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Are intestinal organoids the key to developing personalized therapy for cystic fibrosis?

Intestinal organoids have been utilized to develop personalized therapy for cystic fibrosis patients.

Cystic fibrosis (CF) is a rare genetic disorder caused by a mutation in the CFTR gene. CFTR protein modulator drugs, which are effective in slowing disease progression, have been approved but only for a limited set of genotypes. With more than 2000 different CFTR mutations identified, these mutation specific therapies result in at least 10% of CF patients having no approved modulator drug.

Now, the clinical-stage biopharmaceutical company Proteostasis Therapeutics, Inc. (MA, USA) have announced the results of their ex vivo study, testing CFTR modulators in intestinal organoids of CF patients previously ineligible for CFTR modulator therapies due to the rare CFTR mutation they carry.

The study, presented recently at the Keystone Symposia on Tissue Organoids as Models of Host Physiology and Pathophysiology of Disease (Vancouver, BC, Canada, 19-23 January 2020), involved collecting samples from CF patients with less common genotypes via a rectal suction procedure, and assaying intestinal organoids from these samples.

The resulting intestinal organoids were then used to test responsiveness to Proteostasis’ investigational CFTR modulators, including their potentiator (dirocaftor), the corrector (posenacaftor) and the amplifier (nesolicaftor).

At this time, 329 samples have been collected and tested and preliminary results suggest that 75% of donor organoids can be assessed for responsiveness. The company are currently performing secondary validation of responses to confirm this.

“Access to CFTR modulators in Europe is challenged by either the ineligibility of patients for approved drugs due to their genotype, or by the lack of reimbursement for approved drugs due to their high cost,” explained study coauthor Cornelis van der Ent (Utrecht University, The Netherlands). “An organoid-assay-based personalized medicine approach offers the potential of a new decision-supporting technology to inform clinical decisions and provide each patient with CFTR modulators that lead to their highest possible benefit.”

Once 500 samples have been collected and tested, which is set be achieved at the end of the first quarter of 2020, the researchers intend to use data collected to select patients for a confirmatory clinical trial, known as the CHOICES trial (Crossover trial based on Human Organoid Individual Response in CF – Efficacy Study).

The CHOICES trial is set to begin in mid-2020 and will involve a placebo controlled, double blind, crossover study with an 8-week treatment program and 6 months of uninterrupted dosing. This trial is likely to have huge significance considering it is the first personalized medicine-based study conducted in CF research.

“With advancements in models such as organoid testing used to predict the effectiveness of CFTR modulator treatments, the transition from precision to personalized medicine in this disease is an inevitability,” remarked Geoffrey Gilmartin, coauthor of this study. “Essential to this transition is the introduction of more therapeutic options that expand the treatment choices for patients and physicians.”

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