Towards Precision Therapies for Inherited Disorders of Neurodegeneration with Brain Iron Accumulation.

Background: Neurodegeneration with brain iron accumulation (NBIA) disorders comprise a group of rare but devastating inherited neurological diseases with unifying features of progressive cognitive and motor decline, and increased iron deposition in the basal ganglia. Although at present there are no proven disease-modifying treatments, the severe nature of these monogenic disorders lends to consideration of personalized medicine strategies, including targeted gene therapy. In this review we summarize the progress and future direction towards precision therapies for NBIA disorders. Methods: This review considered all relevant publications up to April 2021 using a systematic search strategy of PubMed and clinical trials databases. Results: We review what is currently known about the underlying pathophysiology of NBIA disorders, common NBIA disease pathways, and how this knowledge has influenced current management strategies and clinical trial design. The safety profile, efficacy and clinical outcome of clinical studies are reviewed. Furthermore, the potential for future therapeutic approaches is also discussed. Discussion: Therapeutic options in NBIAs remain very limited, with no proven disease-modifying treatments at present. However, a number of different approaches are currently under development with increasing focus on targeted precision therapies. Recent advances in the field give hope that novel strategies, such as gene therapy, gene editing and substrate replacement therapies are both scientifically and financially feasible for these conditions. Highlights: This article provides an up-to-date review of the current literature about Neurodegeneration with Brain Iron Accumulation (NBIA), with a focus on disease pathophysiology, current and previously trialed therapies, and future treatments in development, including consideration of potential genetic therapy approaches.