Kathrin Meyer

• PhD
• Professor (Assistant) at Nationwide Children's Hospital

The AAV9 gene therapy vector presented in this study is safe in mice and non-human primates and highly efficacious without causing overexpression toxicity, a major challenge for clinical translation of Rett Syndrome gene therapy vectors to date. Our team designed a new truncated methyl CpG binding protein 2 (MeCP2) promoter allowing widespread expr...

Simple Summary Spinal Muscular Atrophy (SMA) is a genetic disease that can cause infant mortality. It is typically caused by mutations in the SMN1 gene. On the other hand, mutations in the IGHMBP2 gene can lead to a range of diseases, including the rare form of SMA known as SMARD1, as well as Charcot–Marie–Tooth 2S (CMT2S). In this study, we develo...

Anc80L65 is a synthetic, ancestral adeno-associated virus that has high tropism toward retinal photoreceptors after subretinal injection in mice and non-human primates. We characterized, for the first time, the post-intravitreal cell-specific transduction profile of Anc80L65 compared with AAV9. Here we use Anc80L65 and AAV9 to intravitreally delive...

CLN3 disease, caused by biallelic mutations in the CLN3 gene, is a rare pediatric neurodegenerative disease that has no cure or disease modifying treatment. The development of effective treatments has been hindered by a lack of etiological knowledge, but gene replacement has emerged as a promising therapeutic platform for such disorders. Here, we u...

Neutralizing antibody (NAb) activity against the viral capsid of adeno-associated viral (AAV) vectors decreases transduction efficiency, thus limiting transgene expression. Several reports have mentioned a variation in NAb prevalence according to age, AAV serotype, and, most importantly, geographic location. There are currently no reports specifica...

Neurofibromatosis 2 (NF2) is a rare autosomal dominant disorder caused by loss-of-function mutations within the NF2 gene. This leads to tumor formation in the cranial nerves responsible for hearing and balance (bilateral vestibular schwannomas) as well as meningiomas and ependymomas in the brain and spine, which ultimately increases morbidity and r...

The recently discovered neurological disorder NEDAMSS is caused by heterozygous truncations in the transcriptional regulator IRF2BPL. Here, we reprogram patient skin fibroblasts to astrocytes and neurons to study mechanisms of this newly described disease. While full-length IRF2BPL primarily localizes to the nucleus, truncated patient variants sequ...

Neurodegenerative disorders (NDDs), such as Alzheimer’s disease (AD) and Parkinson’s Disease (PD), are a group of heterogeneous diseases that mainly affect central nervous system (CNS) functions. A subset of NDDs exhibit CNS dysfunction and muscle degeneration, as observed in Gangliosidosis 1 (GM1) and late stages of PD. Neuromuscular disorders (NM...

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder affecting 1 in 60,000 people worldwide that originates from aberrant inactivation of the NF2 tumor suppressor gene. This severely debilitating condition is characterized by bilateral vestibular schwannomas and other nervous system tumors such as meningiomas or ependymomas. Althoug...

Background CLN8-Batten disease (CLN8 disease) is a rare neurodegenerative disorder characterized phenotypically by progressive deterioration of motor and cognitive abilities, visual symptoms, epileptic seizures, and premature death. Mutations in CLN8 results in characteristic Batten disease symptoms and brain-wide pathology including accumulation o...

Patient diversity and unknown disease cause are major challenges for drug development and clinical trial design for amyotrophic lateral sclerosis (ALS). Transgenic animal models do not adequately reflect the heterogeneity of ALS. Direct reprogramming of patient fibroblasts to neuronal progenitor cells and subsequent differentiation into patient ast...

ER stress signaling is linked to the pathophysiological and clinical disease manifestations in amyotrophic lateral sclerosis (ALS). Here, we have investigated ER stress-induced adaptive mechanisms in C9ORF72-ALS/FTD, focusing on uncovering early endogenous neuroprotective mechanisms and the crosstalk between pathological and adaptive responses in d...

Amyotrophic lateral sclerosis (ALS) is degenerative disease that progressively destroys motor neurons (MNs). Earlier studies identified EphA4, a receptor tyrosine kinase, as a possible disease-modifying gene. The complex interplay between EphA4 receptor and its ephrin ligands in motor neurons and astrocytes has not yet been fully elucidated, and in...

Neurofibromatosis type 2 (NF2) is a hereditary tumor syndrome characterized by nervous system tumors, primarily schwannomas, meningiomas, and ependymomas, which originate from loss of heterogeneity (LOH) in the NF2 gene. Current treatment options for NF2 are limited to surgery and radiotherapy, but these are often invasive and may lead to further n...

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder affecting 1 in 60,000 people worldwide that originates from aberrant inactivation of the NF2 tumor suppressor gene. NF2 is a severe debilitating condition characterized by bilateral vestibular schwannomas and other nervous system tumors such as meningiomas or ependymomas. Although...

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder affecting 1 in 60,000 people worldwide that originates from aberrant inactivation of the NF2 tumor suppressor gene. NF2 is a severe debilitating condition characterized by bilateral vestibular schwannomas and other nervous system tumors such as meningiomas or ependymomas. Although...

A lack of stratification methods in patients with amyotrophic lateral sclerosis (ALS) is likely implicated in therapeutic failures. Regional diversities and pathophysiological abnormalities in astrocytes from mice with SOD1 mutations (mSOD1-ALS) can now be explored in human patients using somatic cell reprogramming. Here, fibroblasts from four spor...

Background: Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor disability disorder that also manifests characteristic abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in monocarboxylate transporter 8 (MCT8), a specific TH plasma membrane transporter widely expressed in the central nervous system (CNS). MCT8...

Mutations in the Merlin gene on Chromosome 22 cause hereditary tumor syndrome known as Neurofibromatosis type 2 (NF2). Approximately 50% of the NF2 mutations are de novo with no familial history of the disease. The primary tumors developed in these patients are schwannomas, along with meningiomas, ependymomas, and ocular abnormalities. Tumors show...

De novo truncations in Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) lead to severe childhood-onset neurodegenerative disorders. To determine how loss of IRF2BPL causes neural dysfunction, we examined its function in Drosophila and zebrafish. Overexpression of either IRF2BPL or Pits, the Drosophila ortholog, represses Wnt transcript...

Human primary natural killer (NK) cells are being widely advanced for cancer immunotherapy. However, methods for gene editing of these cells have suffered low transduction rates, high cell death, and loss of transgene expression after expansion. Here, we developed a highly efficient method for site-specific gene insertion in NK cells using CRISPR (...

In brief Naeimi Kararoudi et al. present an efficient method using CRISPR and AAV for site-directed gene knockin into human primary NK cells and show proof of concept by generating CD33-specific CAR-NK cells and demonstrating efficacy against AML. This approach has wide potential for therapeutic applications and the study of NK cell biology. SUMMAR...

Allan-Herndon-Dudley syndrome (AHDS) is a severe X-linked intellectual and psychomotor disability disorder accompanied by abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in the monocarboxylate transporter 8 (MCT8), a specific TH transporter widely expressed in the central nervous system. MCT8 gene mutations cause impa...

The regenerative potential of Müller glia (MG) is extraordinary in fish, poor in chick and terrible in mammals. In the chick model, MG readily reprogram into proliferating Müller glia‐derived progenitor cells (MGPCs), but neuronal differentiation is very limited. The factors that suppress the neurogenic potential of MGPCs in the chick are slowly be...

The regenerative potential of Müller glia (MG) is extraordinary in fish, poor in chick and terrible in mammals. In the chick model, MG readily reprogram into proliferating Müller glia-derived progenitor cells (MGPCs), but neuronal differentiation is very limited. The factors that suppress the neurogenic potential of MGPCs in the chick are slowly be...

Research on neurological disorders focuses primarily on the impact of neurons on disease mechanisms. Limited availability of animal models severely impacts the study of cell type specific contributions to disease. Moreover, animal models usually do not reflect variability in mutations and disease courses seen in human patients. Reprogramming method...

In May of 2019, the adeno-associated virus (AAV)-based gene therapy onasemnogene abeparvovec-xioi (Zolgensma) became the second Food and Drug Administration (FDA)-approved gene therapy with designated use for infants diagnosed with spinal muscular atrophy (SMA). The decision came nearly 10 years after results of the first preclinical models were in...

Aging is a major risk factor for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). As metabolic alterations are a hallmark of aging and have previously been observed in ALS, it is important to examine the effect of aging in the context of ALS metabolic function. Here, using a newly established phenotypic metabolic approach,...

Human peripheral blood natural killer (NK) cells have intense antitumor activity and have been used successfully in several clinical trials. Modifying NK cells with a chimeric antigen receptor (CAR) can improve their targeting and increase specificity. Recently, we described an efficient method for gene targeting in NK cells using Cas9/ribonucleopr...

Sarcopenia, or age-related loss of muscle mass and strength, is an important contributor to loss of physical function in older adults. The pathogenesis of sarcopenia is likely multifactorial, but recently the role of neurological degeneration, such as motor unit loss, has received increased attention. Here, we investigated the longitudinal effects...

Sarcopenia, or pathological loss of muscle mass and strength during aging, is an important contributor to loss of physical function in older adults. Sarcopenia is a multifactorial syndrome associated with intrinsic muscle and upstream neurological dysfunction. Exercise is well-established as an effective intervention for sarcopenia, but less is kno...

Astrocytes are highly specialised cells, responsible for CNS homeostasis and neuronal activity. Lack of human in vitro systems able to recapitulate the functional changes affecting astrocytes during ageing represents a major limitation to studying mech-anisms and potential therapies aiming to preserve neuronal health. Here, we show that induced ast...

Human peripheral blood natural killer (NK) cells have intense antitumor activity and have been used successfully in several clinical trials. Modifying NK cells with a chimeric antigen receptor (CAR) can improve their targeting and increase specificity. Recently, we described an efficient method for gene targeting in NK cells using Cas9/ribonucleopr...

Batten Disease is a fatal lysosomal storage disorder characterized by cognitive and [...]

Background: Researchers have estimated that about 50% of pediatric patients with chronic illness adhere to tacrolimus therapy, a medication responsible for preventing critical side effects in patients undergoing hematopoietic stem cell transplantation (HSCT). Objectives: The purpose of this study was to describe patient adherence to tacrolimus by...

CLN8 disease is a rare form of neuronal ceroid lipofuscinosis caused by biallelic mutations in the CLN8 gene, which encodes a transmembrane endoplasmic reticulum protein involved in trafficking of lysosomal enzymes. CLN8 disease patients present with myoclonus, tonic-clonic seizures, and progressive declines in cognitive and motor function, with ma...

CLN8 disease is a rare form of neuronal ceroid lipofuscinosis caused by biallelic mutations in the CLN8 gene, which encodes a transmembrane endoplasmic reticulum protein involved in trafficking of lysosomal enzymes. CLN8 disease patients present with myoclonus, tonic-clonic seizures, and progressive declines in cognitive and motor function, with ma...

Human peripheral blood natural killer (NK) cells have strong antitumor activity and have been used successfully in several clinical trials. Modifying NK cells with a chimeric antigen receptor (CAR) can improve their targeting and increase specificity. However, genetic modification of NK cells has been challenging due to the high expression of innat...

CLN6-Batten disease, a form of neuronal ceroid lipofuscinosis is a rare lysosomal storage disorder presenting with gradual declines in motor, visual, and cognitive abilities and early death by 12-15 years of age. We developed a self-complementary adeno-associated virus serotype 9 (scAAV9) vector expressing the human CLN6 gene under the control of a...

The nuclear-encoded glycyl-tRNA synthetase gene (GARS) is essential for protein translation in both cytoplasm and mitochondria. In contrast, different genes encode the mitochondrial and cytosolic forms of most other tRNA synthetases. Dominant GARS mutations were described in inherited neuropathies, while recessive mutations cause severe childhood-o...

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant or digenic disorder linked to derepression of the toxic DUX4 gene in muscle. There is currently no pharmacological treatment. The emergence of DUX4 enabled development of cell and animal models that could be used for basic and translational research. Since DUX4 is toxic, animal...

Twenty per cent of familial amyotrophic lateral sclerosis (fALS) cases are caused by mutations in the gene encoding human cytosolic Cu/Zn superoxide dismutase (hSOD1). Efficient translation of the therapeutic potential of interfering RNA (RNAi) for the treatment of SOD1-ALS patients requires the development of vectors that are free of significant o...

The nuclear-encoded glycyl-tRNA synthetase gene (GARS) is essential for protein translation in both cytoplasm and mitochondria. In contrast, different genes encode the mitochondrial and cytosolic forms of most other tRNA synthetases. Dominant GARS mutations were described in inherited neuropathies, while recessive mutations cause severe childhood-o...

Background Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in thi...

Heat shock protein beta-1 (HSPB1), is a ubiquitously expressed, multifunctional protein chaperone. Mutations in HSPB1 result in the development of a late-onset, distal hereditary motor neuropathy type II (dHMN) and axonal Charcot-Marie Tooth disease with sensory involvement (CMT2F). The functional consequences of HSPB1 mutations associated with her...

Hexanucleotide repeat expansions in the C9ORF72 gene are the commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Expression of repeat transcripts and dipeptide repeat proteins trigger multiple mechanisms of neurotoxicity. How repeat transcripts get exported from the nucleus is unknown. Here, we show that depl...

Significance Oligodendrocytes have been implicated in disease pathology in amyotrophic lateral sclerosis (ALS) using transgenic mouse models. To date there is no human coculture system available to investigate oligodendrocyte involvement in motor neuron (MN) death in ALS. Our data highlight that oligodendrocytes derived from patients with familial...

A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). C9orf72 encodes two C9orf72 protein isoforms of unclear function. Reduced levels of C9orf72 expression have been reported in C9ALS/FTD patients, and although C9orf72 haploinsufficien...

Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic to motor neurons (MNs) and play a non-cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of MNs to cell death remain unclear. Here we report that astrocytes derived from either mice bearing mutations in genes associated wi...

For the past century, research on neurological disorders has largely focused on the most prominently affected cell types – the neurons. However, with increasing knowledge of the diverse physiological functions of glial cells, their impact on these diseases has become more evident. Thus, many conditions appear to have more complex origins than initi...

Objectives Spinal muscular atrophy (SMA) is caused by reduced levels of survival motor neuron (SMN) protein, which results in motoneuron loss. Therapeutic strategies to increase SMN levels including drug compounds, antisense oligonucleotides, and scAAV9 gene therapy have proved effective in mice. We wished to determine whether reduction of SMN in p...

Spinal Muscular Atrophy (SMA) is caused by deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene. The second gene copy, SMN2, produces some, but not enough, functional SMN protein. SMN is essential to assemble small nuclear ribonucleoproteins (snRNPs) that form the spliceosome. However, it is not clear whether SMA is caused by defects i...

Spinal Muscular Atrophy (SMA) is the most frequent lethal genetic neurodegenerative disorder in infants. The disease is caused by low abundance of the survival of motor neuron (SMN) protein leading to motor neuron degeneration and progressive paralysis. We previously demonstrated that a single intravenous injection (IV) of self-complementary adeno-...

Spinal muscular atrophy is caused by loss of SMN1 and retention of SMN2 resulting in low SMN levels. SMN protein functions in assembling snRNP which are critical in splicing of genes. We have developed mice and pig models of SMA. In both mouse and pig we have investigated early and late rescue of SMN. In pig restoration of SMN early via scAAV9-hSMN...

mt is a cross-disciplinary biomedical journal devoted to publishing the most exciting advances in pharmacology and therapeutics, as they pertain to advances in translational and clinical medicine. It is recognized as one of the most prestigious journals in the field. With an impact factor of 6.825*, mt ranks in the top 4.2% of scientific journals i...

Motor neuron disease or amyotrophic lateral sclerosis is a complex multicompartmental disorder that belongs to a spectrum of neurodegenerative conditions ranging from pure motor neuron disease to frontotemporal dementia. The symptoms and causes of death are determined by the progressive and relentless loss of motor neurons in the motor cortex and s...

Preclinical therapies that restore survival motor neuron (SMN) protein levels can dramatically extend survival in spinal muscular atrophy (SMA) mouse models. Biomarkers are needed to effectively translate these promising therapies to clinical trials. Our objective was to investigate electrophysiological biomarkers of compound muscle action potentia...

Significance Direct conversion is a recently established method to generate neuronal progenitor cells (NPCs) from skin fibroblasts in a fast and efficient manner. In this study, we show that this method can be used to model neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Because the origin of ALS is mainly sporadic with unkn...

Figure S1. Illustration of electrophysiological assessment of the motor unit pool, in vivo. MUNE, motor unit number estimation; CMAP, compound muscle action potential; EMG, electromyography; RNS, repetitive nerve stimulation.

Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (ALS) resulting in progressive motor neuron death through one or more acquired toxicities. Involvement of wild type SOD1 has been linked to sporadic ALS, as misfolded SOD1 has been reported in affected tissues of sporadic patients and toxicity of astrocy...