AIMP2 Gene Disorders: Research Update and Personalized ASO Therapy Options
AIMP2 mutations cause Hypomyelinating Leukodystrophy-17 (HLD17), an ultra-rare neurodevelopmental disorder affecting fewer than 10 individuals worldwide. This gene also plays significant roles in Parkinson's disease and cancer, making it a target for therapeutic development. For families facing an AIMP2 diagnosis, personalized antisense oligonucleotide (ASO) therapy represents the most viable path forward.
What is AIMP2?
AIMP2 (Aminoacyl tRNA Synthetase Complex Interacting Multifunctional Protein 2) encodes a 320-amino acid scaffold protein located on chromosome 7p22.1. The gene contains 4 coding exons and produces a protein essential for two cellular functions:
Protein synthesis scaffolding: AIMP2 serves as a structural component of the multi-tRNA synthetase complex (MSC), which attaches amino acids to their corresponding tRNAs during translation. The protein interacts with nine aminoacyl-tRNA synthetases and two other auxiliary proteins to form this essential molecular machine.
Tumor suppression and cell death regulation: When separated from the MSC, AIMP2 translocates to the nucleus and stabilizes p53, preventing MDM2-mediated degradation. The protein also promotes degradation of FUBP1, a transcriptional activator of MYC, thereby controlling cell proliferation.
Mouse models confirm AIMP2's essential nature. Homozygous Aimp2-null mice show neonatal lethality within 2 days of birth, with severely decreased MSC enzyme activity.
Hypomyelinating Leukodystrophy-17 (HLD17)
HLD17 represents the primary genetic disorder caused by biallelic AIMP2 mutations. First described in 2018, this autosomal recessive condition manifests as severe progressive neurodegeneration.
Clinical presentation
Affected infants present with:
Severe microcephaly: Head circumference up to -10 standard deviations below normal
Refractory seizures: Early-onset multifocal seizures resistant to antiepileptic medications
Profound developmental delay: Complete absence of milestone achievement—children never walk or speak
Progressive motor impairment: Early hypotonia evolving into spastic quadriparesis
Feeding difficulties: Severe failure to thrive requiring gastrostomy tube placement
Brain imaging findings
MRI reveals characteristic abnormalities:
Hypomyelination throughout cerebral white matter (T2-weighted hyperintensity)
Progressive cerebral and cerebellar atrophy
Thinning of the corpus callosum
Bilateral basal ganglia T2 hypointensities
Ventricular enlargement
Spinal cord atrophy
Epidemiology and inheritance
HLD17 qualifies as ultra-rare with only 5 confirmed cases documented globally as of 2025. The disorder follows autosomal recessive inheritance, requiring two mutated AIMP2 copies for disease manifestation. Both parents are typically asymptomatic carriers, with 25% recurrence risk for subsequent pregnancies.
All reported cases occurred in consanguineous families from India and Iran, suggesting higher prevalence in populations with elevated consanguinity rates.
Known AIMP2 mutations
Confirmed pathogenic variants
Two nonsense mutations account for all clinically confirmed HLD17 cases:
Y35X mutation (c.105C>A, p.Tyr35Ter): Identified in four Indian patients, this exon 1 variant creates a premature stop codon at position 35, truncating the protein within its N-terminal AIMP2-LysRS binding domain. A founder effect exists in Indian populations for this mutation.
K155X mutation (c.A463T, p.Lys155Ter): Found in an Iranian patient and first reported in 2022, this exon 3 nonsense mutation truncates the protein within the thioredoxin-like domain and carries a CADD score of 42, indicating highly deleterious effects.
Both mutations are classified as pathogenic based on ACMG/AMP guidelines, meeting criteria including PVS1, PS3, PM2, and PP1.
Additional high-risk variants
Comprehensive computational analysis published in 2024 identified eight additional high-confidence deleterious missense mutations: C23S, D121G, I122S, P128S, W268S, L138Q, V161E, and I188N. These variants affect protein structure by altering charge distribution, changing amino acid size, disrupting hydrophobic cores, and modifying post-translational modification sites.
Disease mechanisms
Molecular pathology in HLD17
Y35X mutant proteins fail to integrate into the MSC, instead forming aggregates in Golgi bodies. This abnormal localization activates Golgi stress signaling via caspase-2, which directly inhibits oligodendrocyte differentiation.
Research published in 2021 demonstrated that caspase-2 knockdown reverses differentiation defects in cellular models, suggesting this pathway as a potential therapeutic target.
Loss of AIMP2 function impairs MSC stability and formation, reducing catalytic activity and disrupting protein translation. This particularly affects rapidly dividing oligodendrocytes responsible for myelin production, resulting in the hypomyelination characteristic of HLD17.
AIMP2 in Parkinson's disease
Recent studies establish AIMP2 as both a diagnostic biomarker and therapeutic target for Parkinson's disease. 2024 research showed that AIMP2 accumulation in the hippocampus causes cognitive deficits through direct neuronal toxicity.
Critically, plasma AIMP2 levels measured by ELISA serve as a reliable molecular biomarker for PD diagnosis. The protein exhibits cell-to-cell transmissibility from neurons to endothelial cells, contributing to disease spread.
AIMP2-DX2 splice variant in cancer
AIMP2-DX2, a splice variant lacking exon 2, exhibits oncogenic properties by competitively inhibiting AIMP2 tumor-suppressive activity. A 2020 study analyzed 51 acute myeloid leukemia (AML) patients and found that 43.1% showed positive AIMP2-DX2 expression at diagnosis, associated with decreased overall survival.
High AIMP2 expression predicts improved response to anti-angiogenic therapies in recurrent glioblastoma, with methylation status at specific CpG sites serving as a predictive biomarker.
Diagnostic approach
Genetic testing strategies
Molecular genetic testing is required for HLD17 diagnosis given the lack of distinctive clinical features differentiating it from 27+ other hypomyelinating leukodystrophies.
Whole exome sequencing (WES): First-tier diagnostic approach, successfully identifying both known pathogenic variants with >98% analytical sensitivity
Targeted gene panels: Commercial leukodystrophy panels include AIMP2 among analyzed genes
Sanger sequencing: Critical for variant confirmation, parental carrier testing, and cascade screening of at-risk relatives
Prenatal diagnosis: Available through chorionic villus sampling or amniocentesis with targeted sequencing for families with known mutations
Variant interpretation follows ACMG/AMP classification guidelines, employing computational tools including SIFT, PolyPhen-2, PROVEAN, CADD, and MutPred2.
Current treatment landscape
Standard of care
No disease-specific treatments, clinical trials, or FDA-approved therapies exist for AIMP2-related disorders. Management follows general leukodystrophy care principles:
Neurological management:
Antiepileptic medications for seizure control (though often refractory)
Spasticity management with baclofen, tizanidine, or benzodiazepines
Botulinum toxin injections for severe spasticity
Rehabilitative care:
Physical therapy to maintain mobility and prevent contractures
Occupational therapy for adaptive equipment and positioning
Speech therapy for alternative communication methods
Supportive interventions:
Gastrostomy tube placement for nutrition
Respiratory management including suction and chest physiotherapy
Orthopedic interventions for contractures and scoliosis
Surveillance:
Brain MRI every 6-12 months
Serial clinical and neurodevelopmental assessments
Growth parameter monitoring
Orthopedic screening
A comprehensive search of ClinicalTrials.gov reveals zero active, recruiting, or completed clinical trials for AIMP2-related conditions.
Research advances 2020-2025
Parkinson's disease therapeutics
Multiple therapeutic interventions targeting AIMP2 aggregation showed promising preclinical results:
Small-molecule inhibitors: 2022 research identified three compounds (SAI-04, SAI-06, SAI-08) that bind AIMP2, disaggregate pre-formed aggregates, and prevent AIMP2/α-synuclein coaggregation in neuronal models.
Dual-target steroid derivatives: SG13-136 demonstrates strong binding affinity for both AIMP2 and α-synuclein with therapeutic protective effects in cellular and mouse models.
Gene therapy: AAV2 vectors delivering AIMP2-DX2 to the substantia nigra rescued motor activity and prevented neuronal death in PD mouse models, representing the first report of AAV-DX2 overexpression showing therapeutic efficacy.
Cancer therapeutics
Multiple compounds targeting AIMP2-DX2 advanced to preclinical testing:
Pyrimethamine: Repurposed antimalarial inducing ubiquitination-mediated DX2 degradation (IC50 of 0.73 μM)
BC-DXI-843: First-in-class PROTAC degrader reducing tumor volume in H460 xenograft mice
BC-DXI-32982: Targets AIMP2-DX2/KRAS interaction (IC50 of 0.18 μM) with dose-dependent tumor reduction
Personalized ASO therapy for AIMP2 disorders
For families affected by AIMP2-related disorders, Nome offers a pathway to personalized treatment through custom antisense oligonucleotide development.
Why ASO therapy for AIMP2?
The molecular characteristics of AIMP2 and its splice variants make them suitable targets for oligonucleotide-based interventions:
Splice modulation potential: Exon-skipping or splice-switching ASOs could modulate AIMP2 expression to restore partial function or prevent toxic gain-of-function from truncated proteins.
Variant-specific targeting: Custom ASOs can be designed for individual pathogenic variants, including the Y35X and K155X mutations.
DX2 splice variant targeting: For cancer and neurodegenerative applications, ASOs targeting AIMP2-DX2 could promote exon 2 inclusion during splicing, shifting the ratio toward tumor-suppressive full-length protein.
This approach builds on FDA-approved precedents including nusinersen (Spinraza) for spinal muscular atrophy and eteplirsen (Exondys 51) for Duchenne muscular dystrophy.
Nome's approach to AIMP2 ASO development
Nome provides end-to-end development of personalized ASO therapeutics through a structured process:
1. Intake and eligibility assessment (free)
Families share genetic data and medical records. Nome's AI-powered intake system analyzes whether a custom ASO therapy looks appropriate for the specific AIMP2 mutation. The team evaluates:
Mutation type and location within the gene
Disease stage and progression
CNS delivery requirements for HLD17
Potential for splice modulation or gene expression modulation
2. 30-day therapeutic development plan
Nome assembles a comprehensive plan including:
ASO molecule design targeting the specific AIMP2 variant
Chemistry modifications (2'-O-methyl, phosphorothioate backbones, locked nucleic acids) to enhance stability and cellular uptake
Delivery strategy (intrathecal for CNS disorders, subcutaneous/IV for systemic applications)
Safety and toxicology testing protocols
CMC (chemistry, manufacturing, controls) pathway
Program economics and transparent milestone-based pricing
3. Partner orchestration
Nome connects families with world-class partners for:
Oligonucleotide synthesis and manufacturing
Preclinical efficacy testing in cellular models
Safety and toxicology studies
Analytical method development
Delivery system optimization
The team manages execution across vendors, ensuring the plan moves from design to action.
4. Regulatory pathway and safety oversight
Before first dose, programs require:
Rigorous laboratory safety testing
FDA permission via Investigational New Drug (IND) application
Clinical monitoring protocols
Nome supports this process with the care team, setting clear expectations and managing regulatory requirements.
5. Delivery and ongoing management
Nome's technology and experts manage the process at every stage—from determining eligibility through building the development plan, executing with partners, gaining approvals, and delivering to patients.
Technical considerations for AIMP2 ASO therapy
For HLD17 (neurodevelopmental disorder):
CNS delivery: Intrathecal administration required, following established protocols used for nusinersen
Oligodendrocyte targeting: Enhanced delivery to myelin-producing cells
Early intervention window: Most effective when initiated before extensive neurodegeneration
Splice modulation: Designed to skip mutant exons or modulate expression levels
For cancer/Parkinson's applications:
AIMP2-DX2 targeting: Splice-switching ASOs promoting exon 2 inclusion
Systemic delivery: Subcutaneous or intravenous routes for non-CNS applications
Patient stratification: Based on AIMP2-DX2/AIMP2 expression ratios measured via RNA-sequencing
Biomarker monitoring: Plasma AIMP2 levels or tumor DX2 expression for treatment response
Speed and cost advantages
Nome compresses traditional ASO development timelines from years to months through:
AI-enabled intake processing that turns records, tests, and notes into development-ready plans
Automated partner matching and vendor orchestration
Transparent monthly fee structure with milestone-based pricing
Target cost significantly below typical $1M+ ASO development programs
Next steps for families with AIMP2 mutations
Immediate actions
Confirm genetic diagnosis: Ensure testing includes comprehensive sequencing with proper variant interpretation. OMIM entry #618006 provides detailed genetic information.
Connect with specialized centers: Leukodystrophy centers including Children's Hospital of Philadelphia, Kennedy Krieger Institute, and Amsterdam Leukodystrophy Centre offer multidisciplinary expertise.
Genetic counseling: Essential for understanding recurrence risks, cascade family screening, and reproductive options including prenatal diagnosis and preimplantation genetic diagnosis.
Join patient registries: Organizations including United Leukodystrophy Foundation and the Global Leukodystrophy Initiative Clinical Trials Network facilitate research participation and connect families.
Exploring personalized therapy with Nome
For families interested in pursuing custom ASO therapy for AIMP2-related disorders:
Submit genetic information: Share diagnostic reports, whole exome sequencing data, and medical records through Nome's secure intake system
Free eligibility assessment: Nome's team evaluates whether personalized ASO therapy is appropriate for the specific mutation and clinical situation
Receive development plan: Within 30 days, obtain a comprehensive roadmap outlining the therapeutic approach, timeline, partners, and costs
Decision point: Review the plan with your medical team and make an informed decision about proceeding with development
Ongoing partnership: If proceeding, Nome manages vendor coordination, regulatory requirements, and the path to treatment delivery
The process is transparent from intake through delivery, with families maintaining control while Nome manages the technical execution.
The future of precision medicine for rare genetic disorders
AIMP2-related disorders exemplify both the challenges and opportunities in rare disease therapeutics. While HLD17 affects fewer than 10 individuals worldwide, creating barriers for traditional pharmaceutical development, recent scientific advances position this field at the forefront of precision medicine.
The identification of specific pathogenic mechanisms, successful gene therapy approaches in mouse models, and the development of splice-modulating compounds create a growing therapeutic pipeline. For families facing an AIMP2 diagnosis today, personalized ASO therapy through platforms like Nome represents the most direct path from molecular diagnosis to individualized treatment.
The era of waiting for population-level drug development to address ultra-rare genetic disorders is ending. Patient-led, AI-enabled approaches to bespoke therapeutic development compress timelines, reduce costs, and provide hope for conditions previously considered untreatable. AIMP2 disorders, once lacking any therapeutic options, now stand at the threshold of precision oligonucleotide medicine tailored to individual mutations.
For families ready to explore personalized therapeutic options, Nome provides the expertise, infrastructure, and partnership to transform genetic information into actionable treatment strategies.
References: All scientific information in this article is sourced from peer-reviewed publications available through PubMed, OMIM, and ClinicalTrials.gov, with specific citations hyperlinked throughout the text.
