP patients, the possibility exists that it may benefit others likely to develop premalignant keratoses and NMSC, such as organ transplant recipients receiving immunosuppressive therapy and individuals who have had numerous psoralen plus UVA photochemotherapy treatments. It may be also be effective for normal individuals.

¿Qué le depara al paciente tras el diagnóstico de trombosis venosa profunda? Estudio de factores pronósticos de la mortalidad, síndrome prostrombótico y calidad de vida / GAT awaits the patient following a diagnosis of deep vein trombosis? A study of the factors predicting mortality, post-thrombotic syndrome and quality of life

Introducción. El pronóstico de una trombosis venosa profunda (TVP) implica considerar complicaciones como el síndrome postrombótico (SPT), la afectación de calidad de vida (CV) y muerte. Objetivos. Describir la historia natural del paciente tras una TVP, y detectar factores pronósticos de muerte, SPT y CV, además del valor pronóstico del dímero D en el diagnóstico de TVP. Pacientes y métodos. Cohorte histórica (n = 118) de pacientes con TVP; período: 1/1/2001-1/12/2002. Control a 3 años. Valoración con escalas visuales, CEAP, eco-Doppler (ED); CV mediante SF-36 y CIVIQ; dímero D mediante ELISA. Resultados. 118 pacientes (55,1% varones; 59,8 años de media). Fallecidos 31,4%, perdidos 16,1%, casos excluidos 5% y válidos para control clínico 49,2%. Riesgo de muerte: 31,4% (IC 95% = 23,2-40,5); el cáncer fue factor pronóstico de muerte, con RR = 2,9 (IC 95% = 1,7-4,8) y supervivencia media 22 meses menor. A los 3 años (n = 58): 29% clínica positiva y 30% CEAP > 2; 49% presentaron SPT (por clínica o CEAP positivo); 74% ED positivo. Acudir a Urgencias con clínica < 9 días ha sido pronóstico para desarrollo de SPT (RR = 2,7; p = 0,045). La CV ha sido significativamente peor en el grupo con SPT en los dos cuestionarios utilizados. Un dímero D ≥ 3,870 µg/L presenta un valor pronóstico positivo del 94%. Conclusiones. Uno de cada tres pacientes con TVP morirá a los tres años. De los supervivientes, uno de cada dos tendrá un SPT, y mermará su CV. Acudir a Urgencias en < 9 días puede ser un indicador indirecto de gravedad clínica. Un dímero D ≥ 3,870 µg/L en el diagnóstico de TVP predice un SPT en un 94% de los casos

INTRODUCTION. To determine the prognosis of deep vein thrombosis (DVT), complications such as postthrombotic syndrome (PTS), impact on the quality of life (QL) and death must be taken into account. AIMS. To describe the natural history of patients following TVP and to detect factors that predict death, PTS and QL, in addition to evaluating the prognostic value of the D-dimer test in diagnosing DVT. PATIENTS AND METHODS. Historical cohort (n = 118) of patients with DVT; period: 1/1/2001-1/12/2002. A clinical control was conducted at 3 years. Assessment with visual scales, CEAP, Doppler ultrasound (DU); QL was evaluated with SF-36 and CIVIQ, and D-dimer by ELISA. RESULTS. 118 patients (55.1% males; mean age 59.8 years). Deaths 31.4%, losses 16.1%, excluded cases 5% and number of valid subjects for clinical control 49.2%. Risk of death: 31.4% (CI 95% = 23.2-40.5); cancer was a factor predictive of death, with RR = 2.9 (CI 95% = 1.7-4.8) and mean survival was 22 months less. At 3 years (n = 58): 29% positive clinical features and 30% CEAP > 2; 49% had PTS (from clinical symptoms or positive CEAP); 74% were DU positive. Going to the Emergency Department with clinical symptoms < 9 days is predictive of the development of PTS (RR = 2.7; p = 0.045). The QL was found to be significantly poorer in the PTS group in both the surveys that were used. A D-dimer test ≥ 3.870 µg/L offered a positive prognostic value of 94%. CONCLUSIONS. One out of every three patients with DVT will die within three years. Of the survivors, one out of every two will have PTS, which will deteriorate his or her QL. Going to the Emergency Department in < 9 days can be an indirect indicator of the severity of the condition. D-dimer ≥ 3.870 µg/L in the diagnosis of DVT is predictive of PTS in 94% of cases

Cyclobutane pyrimidine dimer formation is a molecular trigger for solar-simulated ultraviolet radiation-induced suppression of memory immunity in humans.

We tested the hypothesis that DNA is a target for solar-simulated ultraviolet radiation (ssUVR)-induced suppression of the reactivation of memory immunity in humans. T4N5 liposomes contain the DNA repair enzyme T4 endonuclease V. This cleaves DNA at the site of ultraviolet radiation (UVR)-induced cyclobutane pyrimidine dimers (CPD), initiating DNA repair. It has previously been used to show that CPDs are a key molecular trigger for UVR-induced immunosuppression in mice. To determine whether CPD formation is involved in UVR immunosuppression in humans, nickel-allergic volunteers were irradiated with a range of doses of ssUVR. T4N5 or empty liposomes were then applied after irradiation. Nickel-induced recall immunity was assessed by reflectance spectrometry. T4N5 liposomes inhibited immunosuppression and prevented ssUVR from reducing the number of epidermal dendritic cells. T4N5 liposomes also reduced macrophage infiltration into irradiated epidermis. These studies show that enhanced removal of CPDs from human skin protects from immunosuppression, hence demonstrating that these photolesions are an important molecular event in ssUVR-induced immunosuppression in humans. CPDs also triggered loss of dendritic cells and infiltration by macrophages. It is possible that these changes to antigen presenting cells contribute to ssUVR induced suppression of recall immunity to nickel in humans.

DNA repair, immunosuppression, and skin cancer.

UV radiation (UVR) produces erythema within the first 24 hours of exposure, suppression of the immune system within the first 10 days, and, for many people, over the course of decades, skin cancer. Although UVR damages many skin targets, DNA damage in the form of cyclobutane pyrimidine dimers (CPDs) is an important mediator of these sequelae. The action spectrum for erythema parallels the action spectrum for CPD formation in skin, and in the absence of repair, as in the genetic disease xeroderma pigmentosum (XP), skin cancer rates are dramatically increased. DNA repair in skin can be enhanced by the delivery of DNA repair enzymes encapsulated in liposomes. Used in this way, photoreactivation of CPDs greatly diminishes erythema and the suppression of contact hypersensitivity (CHS). UV endonucleases delivered by liposomes also prevent UV-induced suppression of delayed-type hypersensitivity. In a clinical study of patients with XP, T4 endonuclease V (T4N5) liposome lotion applied for one year reduced the rates of actinic keratosis (AK) and skin cancer compared with placebo. These results showed that strategies to increase sun protection should include measures to reduce DNA damage and increase the rate of DNA repair.