Efficacy of Topical Gentamycin for Hereditary Hypotrichosis Simplex Caused by Nonsense Mutations in CDSN

The scalp-limited for of hereditary hypotrichosis simplex (HHS; MIM146520) is an autosomal dominant form of non-syndromic alopecia which is caused by heterozygous nonsense mutations in the CDSN gene, encoding corneodesmosin (1). The disease features diffuse gradual scalp hair loss that starts in the middle of the first decade of life and progresses to total alopecia till the third decade of life. Recent studies have shown that aminoglycosides have the potential to induce readthrough of nonsense mutations in human cells.

The aim of this study is to investigate whether topical aminoglycosides (Gentamycin) may be beneficial for the treatment of HHS patients carrying nonsense mutations by inducing readthrough.

The Study goals:

To assess the short and long term efficacy of topical gentamycin for the treatment of hereditary hypotrichosis simplex caused by nonsense heterozygous mutations in CDSN.

The primary end point:

To assess scalp hair growth during study period as compared to baseline. Hair growth will be evaluated during enrollment and every 4 weeks. The secondary end points will be time to regrowth for determining efficacy.

Study design: An open label one arm prospective study designed to evaluate the short and long term efficacy of topical gentamycin for the treatment of 8 patients with hypotrichosis simplex of the scalp.

Patients with hypotrichosis simplex of the scalp carrying a nonsense heterozygous mutation in the CDSN gene, who are eligible to the study based on inclusion/exclusion criteria, will sign the informed consent and will start to apply on the right half of scalp topical Gentamycin twice daily. The medication will not be applied to the left half of the scalp. Other local treatments to the scalp should be avoided during the study period. Daily oral medications are allowed. The patients will undergo general blood examination tests at baseline and every 4 weeks for safety measures. Blood tests include CBC, renal and liver function tests. Gentamycin levels will be assessed every 4 weeks.

Assessments on Visit 1:

Inclusion and exclusion criteria (including verifying normal hearing test at baseline prior to enrollment) Enrollment Baseline lab tests (CBC, renal and liver function tests) Physical exam SALT score Vellus hairs presence Pull test Patients self-assessment scale Photographs

Assessments on Follow up visits (every 4 weeks for a total of 6 months):

Physical exam Local site reactions SALT score Half head assessment Vellus hair presence Pull test Patients self-assessment scale Blood tests (CBC, renal and liver function tests) and gentamycin levels Photographs

Study withdrawal:

Patients with serious side effects of Gentamycin topical treatment such as hearing loss and impaired renal function or other serious side effect that according to the investigator judgment might jeopardize the patient's health. These are unexpected via local application and in the presence of intact skin.

Eligibility Criteria:
Inclusion Criteria:

1. Patients with hypotrichosis simplex of the scalp carrying a nonsense heterozygous mutation in the CDSN gene
2. Patients 18 years of age or older
3. Patient with normal hearing assessment within 30 days prior to treatment with the investigational drug
4. Patients with normal liver and renal function

Exclusion Criteria:

1. Patients with Hypotrichosis simplex of the scalp with no identified mutation in CDSN
2. Patients under 18 years of age
3. Patients with known hearing loss and renal and liver insufficiency
4. Patients with impaired skin barrier over the scalp such as bruise, ulcer, erosion etc.
5. Pregnancy and breastfeeding