Emerging therapies for childhood-onset movement disorders

Abstract

Purpose of review: We highlight novel and emerging therapies in the treatment of childhood-onset movement disorders. We structured this review by therapeutic entity (small molecule drugs, RNA-targeted therapeutics, gene replacement therapy, and neuromodulation), recognizing that there are two main approaches to treatment: symptomatic (based on phenomenology) and molecular mechanism-based therapy or 'precision medicine' (which is disease-modifying).

Recent findings: We highlight reports of new small molecule drugs for Tourette syndrome, Friedreich's ataxia and Rett syndrome. We also discuss developments in gene therapy for aromatic l-amino acid decarboxylase deficiency and hereditary spastic paraplegia, as well as current work exploring optimization of deep brain stimulation and lesioning with focused ultrasound.

Summary: Childhood-onset movement disorders have traditionally been treated symptomatically based on phenomenology, but focus has recently shifted toward targeted molecular mechanism-based therapeutics. The development of precision therapies is driven by increasing capabilities for genetic testing and a better delineation of the underlying disease mechanisms. We highlight novel and exciting approaches to the treatment of genetic childhood-onset movement disorders while also discussing general challenges in therapy development for rare diseases. We provide a framework for molecular mechanism-based treatment approaches, a summary of specific treatments for various movement disorders, and a clinical trial readiness framework.

Figure 1.. Overview of existing and emerging therapies fall for childhood-onset movement disorders.

Therapeutic approaches fall into three categories: Traditional phenomenology-based symptomatic treatment approaches which includes small molecule drugs, non-pharmacological treatments (e.g. physical therapy, equipment and adaptive devices), and invasive or surgical approaches (i.e. botulinum toxin injections, selective dorsal rhizotomy, or deep brain stimulation). A subset of phenomenology-based approaches have established efficacy in specific etiologies, these are further highlighted in Table 1 and include small molecule drugs (e.g. carbamazepine for paroxysmal kinesigenic dyskinesia), dietary treatments (e.g. ketogenic diet for paroxysmal exercise induced dyskinesia), and deep brain stimulation (e.g. for TOR1A-associated dystonia). An emerging and growing category of newer treatments is based on the molecule mechanism, usually for genetic movement disorders. We defined these as disease-modifying therapies that are rationally targeted against specific molecular structures implicated in disease pathogenesis. A crucial first step is the recognition of the main cell autonomous molecular mechanism upstream of cellular, metabolic or circuitry changes. Broad categories include bi-allelic loss-of-function variants, heterozygous variants leading to haploinsufficiency, and heterozygous variants leading to a dominant-negative effects or toxic gain of function. Different therapeutic entities can rationally chosen and matched to these key mechanism, supporting testing and development as highlighted in Figure 3. Additionally, specific variants, often in individual cases or small number of individuals, might be amenable to antisense oligonucleotide (ASO), the classic example would be variants that introduce a cryptic splice site that can be blocked to restore a normal splicing pattern.

Figure 2.. Therapeutic levels targeted by existing and emerging therapies for childhood-onset movement disorders.

Childhood-onset movement disorders can be understood at different levels, ranging from variants in DNA to complex phenomenology. Each ascending level is the results of the sum or composite of the preceding level. By understanding and appreciating disease mechanisms at different level, therapeutic targets and entities can be developed and tailored. Examples of existing and emerging therapies are matched to the appropriate level. Abbreviations: AADC: aromatic l-amino acid decarboxylase; SPG50: Spastic Paraplegia 50; FRDA: Friedreich’s Ataxia; ADCY5: adenylyl cyclase 5; NMDA-RE: N-methyl D-aspartate receptor encephalitis; PED: paroxysmal exercise induced dyskinesia; VMAT2: vesicular monoamine transporter 2; PT: physical therapy; OT: occupational therapy.

Figure 3.. A framework for the development of novel therapeutics for childhood-onset movement disorders and other rare diseases.

In the era of advancing genetic disorder identification, conducting structured multi-center studies is imperative for comprehensively documenting the natural history of rare diseases and establishing the necessary infrastructure for evaluating emerging therapies. The framework presented here highlights key steps between the recognition of an unmet clinical need and the implementation of a new therapy in clinical care. Emphasis is placed on the early recognition and implementation of key tasks at every step of the development pipeline. Potential challenges and limiting factors are also highlighted. The initial pivotal step involves access to genomic platforms capable of pinpointing causative variant(s) and highlighting potential molecular mechanism-based therapeutic avenues. Recognizing these conditions early is paramount, particularly given that the therapeutic window for progressive movement disorders may be narrower than currently estimated. While cross-sectional phenotyping studies contribute to understanding the spectrum of disease manifestations, subsequent prospective longitudinal natural history studies become essential. These studies play a crucial role in defining disease progression, assessing morbidity and mortality (thereby informing risk/benefit discussions for experimental therapeutics), and evaluating potential biomarkers and endpoints for interventional trials. In the pre-clinical development phase of novel mechanism-based therapies, the establishment of key molecular or cellular disease phenotypes in disease models facilitates in vitro and in vivo proof-of-concept experiments. Upon completing IND-enabling studies, the design of phase 1/2 trials becomes a notable challenge, requiring not only safety testing but also the maximization of insights derived from secondary endpoints assessing efficacy. Subsequent studies encounter difficulties associated with small patient populations and the need to demonstrate meaningful benefits, such as improvement or, more realistically, a slowing of progression within a relatively short timeframe. The high costs related to manufacturing and pivotal studies pose a significant hurdle, making some programs commercially non-viable. This underscores the critical importance of developing platform technologies to mitigate costs, fostering a supportive regulatory environment, and promoting innovative, investigator-driven, and grant-funded clinical studies that effectively de-risk novel therapeutic approaches for the rare disease community.