Unleashing the potential of mRNA therapeutics for inherited neurological diseases.

Neurological monogenic loss-of-function diseases are hereditary disorders resulting from gene mutations that decrease or abolish the normal function of the encoded protein. These conditions pose significant therapeutic challenges, which may be resolved through the development of innovative therapeutic strategies. RNA-based technologies, such as mRNA replacement therapy, have emerged as promising and increasingly viable treatments. Notably, mRNA therapy exhibits significant potential as a mutation-agnostic approach that can address virtually any monogenic loss-of-function disease. Therapeutic mRNA carries the information for a healthy copy of the defective protein, bypassing the problem of targeting specific genetic variants. Moreover, unlike conventional gene therapy, mRNA-based drugs are delivered through a simplified process that requires only transfer to the cytoplasm, thereby reducing the mutagenic risks related to DNA integration. Additionally, mRNA therapy exerts a transient effect on target cells, minimizing the risk of long-term unintended consequences. The remarkable success of mRNA technology for developing COVID-19 vaccines has rekindled interest in mRNA as a cost-effective method for delivering therapeutic proteins. However, further optimization is required to enhance mRNA delivery, particularly to the central nervous system, while minimizing adverse drug reactions and toxicity. In this comprehensive review, we delve into past, present, and ongoing applications of mRNA therapy for neurological monogenic loss-of-function diseases. We also discuss the promises and potential challenges presented by mRNA therapeutics in this rapidly advancing field. Ultimately, we underscore the full potential of mRNA therapy as a game-changing therapeutic approach for neurological disorders.

A novel CACNA1A R2201W variant in a woman with hemiplegic migraine.

INTRODUCTION: Familial hemiplegic migraine type 1 (FHM1) is a monogenic rare disease that is characterized by migraine attacks accompanied by unilateral weakness and is caused by mutations in the CACNA1A gene. We report the case of a patient with a clinical history consistent with hemiplegic migraine who underwent genetic testing that revealed a variant in the CACNA1A gene. CASE PRESENTATION: A 68-year-old woman was evaluated for progressive postural instability and subjective cognitive decline. She had suffered from recurrent migraine episodes accompanied by fully reversible unilateral weakness that had started around the age of thirty and had fully disappeared at the time of evaluation. Magnetic resonance imaging (MRI) showed an extensive leukoencephalopathy, with features suggestive of small vessel disease, significantly progressing over the years. Exome sequencing revealed the heterozygous variant c.6601C>T (p.Arg2201Trp) in the CACNA1A gene. This variant, located in a highly conserved region, causes the substitution of arginine with tryptophan at codon 2202 of exon 47, with a high likelihood of a damaging effect on protein activity and/or structure. DISCUSSION: This is the first report describing the missense mutation c.6601C>T (p.Arg2201Trp) in heterozygosity in the CACNA1A gene in a patient with clinical features of hemiplegic migraine. The presence of a diffuse leukoencephalopathy on MRI is not typical of hemiplegic migraine and may suggest a phenotypic variant related to this mutation or result from the combined effect of the patient's comorbidities.

Therapeutic strategies in vascular cognitive impairment: A systematic review of population, intervention, comparators, and outcomes.

INTRODUCTION: Vascular cognitive impairment (VCI) is a common and heterogeneous condition, clinically and pathophysiologically, that still lacks approved treatment. METHODS: We reviewed evidence from randomized and non-randomized clinical trials in VCI to explore whether any therapeutic option warrants further investigation and to assess possible flaws in previous studies. RESULTS: We identified 118 studies after searching PubMed and Embase, including 19,223 participants and 5 different VCI subtypes. We found 63 different types of intervention (51 pharmacologic, 5 employing physical agent application, 7 rehabilitation approaches) compared with either placebo, best medical treatment, or other interventions. Treatment efficacy was assessed through 125 outcome measures (with a clearly pre-specified primary outcome in 50.8% of studies). DISCUSSION: Therapeutic trials in VCI have been heterogeneous in terms of populations, types of interventions, and outcomes. Overall, a lack of clear pathophysiological rationale for tested interventions seems to emerge, together with the need to homogenize trial study design.