Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a very rare and uniformly fatal genetic condition that affects the microvasculature. Symptoms begin in adulthood (usually in the 40s) and include loss of vision, mini-strokes, and dementia. RVCL includes three conditions which were previously thought to be distinct: hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS); cerebroretinal vasculopathy (CRV); and hereditary vascular retinopathy (HVR). RVCL is inherited in an autosomal dominant manner and is caused by carboxyl (C)-terminal heterozygous frameshift (fs) mutations in TREX1 (Three Prime Repair Exonuclease 1). There is no treatment for RVCL, only symptomatic management.
TREX1 is an endoplasmic reticulum (ER)-associated (i.e., intracellular) enzyme that, in addition to its DNA repair activities, may regulate sugar metabolism in the ER. TREX1 mutations have also been associated with several autoimmune and autoinflammatory diseases. In RVCL, fs mutations of TREX1 result in C-terminal truncation and this dysregulates the oligosaccharyltransferase (OST) complex leading to free glycan release from dolichol carriers. In mouse models and in patient-derived cells, inhibiting OST with aclarubicin may correct glycan and immune defects associated with fs mutations of TREX1 (Hasan, M. et al., Immunity 43: 1-12, 2015).
Aclarubicin (aka aclacinomycin, aclacinomycin-A) is an anthracycline antibiotic isolated from Streptomyces galilaeus cultures. Aclarubicin has been shown to have a broad spectrum of anti-tumor activity. Aclarubicin was utilized for treatment of various cancers in Phase 1 and 2 studies in the United States of American (USA) in the 1980's and 1990's. While no longer clinically employed in the USA, it is commonly used in China and Japan, often as part of a combination drug therapy program for certain malignancies.
Aclarubicin is typically administered over 3-5 consecutive days, however, alternative schedules such as weekly or monthly have been evaluated. In solid tumors, the maximum tolerated dose (MTD) of 4-day dosing was 30 mg/m2/day; marrow suppression was dose limiting, otherwise the regimen was well tolerated. Additionally, a Phase II study in acute myeloblastic leukemia was conducted using 100mg/m2 per day for three days and repeated at days 14-16 if marrow hypoplasia was not produced. Toxic effects of this regimen included severe neutropenia, nasea/vomiting, and diarrhea. No changes were noted in left ventricular ejection fraction or no cardiac symptoms developed.
RVCL is caused by fs mutations in the C-terminus of TREX1 resulting in low-grade free glycan release, immune activation, and possibly autoantibody production due in part to dysregulation of the OST complex. Inhibiting OST with aclarubicin corrects these glycan and immune defects in mouse models and in patient-derived cells. Thus, inhibiting OST with aclarubicin might be a therapeutic option for patients with RVCL.
Given the poor prognosis of RVCL, the lack of treatment options, and the pre-clinical data on OST inhibition by aclarubicin in mice, there is strong rationale for conducting a clinical trial of aclarubicin in patients with RVCL.
In this pilot study, aclarubicin will be administered initially at \~ 20% of the single-agent maximum tolerated dose (MTD) in oncology studies. Assessments will be made every six months as to objectives of the study. Patients that do not have clear objective response may have their dose level increased with permission of the principal investigator permitting the patient has not previously experienced any toxicities requiring dose modifications. A patient who has clear objective progression at any time may also have their dose escalated as long as they have completed 1 full cycle at their current dose level. Maximum dose level will be 24 mg/m2/day. The aim of aclarubicin administration in RVCL is not to induce apoptosis, as in oncology studies, but rather to modulate intracellular functions and, thus, a reduced dose will be utilized.
