CRISPR-Based Gene Therapies: From Preclinical to Clinical Treatments.

In recent years, clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) protein have emerged as a revolutionary gene editing tool to treat inherited disorders affecting different organ systems, such as blood and muscles. Both hematological and neuromuscular genetic disorders benefit from genome editing approaches but face different challenges in their clinical translation. The ability of CRISPR/Cas9 technologies to modify hematopoietic stem cells ex vivo has greatly accelerated the development of genetic therapies for blood disorders.

CRISPR-Cas9 KO Cell Line Generation and Development of a Cell-Based Potency Assay for rAAV-FKRP Gene Therapy.

Limb-Girdle Muscular Dystrophy R9 (LGMDR9) is a dystroglycanopathy caused by Fukutin-related protein (FKRP) defects leading to the deficiency of α-DG glycosylation, essential to membrane integrity. Recombinant adeno-associated viral vector (rAAV) gene therapy offers great therapeutic promise for such neuromuscular disorders. Pre-clinical studies have paved the way for a phase 1/2 clinical trial aiming to evaluate the safety and efficacy of FKRP gene therapy in LGMDR9 patients.

CLDN1 Sensitizes Triple-Negative Breast Cancer Cells to Chemotherapy.

Triple-negative breast cancer (TNBC) is an aggressive subtype that constitutes 15-20% of breast cancer cases worldwide. Current therapies often evolve into chemoresistance and lead to treatment failure. About 77% of the TNBC lacks claudin-1 (CLDN1) expression, a major tight junction component, and this absence is correlated with poorer prognostic.

AB186 Inhibits Migration of Triple-Negative Breast Cancer Cells and Interacts with α-Tubulin.

Breast cancer is one of the leading causes of cancer-related death among females worldwide. A major challenge is to develop innovative therapy in order to treat breast cancer subtypes resistant to current treatment. In the present study, we examined the effects of two Troglitazone derivatives Δ2-TGZ and AB186.

Skeletal Muscle Cells Derived from Induced Pluripotent Stem Cells: A Platform for Limb Girdle Muscular Dystrophies.

Limb girdle muscular dystrophies (LGMD), caused by mutations in 29 different genes, are the fourth most prevalent group of genetic muscle diseases. Although the link between LGMD and its genetic origins has been determined, LGMD still represent an unmet medical need. Here, we describe a platform for modeling LGMD based on the use of human induced pluripotent stem cells (hiPSC).

Claudin 1 inhibits cell migration and increases intercellular adhesion in triple-negative breast cancer cell line.

Triple-negative "claudin 1 low" subtype represents around 15% of breast cancer and displays poor prognosis. The loss of claudin 1 is correlated with increased invasiveness and higher recurrence of the disease. Claudin 1 constitutes the backbone of the tight junction and is involved in cell-cell adhesion and migration processes.

Pro-apoptotic effect of Δ2-TGZ in "claudin-1-low" triple-negative breast cancer cells: involvement of claudin-1.

Purpose: 40% of triple-negative breast cancer (TNBC) do not express claudin-1, a major constituent of tight junction. Patients with these "claudin-1-low" tumors present a higher relapse incidence. A major challenge in oncology is the development of innovative therapies for such poor prognosis tumors.

Reprofiling of Troglitazone Towards More Active and Less Toxic Derivatives: A New Hope for Cancer Treatment?

The existence of unresponsive tumors and the appearance of resistant tumors during the course of treatments both justify that we increase urgently the panel of pharmacological molecules able to fight cancer. An interesting strategy is drug reprofiling (also known as drug repositioning, drug repurposing or drug retasking) that consists of identifying and developing new uses for existing drugs. This review illustrates drug reprofiling with troglitazone (TGZ), a synthetic PPARγ agonist initially used for the treatment of type II diabetes.