RARE DISEASE
Aromatic L-amino acid decarboxylase deficiency
Aromatic L-amino acid decarboxylase deficiency
Aromatic L-amino acid decarboxylase deficiency
Synonyms: AADC deficiency
Synonyms: AADC deficiency
Synonyms: AADC deficiency
Drug discovery
6
drugs
With orphan designations
Overview
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder caused by DDC gene mutations, resulting in impaired synthesis of dopamine and serotonin. Clinical features include hypotonia, oculogyric crises, developmental delay, autonomic dysfunction, and movement disorders. Diagnosis relies on genetic testing, CSF neurotransmitter analysis (low 5-HIAA/HVA, elevated 3-OMD), and reduced plasma AADC activity. Management involves dopamine agonists, MAO inhibitors, and multidisciplinary care, with emerging gene therapies showing promise [1][6][9][12].
Burden
Annual healthcare costs average $68,000 (direct + indirect), driven by frequent specialist visits and hospitalizations [2][4]
85% experience sleep disturbances; 80% require lifelong caregiver support [4][13]
Severe phenotypes correlate with premature mortality and profound developmental disability [2][6]
Therapies
Pharmacologic: Dopamine agonists (pramipexole/rotigotine), MAO inhibitors (selegiline), and pyridoxine [3][5][16]
Gene therapy: Eladocagene exuparvovec (FDA/EMA-approved) demonstrates motor improvement in 61% of severe cases [12][19]
Supportive: Physiotherapy, enteral feeding, and autonomic symptom management [1][6]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
178 drug discovery papers about Aromatic L-amino acid decarboxylase deficiency, with 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
178 drug discovery papers about Aromatic L-amino acid decarboxylase deficiency, with 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-04 | Adult-onset levodopa-unresponsive parkinsonism as the presenting feature of aromatic l-amino acid decarboxylase deficiency
Introduction: Aromatic L-amino acid decarboxylase is a critical enzyme required for the final step in the synthesis of dopamine and serotonin, two important neurotransmitters. Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder of neurotransmitter biosynthesis caused by pathogenic variants in the dopa decarboxylase (DDC) gene. An absence or decrease of dopamine and serotonin levels may lead to severe motor and neurodevelopmental impairments. It classically presents within the first 6 months of life with a triad of hypotonia, oculogyric crises and developmental delay. Adult-onset presentations are extremely rare and underreported. Case description: We report the case of a 53-year-old man who presented with progressive left-sided bradykinesia, stiffness, rigidity and resting tremor over a year and a half. Examination demonstrated asymmetrical parkinsonism including facial hypomimia, cogwheel rigidity and a reduced arm swing on the left. A trial of levodopa of up to 1000 mg levodopa equivalent daily dose did not improve his condition. Magnetic resonance imaging of the brain was reported as normal without radiological signs of atypical parkinsonian neurodegenerative disorders. An autoimmune and onconeural antibody panel was negative. The patient’s symptoms progressively deteriorated and he noted dysphagia requiring a tailored feeding plan Dopamine transporter single-photon emission computed tomography was performed demonstrating a marked reduction of nigrostriatal synaptic integrity at the right putamen and modest reduction at the left putamen. Targeted genetic testing identified a homozygous missense variant [NM_000790.3: c.710T>C p. (Phe237Ser)] in the DDC gene, establishing the diagnosis of AADC deficiency. Levodopa was substituted with a direct dopamine agonist (ropinirole) which resulted in a modest clinical improvement; however, dose escalation was limited by nausea. The patient subsequently developed neuropsychiatric symptoms which were managed with mirtazapine and sodium valproate. Conclusion: This case expands the recognised phenotypic spectrum of AADC deficiency and highlights the importance of considering neurotransmitter biosynthesis defects in levodopa-unresponsive adult parkinsonism.
2025-07-24 | A CRISPR/Cas9 knockout model for AADC deficiency reveals structural loop3 instability as a key driver of catalytic failure.
The CRISPR-Cas9 dopa decarboxylase (DDC) gene knockout SH-SY5Y model for aromatic L-amino acid decarboxylase (AADC) deficiency provides a valuable neuronal platform for functional and structural investigation of pathogenic variants. In their study, Bertoldi et al. successfully recapitulate the biochemical and metabolic hallmarks of AADC deficiency using the AADC catalytic variants R347Q and L353P. Their combined structural and cellular approach identifies loop3 dynamics as a critical determinant of enzymatic dysfunction. This model may pave the way for the development of precision therapies.
2025-01-24 | Case Series of Anesthetic Management of Gene Therapy in Children With Aromatic L-Amino Acid Decarboxylase Deficiency.
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare life-threatening inborn error of neurotransmitter biosynthesis. It is characterized by deficient biosynthesis of neurotransmitters dopamine and serotonin, leading to catecholamines deficiency and sympathetic deprivation, while the parasympathetic system remains functional. Since 2012, gene therapy has led to clinical improvements in symptoms and motor function with a severe phenotype. General anesthesia of children with AADC deficiency is challenging. Describe prolonged anesthesia management of children with aromatic L-amino acid decarboxylase deficiency undergoing stereotactically guided gene therapy. Prospective reporting of epidemiologic and anesthetics data of four children consecutively undergoing magnetic resonance-guided direct delivery of an AADC vector for gene therapy under general anesthesia. General anesthesia was initiated with sevoflurane and ketamine and rocuronium was the neuromuscular blocking agent of choice throughout the procedures. Intraoperative hemodynamic monitoring included an arterial line. All children required low doses of diluted norepinephrine during the intraoperative period. No dysautomic episodes as well as no episode of severe hypotension and no severe hypoglycemia were reported throughout the procedures. Vasopressor support was discontinued for all children at the end of the procedures. Moreover, no peroperative and postoperative effects secondary to AADC vector injection were noted. Using an anesthetic plan based on atropine, ketamine, sevoflurane, and a titrated infusion of norepinephrine, prolonged anesthesia appeared to be safe and reproductible in this population.
2024-05-31 | Selective Serotonin Reuptake Inhibitor Treatment Post Gene Therapy for an Ultrarare Neurometabolic Disorder (AADC Deficiency).
A 7-year-old girl presented with persistent anxiety symptoms for several years following gene therapy for an ultrarare neurometabolic disorder (aromatic L-amino acid decarboxylase [AADC] deficiency). AADC is the final enzyme in the monoamine synthesis pathway (Figure 1).1 Its absence results in a severe combined deficiency in serotonin, dopamine, epinephrine, and norepinephrine, causing significant developmental delays, hypotonia, and dystonia. The incidence of AADC deficiency is estimated at ∼1 in 500,000,2 and ∼200 cases have been described.1 Recently available disease-modifying gene therapy for this condition dramatically improves motor symptoms, and received regulatory approval in some regions in 2022.2 There are no data to guide psychiatric care post gene therapy for AADC or other neurologic disorders to date.3.
2024-04-24 | Neurodegenerative Etiology of Aromatic L-Amino Acid Decarboxylase Deficiency: a Novel Concept for Expanding Treatment Strategies.
Aromatic l-amino acid decarboxylase deficiency (AADC-DY) is caused by one or more mutations in the DDC gene, resulting in the deficit in catecholamines and serotonin neurotransmitters. The disease has limited therapeutic options with relatively poor clinical outcomes. Accumulated evidence suggests the involvement of neurodegenerative mechanisms in the etiology of AADC-DY. In the absence of neurotransmitters' neuroprotective effects, the accumulation and the chronic presence of several neurotoxic metabolites including 4-dihydroxy-L-phenylalanine, 3-methyldopa, and homocysteine, in the brain of subjects with AADC-DY, promote oxidative stress and reduce the cellular antioxidant and methylation capacities, leading to glial activation and mitochondrial dysfunction, culminating to neuronal injury and death. These pathophysiological processes have the potential to hinder the clinical efficacy of treatments aimed at increasing neurotransmitters' synthesis and or function. This review describes in detail the mechanisms involved in AADC-DY neurodegenerative etiology, highlighting the close similarities with those involved in other neurodegenerative diseases. We then offer novel strategies for the treatment of the disease with the objective to either reduce the level of the metabolites or counteract their prooxidant and neurotoxic effects. These treatment modalities used singly or in combination, early in the course of the disease, will minimize neuronal injury, preserving the functional integrity of neurons, hence improving the clinical outcomes of both conventional and unconventional interventions in AADC-DY. These modalities may not be limited to AADC-DY but also to other metabolic disorders where a specific mutation leads to the accumulation of prooxidant and neurotoxic metabolites.
gene therapies
2026-03-06 | Frameless stereotactic infusion of gene therapy into the putamen for AADC deficiency in children: technical and organizational aspects of implementation in Russia
Aim. To present the authors’ experience in implementing a frameless stereotactic infusion technique of a gene preparation using an adeno-associated vectored virus into the subcortical structures of the brain in children with aromatic L-amino acid decarboxylase deficiency (AADCd), with an emphasis on technical and organizational aspects. Materials and methods. From November 2024 to December 2025, six bilateral infusions of eladocagen exuparvovec (Upstaza®) were administered into the putamen of children with genetically confirmed AADCd in the Department of Pediatric Neurosurgery of the Russian Children’s Clinical Hospital. The key stages of patient selection, regulatory support, preoperative planning based on brain magnetic resonance imaging data, features of frameless navigation, the Z-shaped convection-enhanced infusion technique, and measures for preventing intra- and postoperative complications are described. The analysis of clinical outcomes is deliberately not presented in this work and is planned for a separate publication after increasing the sample size and follow-up observation. Results. In all 6 cases, accurate drug delivery to the putamen was ensured in accordance with preoperative planning, and no intraoperative complications were observed. Early postoperative magnetic resonance imaging monitoring revealed no clinically significant hemorrhagic or ischemic brain damage. In all cases, improvements in motor and autonomic symptoms of varying severity were noted during the first months of follow-up. Conclusion. The presented experience demonstrates the technical feasibility and safety of frameless stereotactic gene therapy for AADCd in children in a Federal Center setting. The proposed method can serve as the basis for a national treatment protocol for AADCd and the establishment of a reference center for gene therapy for central nervous system diseases.
2026-01-05 | mGem: AAV, from almost a virus to an awesome vector-or is it?
Adeno-associated virus (AAV) vectors have taken center stage for gene therapy and have shown clinical efficacy in 15 human diseases to date. The Food and Drug Administration has approved seven AAV "drugs" for one-time treatment respectively for Leber's congenital amaurosis, spinal muscular atrophy, hemophilia B, Duchenne muscular dystrophy, hemophilia A, and aromatic L-amino acid decarboxylase deficiency. Despite these remarkable developments, it has become increasingly clear that the first generation of AAV vectors is less than optimal since in most, if not all, cases, exceedingly high doses are needed to achieve clinical efficacy, and as a consequence, in some patients, serious adverse events have been observed, and to date, at least 21 patients have died. Thus, there is a need to reassess the limitations of the first generation of AAV vectors as well as an urgent need to develop the next generation of AAV vectors that are safe and effective.
2025-11-27 | Emerging Technologies Tackling Adeno-Associated Viruses (AAV) Immunogenicity in Gene Therapy Applications.
Adeno-associated viral vectors have proven to be a safe and effective gene therapy delivery system. Over the past decade, the approval of AAV gene therapies made a revolution in treatment of severe hereditary diseases, including spinal muscular atrophy, AADC deficiency, and others. Recombinant AAV-based therapeutics are currently intended for single administration. Safety concerns arise from immune responses to AAV and the resulting transgene, which can render subsequent injections ineffective. It remains unclear whether patients who have received an AAV-based gene therapy will need re-administration in the future. Furthermore, since many people have neutralizing antibodies or memory T cells against AAV from natural infections, it is crucial to overcome pre-existing immunity. This review considers existing modern approaches aimed to overcome both pre-existing natural immunity and immunity obtained after the administration of a gene therapy drug, which include various modifications of the viral drug (capsid modification, codon optimization), the use of empty capsid traps, and pharmacological support (immunosuppressive corticosteroids, inhibitors of various branches of the immune response, nanoparticles, IgG-degrading enzymes). The goal of this review is to illustrate the importance of this challenge and to highlight potential strategies for overcoming immunity to AAV-based gene therapies, contributing to the development of a successful therapeutic gene delivery platform.
2024-12-09 | Imaging readiness in the gene therapy era‐exploring standardized protocols for response assessment
Figure S1: Example of a disease specific imaging-based pathway for PLA2G6-associated neurodegeneration (PLAN). Top left: Sagittal T1 weighted image (A) shows claval hypertrophy (arrow), and cerebellar atrophy (block arrow). Coronal T2 weighted image (B) shows hyperintensity involving the nucleus accumbens bilaterally. Bottom left: Axial DWI (A) and ADC (B) images show symmetric reduced diffusivity involving the caudate and putamina (dashed arrows). Top right and bottom right: Quantification of cerebellar volume and iron deposition over time utilizing quantitative susceptibility mapping and volumetric data. Figure S2: Stereotactic robot assisted injection of AAV2-based gene therapy for aromatic L-amino acid decarboxylase (AADC) deficiency. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
2024-10-22 | Optimizing the anesthetic care of patients with aromatic l-amino acid decarboxylase deficiency.
Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder that results in a lack of the monoamine neurotransmitters dopamine, serotonin, norepinephrine, and epinephrine. Patients present with a wide spectrum of symptoms, including motor and autonomic dysfunction, hypotonia, and developmental delay, often before the age of one. Until recently, treatment options were limited to symptom control, but the recent approval of the first gene therapy for AADC deficiency in Europe and the UK has provided an alternative to treating symptoms for this disease. Eladocagene exuparvovec is a one-time gene therapy, administered bilaterally to the putamen by magnetic resonance imaging-guided stereotactic neurosurgery. While administration of the gene therapy itself is minimally invasive, the anesthetic management of patients with AADC deficiency is challenging due to the absence of sympathetic regulation secondary to the lack of adrenergic neurotransmitters. Optimal anesthetic management requires an understanding of the complex and heterogeneous nature of the disease. Hemodynamic instability, temperature dysregulation, and hypoglycemia are of primary concern, but there are also challenges regarding intravenous access and airway management. A thorough preoperative assessment is essential and should be guided by the patient's history. Advanced planning is necessary regarding the timing of the procedure schedule and operative plan; meticulous preparation, simulation for the operating room, as well as communication with all perioperative staff members, are crucial. Intraoperatively, utmost care must be taken to protect the skin, maintain body temperature, and to prepare for inotropic and/or glycemic support as needed. Postoperative intensive care management is necessary for consideration of postoperative extubation and provision of supportive care. With careful planning, preparation, and vigilance, patients with AADC deficiency can safely undergo anesthesia.
small molecules
2026-09-04 | Adult-onset levodopa-unresponsive parkinsonism as the presenting feature of aromatic l-amino acid decarboxylase deficiency
Introduction: Aromatic L-amino acid decarboxylase is a critical enzyme required for the final step in the synthesis of dopamine and serotonin, two important neurotransmitters. Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder of neurotransmitter biosynthesis caused by pathogenic variants in the dopa decarboxylase (DDC) gene. An absence or decrease of dopamine and serotonin levels may lead to severe motor and neurodevelopmental impairments. It classically presents within the first 6 months of life with a triad of hypotonia, oculogyric crises and developmental delay. Adult-onset presentations are extremely rare and underreported. Case description: We report the case of a 53-year-old man who presented with progressive left-sided bradykinesia, stiffness, rigidity and resting tremor over a year and a half. Examination demonstrated asymmetrical parkinsonism including facial hypomimia, cogwheel rigidity and a reduced arm swing on the left. A trial of levodopa of up to 1000 mg levodopa equivalent daily dose did not improve his condition. Magnetic resonance imaging of the brain was reported as normal without radiological signs of atypical parkinsonian neurodegenerative disorders. An autoimmune and onconeural antibody panel was negative. The patient’s symptoms progressively deteriorated and he noted dysphagia requiring a tailored feeding plan Dopamine transporter single-photon emission computed tomography was performed demonstrating a marked reduction of nigrostriatal synaptic integrity at the right putamen and modest reduction at the left putamen. Targeted genetic testing identified a homozygous missense variant [NM_000790.3: c.710T>C p. (Phe237Ser)] in the DDC gene, establishing the diagnosis of AADC deficiency. Levodopa was substituted with a direct dopamine agonist (ropinirole) which resulted in a modest clinical improvement; however, dose escalation was limited by nausea. The patient subsequently developed neuropsychiatric symptoms which were managed with mirtazapine and sodium valproate. Conclusion: This case expands the recognised phenotypic spectrum of AADC deficiency and highlights the importance of considering neurotransmitter biosynthesis defects in levodopa-unresponsive adult parkinsonism.
2025-07-24 | A CRISPR/Cas9 knockout model for AADC deficiency reveals structural loop3 instability as a key driver of catalytic failure.
The CRISPR-Cas9 dopa decarboxylase (DDC) gene knockout SH-SY5Y model for aromatic L-amino acid decarboxylase (AADC) deficiency provides a valuable neuronal platform for functional and structural investigation of pathogenic variants. In their study, Bertoldi et al. successfully recapitulate the biochemical and metabolic hallmarks of AADC deficiency using the AADC catalytic variants R347Q and L353P. Their combined structural and cellular approach identifies loop3 dynamics as a critical determinant of enzymatic dysfunction. This model may pave the way for the development of precision therapies.
2025-01-24 | Case Series of Anesthetic Management of Gene Therapy in Children With Aromatic L-Amino Acid Decarboxylase Deficiency.
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare life-threatening inborn error of neurotransmitter biosynthesis. It is characterized by deficient biosynthesis of neurotransmitters dopamine and serotonin, leading to catecholamines deficiency and sympathetic deprivation, while the parasympathetic system remains functional. Since 2012, gene therapy has led to clinical improvements in symptoms and motor function with a severe phenotype. General anesthesia of children with AADC deficiency is challenging. Describe prolonged anesthesia management of children with aromatic L-amino acid decarboxylase deficiency undergoing stereotactically guided gene therapy. Prospective reporting of epidemiologic and anesthetics data of four children consecutively undergoing magnetic resonance-guided direct delivery of an AADC vector for gene therapy under general anesthesia. General anesthesia was initiated with sevoflurane and ketamine and rocuronium was the neuromuscular blocking agent of choice throughout the procedures. Intraoperative hemodynamic monitoring included an arterial line. All children required low doses of diluted norepinephrine during the intraoperative period. No dysautomic episodes as well as no episode of severe hypotension and no severe hypoglycemia were reported throughout the procedures. Vasopressor support was discontinued for all children at the end of the procedures. Moreover, no peroperative and postoperative effects secondary to AADC vector injection were noted. Using an anesthetic plan based on atropine, ketamine, sevoflurane, and a titrated infusion of norepinephrine, prolonged anesthesia appeared to be safe and reproductible in this population.
2024-05-31 | Selective Serotonin Reuptake Inhibitor Treatment Post Gene Therapy for an Ultrarare Neurometabolic Disorder (AADC Deficiency).
A 7-year-old girl presented with persistent anxiety symptoms for several years following gene therapy for an ultrarare neurometabolic disorder (aromatic L-amino acid decarboxylase [AADC] deficiency). AADC is the final enzyme in the monoamine synthesis pathway (Figure 1).1 Its absence results in a severe combined deficiency in serotonin, dopamine, epinephrine, and norepinephrine, causing significant developmental delays, hypotonia, and dystonia. The incidence of AADC deficiency is estimated at ∼1 in 500,000,2 and ∼200 cases have been described.1 Recently available disease-modifying gene therapy for this condition dramatically improves motor symptoms, and received regulatory approval in some regions in 2022.2 There are no data to guide psychiatric care post gene therapy for AADC or other neurologic disorders to date.3.
2024-04-24 | Neurodegenerative Etiology of Aromatic L-Amino Acid Decarboxylase Deficiency: a Novel Concept for Expanding Treatment Strategies.
Aromatic l-amino acid decarboxylase deficiency (AADC-DY) is caused by one or more mutations in the DDC gene, resulting in the deficit in catecholamines and serotonin neurotransmitters. The disease has limited therapeutic options with relatively poor clinical outcomes. Accumulated evidence suggests the involvement of neurodegenerative mechanisms in the etiology of AADC-DY. In the absence of neurotransmitters' neuroprotective effects, the accumulation and the chronic presence of several neurotoxic metabolites including 4-dihydroxy-L-phenylalanine, 3-methyldopa, and homocysteine, in the brain of subjects with AADC-DY, promote oxidative stress and reduce the cellular antioxidant and methylation capacities, leading to glial activation and mitochondrial dysfunction, culminating to neuronal injury and death. These pathophysiological processes have the potential to hinder the clinical efficacy of treatments aimed at increasing neurotransmitters' synthesis and or function. This review describes in detail the mechanisms involved in AADC-DY neurodegenerative etiology, highlighting the close similarities with those involved in other neurodegenerative diseases. We then offer novel strategies for the treatment of the disease with the objective to either reduce the level of the metabolites or counteract their prooxidant and neurotoxic effects. These treatment modalities used singly or in combination, early in the course of the disease, will minimize neuronal injury, preserving the functional integrity of neurons, hence improving the clinical outcomes of both conventional and unconventional interventions in AADC-DY. These modalities may not be limited to AADC-DY but also to other metabolic disorders where a specific mutation leads to the accumulation of prooxidant and neurotoxic metabolites.
gene therapies
2026-03-06 | Frameless stereotactic infusion of gene therapy into the putamen for AADC deficiency in children: technical and organizational aspects of implementation in Russia
Aim. To present the authors’ experience in implementing a frameless stereotactic infusion technique of a gene preparation using an adeno-associated vectored virus into the subcortical structures of the brain in children with aromatic L-amino acid decarboxylase deficiency (AADCd), with an emphasis on technical and organizational aspects. Materials and methods. From November 2024 to December 2025, six bilateral infusions of eladocagen exuparvovec (Upstaza®) were administered into the putamen of children with genetically confirmed AADCd in the Department of Pediatric Neurosurgery of the Russian Children’s Clinical Hospital. The key stages of patient selection, regulatory support, preoperative planning based on brain magnetic resonance imaging data, features of frameless navigation, the Z-shaped convection-enhanced infusion technique, and measures for preventing intra- and postoperative complications are described. The analysis of clinical outcomes is deliberately not presented in this work and is planned for a separate publication after increasing the sample size and follow-up observation. Results. In all 6 cases, accurate drug delivery to the putamen was ensured in accordance with preoperative planning, and no intraoperative complications were observed. Early postoperative magnetic resonance imaging monitoring revealed no clinically significant hemorrhagic or ischemic brain damage. In all cases, improvements in motor and autonomic symptoms of varying severity were noted during the first months of follow-up. Conclusion. The presented experience demonstrates the technical feasibility and safety of frameless stereotactic gene therapy for AADCd in children in a Federal Center setting. The proposed method can serve as the basis for a national treatment protocol for AADCd and the establishment of a reference center for gene therapy for central nervous system diseases.
2026-01-05 | mGem: AAV, from almost a virus to an awesome vector-or is it?
Adeno-associated virus (AAV) vectors have taken center stage for gene therapy and have shown clinical efficacy in 15 human diseases to date. The Food and Drug Administration has approved seven AAV "drugs" for one-time treatment respectively for Leber's congenital amaurosis, spinal muscular atrophy, hemophilia B, Duchenne muscular dystrophy, hemophilia A, and aromatic L-amino acid decarboxylase deficiency. Despite these remarkable developments, it has become increasingly clear that the first generation of AAV vectors is less than optimal since in most, if not all, cases, exceedingly high doses are needed to achieve clinical efficacy, and as a consequence, in some patients, serious adverse events have been observed, and to date, at least 21 patients have died. Thus, there is a need to reassess the limitations of the first generation of AAV vectors as well as an urgent need to develop the next generation of AAV vectors that are safe and effective.
2025-11-27 | Emerging Technologies Tackling Adeno-Associated Viruses (AAV) Immunogenicity in Gene Therapy Applications.
Adeno-associated viral vectors have proven to be a safe and effective gene therapy delivery system. Over the past decade, the approval of AAV gene therapies made a revolution in treatment of severe hereditary diseases, including spinal muscular atrophy, AADC deficiency, and others. Recombinant AAV-based therapeutics are currently intended for single administration. Safety concerns arise from immune responses to AAV and the resulting transgene, which can render subsequent injections ineffective. It remains unclear whether patients who have received an AAV-based gene therapy will need re-administration in the future. Furthermore, since many people have neutralizing antibodies or memory T cells against AAV from natural infections, it is crucial to overcome pre-existing immunity. This review considers existing modern approaches aimed to overcome both pre-existing natural immunity and immunity obtained after the administration of a gene therapy drug, which include various modifications of the viral drug (capsid modification, codon optimization), the use of empty capsid traps, and pharmacological support (immunosuppressive corticosteroids, inhibitors of various branches of the immune response, nanoparticles, IgG-degrading enzymes). The goal of this review is to illustrate the importance of this challenge and to highlight potential strategies for overcoming immunity to AAV-based gene therapies, contributing to the development of a successful therapeutic gene delivery platform.
2024-12-09 | Imaging readiness in the gene therapy era‐exploring standardized protocols for response assessment
Figure S1: Example of a disease specific imaging-based pathway for PLA2G6-associated neurodegeneration (PLAN). Top left: Sagittal T1 weighted image (A) shows claval hypertrophy (arrow), and cerebellar atrophy (block arrow). Coronal T2 weighted image (B) shows hyperintensity involving the nucleus accumbens bilaterally. Bottom left: Axial DWI (A) and ADC (B) images show symmetric reduced diffusivity involving the caudate and putamina (dashed arrows). Top right and bottom right: Quantification of cerebellar volume and iron deposition over time utilizing quantitative susceptibility mapping and volumetric data. Figure S2: Stereotactic robot assisted injection of AAV2-based gene therapy for aromatic L-amino acid decarboxylase (AADC) deficiency. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
2024-10-22 | Optimizing the anesthetic care of patients with aromatic l-amino acid decarboxylase deficiency.
Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder that results in a lack of the monoamine neurotransmitters dopamine, serotonin, norepinephrine, and epinephrine. Patients present with a wide spectrum of symptoms, including motor and autonomic dysfunction, hypotonia, and developmental delay, often before the age of one. Until recently, treatment options were limited to symptom control, but the recent approval of the first gene therapy for AADC deficiency in Europe and the UK has provided an alternative to treating symptoms for this disease. Eladocagene exuparvovec is a one-time gene therapy, administered bilaterally to the putamen by magnetic resonance imaging-guided stereotactic neurosurgery. While administration of the gene therapy itself is minimally invasive, the anesthetic management of patients with AADC deficiency is challenging due to the absence of sympathetic regulation secondary to the lack of adrenergic neurotransmitters. Optimal anesthetic management requires an understanding of the complex and heterogeneous nature of the disease. Hemodynamic instability, temperature dysregulation, and hypoglycemia are of primary concern, but there are also challenges regarding intravenous access and airway management. A thorough preoperative assessment is essential and should be guided by the patient's history. Advanced planning is necessary regarding the timing of the procedure schedule and operative plan; meticulous preparation, simulation for the operating room, as well as communication with all perioperative staff members, are crucial. Intraoperatively, utmost care must be taken to protect the skin, maintain body temperature, and to prepare for inotropic and/or glycemic support as needed. Postoperative intensive care management is necessary for consideration of postoperative extubation and provision of supportive care. With careful planning, preparation, and vigilance, patients with AADC deficiency can safely undergo anesthesia.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
6 orphan drug designations for Aromatic L-amino acid decarboxylase deficiency, including 2 approved therapies.
6 orphan drug designations for Aromatic L-amino acid decarboxylase deficiency, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
a recombinant adeno-associated virus serotype 9-based vector containing an expression cassette of the human AADC and human GDNF genes | gene therapies | FDA | Shanghai Vitalgen BioPharma Co., Ltd. | |
6-[18F] fluoro-L-m-tyrosine | small molecules | FDA | — | Advanced Imaging Projects, LLC |
adeno-associated virus type 2 encoding human aromatic L-amino acid decarboxylase | gene therapies | FDA | University of California San Francisco | |
L-3,4-Dihydroxy-6-[18F]fluorophenylalanine | small molecules | FDA | — | Advanced Imaging Projects, LLC |
Recombinant adeno-associated viral vector serotype 2 carrying the gene for the human aromatic L-amino acid decarboxylase protein [Upstaza] | gene therapies | EMA | Approved | PTC Therapeutics International Limited |
eladocagene exuparvovec-tneq [Kebilidi] | gene therapies | FDA | Approved | PTC Therapeutics, Inc. |
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