Intrathecal Gene Therapy for Giant Axonal Neuropathy.

BACKGROUND: Giant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic, neurodegenerative disorder caused by biallelic loss-of-function variants in GAN, the gene encoding gigaxonin. METHODS: We conducted an intrathecal dose-escalation study of scAAV9/JeT-GAN (a self-complementary adeno-associated virus-based gene therapy containing the GAN transgene) in children with giant axonal neuropathy. Safety was the primary end point. The key secondary clinical end point was at least a 95% posterior probability of slowing the rate of change (i.e., slope) in the 32-item Motor Function Measure total percent score at 1 year after treatment, as compared with the pretreatment slope. RESULTS: One of four intrathecal doses of scAAV9/JeT-GAN was administered to 14 participants - 3.5×1013 total vector genomes (vg) (in 2 participants), 1.2×1014 vg (in 4), 1.8×1014 vg (in 5), and 3.5×1014 vg (in 3). During a median observation period of 68.7 months (range, 8.6 to 90.5), of 48 serious adverse events that had occurred, 1 (fever) was possibly related to treatment; 129 of 682 adverse events were possibly related to treatment. The mean pretreatment slope in the total cohort was -7.17 percentage points per year (95% credible interval, -8.36 to -5.97). At 1 year after treatment, posterior mean changes in slope were -0.54 percentage points (95% credible interval, -7.48 to 6.28) with the 3.5×1013-vg dose, 3.23 percentage points (95% credible interval, -1.27 to 7.65) with the 1.2×1014-vg dose, 5.32 percentage points (95% credible interval, 1.07 to 9.57) with the 1.8×1014-vg dose, and 3.43 percentage points (95% credible interval, -1.89 to 8.82) with the 3.5×1014-vg dose. The corresponding posterior probabilities for slowing the slope were 44% (95% credible interval, 43 to 44); 92% (95% credible interval, 92 to 93); 99% (95% credible interval, 99 to 99), which was above the efficacy threshold; and 90% (95% credible interval, 89 to 90). Between 6 and 24 months after gene transfer, sensory-nerve action potential amplitudes increased, stopped declining, or became recordable after being absent in 6 participants but remained absent in 8. CONCLUSIONS: Intrathecal gene transfer with scAAV9/JeT-GAN for giant axonal neuropathy was associated with adverse events and resulted in a possible benefit in motor function scores and other measures at some vector doses over a year. Further studies are warranted to determine the safety and efficacy of intrathecal AAV-mediated gene therapy in this disorder. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, NCT02362438.).

Giant axonal neuropathy: cross-sectional analysis of a large natural history cohort.

Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease with early childhood onset that presents as a prominent sensorimotor neuropathy and commonly progresses to affect both the PNS and CNS. The disease is caused by biallelic mutations in the GAN gene located on 16q23.2, leading to loss of functional gigaxonin, a substrate specific ubiquitin ligase adapter protein necessary for the regulation of intermediate filament turnover. Here, we report on cross-sectional data from the first study visit of a prospectively collected natural history study of 45 individuals, age range 3-21 years with genetically confirmed GAN to describe and cross-correlate baseline clinical and functional cohort characteristics. We review causative variants distributed throughout the GAN gene in this cohort and identify a recurrent founder mutation in individuals with GAN of Mexican descent as well as cases of recurrent uniparental isodisomy. Through cross-correlational analysis of measures of strength, motor function and electrophysiological markers of disease severity, we identified the Motor Function Measure 32 to have the strongest correlation across measures and age in individuals with GAN. We analysed the Motor Function Measure 32 scores as they correspond to age and ambulatory status. Importantly, we identified and characterized a subcohort of individuals with a milder form of GAN and with a presentation similar to Charcot-Marie-Tooth disease. Such a clinical presentation is distinct from the classic presentation of GAN, and we demonstrate how the two groups diverge in performance on the Motor Function Measure 32 and other functional motor scales. We further present data on the first systematic clinical analysis of autonomic impairment in GAN as performed on a subset of the natural history cohort. Our cohort of individuals with genetically confirmed GAN is the largest reported to date and highlights the clinical heterogeneity and the unique phenotypic and functional characteristics of GAN in relation to disease state. The present work is designed to serve as a foundation for a prospective natural history study and functions in concert with the ongoing gene therapy trial for children with GAN.

Radiation safety education and diagnostic imaging in pediatric patients with surgically treated hydrocephalus: the patient and family perspective.

PURPOSE: Surgically treated hydrocephalus patients are frequently imaged with head computed tomography (CT), and risk/benefit communication with families is inconsistent and unknown. We aimed to educate patients and caregivers about radiation safety in CT and explore their communication preferences. METHODS: We conducted a pediatric CT radiation safety and diagnostic imaging educational workshop for patients and caregivers at a national conference on hydrocephalus to characterize current practice and desired communication about CT imaging. Our workshop consisted of an interactive educational intervention with pre-/post-session surveys followed by feedback from participants. RESULTS: Our session included 34 participants (100% response rate for surveys) with 28 being parents of individuals with hydrocephalus. A total of 76% (n = 26) participants showed an increase in knowledge after the session (p < 0.01). All participants (N = 34) uniformly desired risk/benefit discussions before CT scans. However, 71% stated that they were not informed of risks/benefits of CT scans by a medical professional. Following the session, the number of participants indicating that informed consent should be obtained before CT scans increased from 30 to 33. Respondents also revealed that 14% of children and young adults had received > 100 CT scans for shunt evaluation with the median being 25 scans (IQR 20). CONCLUSIONS: Caregivers desire and deserve to be empowered through education and social support, and continuously engaged through sharing decisions and co-designing care plans. The neurosurgical community is in an ideal position to collaborate with radiologists, primary care providers, and parents in the development and testing of credible, high-quality online and social media resources.

Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease.

PURPOSE: Giant axonal neuropathy (GAN) is an inherited severe sensorimotor neuropathy. The aim of this research was to investigate the neuropathologic features and clinical autonomic nervous system (ANS) phenotype in two GAN knockout (KO) mouse models. Little is known about ANS involvement in GAN in humans, but autonomic signs and symptoms are commonly reported in early childhood. METHODS: Routine histology and immunohistochemistry was performed on GAN KO mouse specimens taken at various ages. Enteric dysfunction was assessed by quantifying the frequency, weight, and water content of defecation in GAN KO mice. RESULTS: Histological examination of the enteric, parasympathetic and sympathetic ANS of GAN KO mice revealed pronounced and widespread neuronal perikaryal intermediate filament inclusions. These neuronal inclusions served as an easily identifiable, early marker of GAN in young GAN KO mice. Functional studies identified an age-dependent alteration in fecal weight and defecation frequency in GAN KO mice. CONCLUSIONS: For the first time in the GAN KO mouse model, we described the early, pronounced and widespread neuropathologic features involving the ANS. In addition, we provided evidence for a clinical autonomic phenotype in GAN KO mice, reflected in abnormal gastrointestinal function. These findings in GAN KO mice suggest that consideration should be given to ANS involvement in human GAN, especially when considering treatments and patient care.

The health risks of ionizing radiation from computed tomography.

Concerns have increased about the potential health risks of ionizing radiation from computed tomography (CT) scans. This paper discusses the biological effects of radiation, describes research findings related to CT use, cites strategies for radiation dose reduction, and emphasizes the need to be judicious in ordering CT scans for children.

Gigaxonin, mutated in Giant Axonal Neuropathy, interacts with TDP-43 and other RNA binding proteins.

Giant Axonal Neuropathy (GAN) is a neurodegenerative disease caused by loss-of-function mutations in the KLHL16 gene, encoding the cytoskeleton regulator gigaxonin. In the absence of functional gigaxonin, intermediate filament (IF) proteins accumulate in neurons and other cell types due to impaired turnover and transport. GAN neurons exhibit distended, swollen axons and distal axonal degeneration, but the mechanisms behind this selective neuronal vulnerability are unknown. Our objective was to identify novel gigaxonin interactors pertinent to GAN neurons. Unbiased proteomics revealed a statistically significant predominance of RNA-binding proteins (RBPs) within the soluble gigaxonin interactome and among differentially-expressed proteins in iPSC-neuron progenitors from a patient with classic GAN. Among the identified RBPs was TAR DNA-binding protein 43 (TDP-43), which associated with the gigaxonin protein and its mRNA transcript. TDP-43 co-localized within large axonal neurofilament IFs aggregates in iPSC-motor neurons derived from a GAN patient with the 'axonal CMT-plus' disease phenotype. Our results implicate RBP dysfunction as a potential underappreciated contributor to GAN-related neurodegeneration.

Diffusion tensor imaging based network analysis detects alterations of neuroconnectivity in patients with clinically early relapsing-remitting multiple sclerosis.

Although it is inarguable that conventional MRI (cMRI) has greatly contributed to the diagnosis and assessment of multiple sclerosis (MS), cMRI does not show close correlation with clinical findings or pathologic features, and is unable to predict prognosis or stratify disease severity. To this end, diffusion tensor imaging (DTI) with tractography and neuroconnectivity analysis may assist disease assessment in MS. We, therefore, attempted this pilot study for initial assessment of early relapsing-remitting MS (RRMS). Neuroconnectivity analysis was used for evaluation of 24 early RRMS patients within 2 years of presentation, and compared to the network measures of a group of 30 age-and-gender-matched normal control subjects. To account for the situation that the connections between two adjacent regions may be disrupted by an MS lesion, a new metric, network communicability, was adopted to measure both direct and indirect connections. For each anatomical area, the brain network communicability and average path length were computed and compared to characterize the network changes in efficiencies. Statistically significant (P < 0.05) loss of communicability was revealed in our RRMS cohort, particularly in the frontal and hippocampal/parahippocampal regions as well as the motor strip and occipital lobes. Correlation with the 25-foot Walk test with communicability measures in the left superior frontal (r = -0.71) as well as the left superior temporal gyrus (r = -0.43) and left postcentral gyrus (r = -0.41) were identified. Additionally identified were increased communicability between the deep gray matter structures (left thalamus and putamen) with the major interhemispheric and intrahemispheric white matter tracts, the corpus callosum, and cingulum, respectively. These foci of increased communicability are thought to represent compensatory changes. The proposed DTI-based neuroconnectivity analysis demonstrated quantifiable, structurally relevant alterations of fiber tract connections in early RRMS and paves the way for longitudinal studies in larger patient groups.

Stability dynamics of neurofilament and GFAP networks and protein fragments.

Neurofilaments (NFs) and GFAP are cytoskeletal intermediate filaments (IFs) that support cellular processes unfolding within the uniquely complex environments of neurons and astrocytes, respectively. This review highlights emerging concepts on the transitions between stable and destabilized IF networks in the nervous system. While self-association between transiently structured low-complexity IF domains promotes filament assembly, the opposing destabilizing actions of phosphorylation-mediated filament severing facilitate faster intracellular transport. Cellular proteases, including caspases and calpains, produce a variety of IF fragments, which may interact with N-degron and C-degron pathways of the protein degradation machinery. The rapid adoption of NF and GFAP-based clinical biomarker tests is contrasted with the lagging understanding of the dynamics between the native IF proteins and their fragments.

Pituitary adenoma associated with xanthogranuloma.

Xanthogranuloma (XG) of the sellar region is a non-neoplastic inflammatory lesion characterized histologically by recent and remote hemorrhage, necrotic debris, fibrosis, chronic inflammation, and cholesterol clefts with associated foreign-body giant cells. The inflammatory lesion was recognized by the World Health Organization in 2000. XG of the sellar region is rare. Cases of pituitary adenoma (PA) with an associated XG (PA/XG) are extremely rare, with a total of 16 cases in the literature. PA/XG lacks specific clinical and radiologic signs, making pre-operative diagnosis challenging. Herein, we report a case of PA/XG, describe the radiologic and pathologic findings, and discuss the role of so-called silent or "subclinical pituitary apoplexy" in the possible histogenesis of PA/XGs.

Intermediate filament dysregulation in astrocytes in the human disease model of KLHL16 mutation in giant axonal neuropathy (GAN).

Giant Axonal Neuropathy (GAN) is a pediatric neurodegenerative disease caused by KLHL16 mutations. KLHL16 encodes gigaxonin, which regulates intermediate filament (IF) turnover. Previous neuropathological studies and examination of postmortem brain tissue in the current study revealed involvement of astrocytes in GAN. To develop a clinically-relevant model, we reprogrammed skin fibroblasts from seven GAN patients to pluripotent stem cells (iPSCs), which were used to generate neural progenitor cells (NPCs), astrocytes, and brain organoids. Multiple isogenic control clones were derived via CRISPR/Cas9 gene editing of one patient line carrying the G332R gigaxonin mutation. All GAN iPSCs were deficient for gigaxonin and displayed patient-specific increased vimentin expression. GAN NPCs had lower nestin expression and fewer nestin-positive cells compared to isogenic controls, but nestin morphology was unaffected. GAN brain organoids were marked by the presence of neurofilament and GFAP aggregates. GAN iPSC-astrocytes displayed striking dense perinuclear vimentin and GFAP accumulations and abnormal nuclear morphology. In over-expression systems, GFAP oligomerization and perinuclear aggregation were augmented in the presence of vimentin. GAN patient cells with large perinuclear vimentin aggregates accumulated significantly more nuclear KLHL16 mRNA compared to cells without vimentin aggregates. As an early effector of KLHL16 mutations, vimentin may be a potential target in GAN.

Intermediate filament dysregulation and astrocytopathy in the human disease model of KLHL16 mutation in giant axonal neuropathy (GAN).

Giant Axonal Neuropathy (GAN) is a pediatric neurodegenerative disease caused by KLHL16 mutations. KLHL16 encodes gigaxonin, a regulator of intermediate filament (IF) protein turnover. Previous neuropathological studies and our own examination of postmortem GAN brain tissue in the current study revealed astrocyte involvement in GAN. To study the underlying mechanisms, we reprogrammed skin fibroblasts from seven GAN patients carrying different KLHL16 mutations to iPSCs. Isogenic controls with restored IF phenotypes were derived via CRISPR/Cas9 editing of one patient carrying a homozygous missense mutation (G332R). Neural progenitor cells (NPCs), astrocytes, and brain organoids were generated through directed differentiation. All GAN iPSC lines were deficient for gigaxonin, which was restored in the isogenic control. GAN iPSCs displayed patient-specific increased vimentin expression, while GAN NPCs had decreased nestin expression compared to isogenic control. The most striking phenotypes were observed in GAN iPSC-astrocytes and brain organoids, which exhibited dense perinuclear IF accumulations and abnormal nuclear morphology. GAN patient cells with large perinuclear vimentin aggregates accumulated nuclear KLHL16 mRNA. In over-expression studies, GFAP oligomerization and perinuclear aggregation were potentiated in the presence of vimentin. As an early effector of KLHL16 mutations, vimentin may serve as a potential therapeutic target in GAN.

Radiology's ethical responsibility for healthcare reform: tempering the overutilization of medical imaging and trimming down a heavyweight.

In this review we describe the problem of overutilization of high-cost imaging modalities, especially magnetic resonance imaging (MRI) and computed tomography (CT). The overuse of CT is numerically more dramatic and also carries with it the not insignificant risk of harm to patients, namely, induction of radiation-induced malignancies. We report what is known of these risks in various imaging scenarios. The use of Radiology Business Managers is described as a means adopted to control overuse and the limitations of this strategy. The imperative of appropriate utilization is focused on, with emphasis placed on computer-based medical decision support. Impediments to appropriate use, however, exist, with concerns of medicolegal liability high on the list of these issues. Finally, we recommend that radiologists take the lead in the reform process by implementing strategies such as decision support.

Combined hepatocellular carcinoma-cholangiocarcinoma: report of MR appearance in eleven patients.

PURPOSE: To describe the magnetic resonance imaging (MRI) appearance of hepatic combined hepatocellular-cholangiocarcinoma (cHCC-CC) in 11 patients. MATERIALS AND METHODS: The database of the Department of Pathology was cross-referenced with the MRI database to identify patients with confirmed cHCC-CC who had undergone MRI. Eleven consecutive patients were included (seven female, mean age 57.6 years). All patients were Caucasian. Five of 11 had a clinical history of chronic liver disease. Two radiologists retrospectively analyzed the images in consensus. RESULTS: cHCC-CC was a single mass in 10/11 patients. Margins were well-defined in 6/11. All tumors showed heterogeneous hyperintensity on T2. On postcontrast imaging, 6/11 showed early ring-enhancement (four noncirrhotic), with progressive enhancement in central portions, and 5/11 patients showed a diffuse heterogeneous early enhancement. Three of these five were cirrhotic and displayed partial washout with portions of contrast retention on later phases. Other findings included: late capsule enhancement (two patients), biliary dilatation (one), venous invasion (three), lymphadenopathy (six), and findings of cirrhosis (five). CONCLUSION: cHCC-CC presents most commonly as a single mass. Five of 11 had MR findings of cirrhosis. Clues to the diagnosis were moderately high signal on T2, portions of tumor that show progressive enhancement/contrast retention, and frequent lack of capsule. Early enhancement patterns included early ring-enhancement and diffuse heterogeneous enhancement.

Calpain-mediated proteolysis of vimentin filaments is augmented in giant axonal neuropathy fibroblasts exposed to hypotonic stress.

Giant Axonal Neuropathy (GAN) is a pediatric neurodegenerative disease caused by loss-of-function mutations in the E3 ubiquitin ligase adaptor gigaxonin, which is encoded by the KLHL16 gene. Gigaxonin regulates the degradation of multiple intermediate filament (IF) proteins, including neurofilaments, GFAP, and vimentin, which aggregate in GAN patient cells. Understanding how IFs and their aggregates are processed under stress can reveal new GAN disease mechanisms and potential targets for therapy. Here we tested the hypothesis that hypotonic stress-induced vimentin proteolysis is impaired in GAN. In both GAN and control fibroblasts exposed to hypotonic stress, we observed time-dependent vimentin cleavage that resulted in two prominent ∼40-45 kDa fragments. However, vimentin proteolysis occurred more rapidly and extensively in GAN cells compared to unaffected controls as both fragments were generated earlier and at 4-6-fold higher levels. To test enzymatic involvement, we determined the expression levels and localization of the calcium-sensitive calpain proteases-1 and -2 and their endogenous inhibitor calpastatin. While the latter was not affected, the expression of both calpains was 2-fold higher in GAN cells compared to control cells. Moreover, pharmacologic inhibition of calpains with MDL-28170 or MG-132 attenuated vimentin cleavage. Imaging analysis revealed striking colocalization between large perinuclear vimentin aggregates and calpain-2 in GAN fibroblasts. This colocalization was dramatically altered by hypotonic stress, where selective breakdown of filaments over aggregates occurred rapidly in GAN cells and coincided with calpain-2 cytoplasmic redistribution. Finally, mass spectrometry-based proteomics revealed that phosphorylation at Ser-412, located at the junction between the central "rod" domain and C-terminal "tail" domain on vimentin, is involved in this stress response. Over-expression studies using phospho-deficient and phospho-mimic mutants revealed that Ser-412 is important for filament organization, solubility dynamics, and vimentin cleavage upon hypotonic stress exposure. Collectively, our work reveals that osmotic stress induces calpain- and proteasome-mediated vimentin degradation and IF network breakdown. These effects are significantly augmented in the presence of disease-causing KLHL16 mutations that alter intermediate filament organization. While the specific roles of calpain-generated vimentin IF fragments in GAN cells remain to be defined, this proteolytic pathway is translationally-relevant to GAN because maintaining osmotic homeostasis is critical for nervous system function.

Longitudinal regression analysis of spatial-temporal growth patterns of geometrical diffusion measures in early postnatal brain development with diffusion tensor imaging.

Although diffusion tensor imaging (DTI) has provided substantial insights into early brain development, most DTI studies based on fractional anisotropy (FA) and mean diffusivity (MD) may not capitalize on the information derived from the three principal diffusivities (e.g. eigenvalues). In this study, we explored the spatial and temporal evolution of white matter structures during early brain development using two geometrical diffusion measures, namely, linear (Cl) and planar (Cp) diffusion anisotropies, from 71 longitudinal datasets acquired from 29 healthy, full-term pediatric subjects. The growth trajectories were estimated with generalized estimating equations (GEE) using linear fitting with logarithm of age (days). The presence of the white matter structures in Cl and Cp was observed in neonates, suggesting that both the cylindrical and fanning or crossing structures in various white matter regions may already have been formed at birth. Moreover, we found that both Cl and Cp evolved in a temporally nonlinear and spatially inhomogeneous manner. The growth velocities of Cl in central white matter were significantly higher when compared to peripheral, or more laterally located, white matter: central growth velocity Cl=0.0465±0.0273/log(days), versus peripheral growth velocity Cl=0.0198±0.0127/log(days), p<10⁻6. In contrast, the growth velocities of Cp in central white matter were significantly lower than that in peripheral white matter: central growth velocity Cp=0.0014±0.0058/log(days), versus peripheral growth velocity Cp=0.0289±0.0101/log(days), p<10⁻6. Depending on the underlying white matter site which is analyzed, our findings suggest that ongoing physiologic and microstructural changes in the developing brain may exert different effects on the temporal evolution of these two geometrical diffusion measures. Thus, future studies utilizing DTI with correlative histological analysis in the study of early brain development are warranted.

Comparison of the incidence of pancreatic abnormalities between high risk and control patients: prospective pilot study with 3 Tesla MR imaging.

PURPOSE: To compare the incidence of pancreatic abnormalities detected by MR imaging between high-risk patients and control patients. MATERIALS AND METHODS: Forty-one consecutive patients who had two or more first-degree relatives with pancreatic cancer and who were asymptomatic with no clinical evidence of pancreatic cancer were prospectively included in this study. A control group was obtained by reviewing consecutive patients undergoing 3 Tesla (T) MRI examinations for nonpancreatic indications. On MR imaging, the presence of pancreatic abnormalities were evaluated in consensus by two radiologists who were blinded to clinical history. Pancreatic abnormalities were categorized as developmental abnormalities, mass-type lesions, inflammatory disease, and others. RESULTS: Overall, the incidence of pancreatic abnormalities was greater in the high-risk group than in the control group, but not statistically significant (P = 0.244). In the high-risk group, a total of 16 patients (39%) were diagnosed with pancreatic abnormalities, whereas in the control group, 11 patients (25%) were diagnosed with pancreatic abnormalities. Regarding mass-type lesions, there was a significant difference in incidence between the high-risk group, with a total of seven patients (17%), and the control group, with one patient (2%) (P = 0.028). There were no cases of imaging diagnosis of pancreatic cancer or tissue evaluation by surgical pathology in either group. CONCLUSION: Our prospective pilot study demonstrated a higher incidence of mass-type lesions in patients at increased risk for pancreatic cancer.

Growth of uterine leiomyomata among premenopausal black and white women.

Uterine leiomyomata (fibroids) are the leading cause of hysterectomy in the United States. Black women have a greater fibroid burden than whites, yet no study has systematically evaluated the growth of fibroids in blacks and whites. We prospectively tracked growth for 262 fibroids (size range: 1-13 cm in diameter) from 72 premenopausal participants (38 blacks and 34 whites). Fibroid volume was measured by computerized analysis of up to four MRI scans over 12 months. We used mixed effects models to identify factors that are associated with growth, and results were converted to percent change per 6 months for clinical relevance. The median growth rate was 9% (range: -89% to +138%). Seven percent of fibroids regressed (>20% shrinkage). Tumors from the same woman grew at different rates (within-woman component of variation was twice the component among women; both were significant, P < 0.001). Black and white women less than 35 years of age had similar fibroid growth rates. However, growth rates declined with age for whites but not for blacks (P = 0.05). The odds of a tumor growing more than 20% in 6 months also decreased with age for whites but not for blacks (P < 0.01). Growth rates were not influenced by tumor size, location, body mass index, or parity. We conclude that (i) spontaneous regression of fibroids occurs; (ii) fibroids from the same woman grow at different rates, despite a uniform hormonal milieu; (iii) fibroid size does not predict growth rate; and (iv) age-related differences in fibroid growth between blacks and whites may contribute to the higher symptom burden for black women.

Extensive rod and cone photoreceptor-cell degeneration in rat models of giant axonal neuropathy: implications for gene therapy of human disease.

Background: Giant axonal neuropathy (GAN; ORPHA: 643; OMIM# 256850) is a rare, hereditary, pediatric neurodegenerative disorder associated with intracellular accumulations of intermediate filaments (IFs). Validation of therapeutic efficacy and viral vector delivery systems with GAN knockout (KO) mouse models has provided the springboard for the development of a viral vector being delivered intrathecally in an ongoing Phase I gene therapy clinical trial for the treatment of children with GAN (https://clinicaltrials.gov/ct2/show/NCT02362438).Purpose: To characterize the ocular pathologic phenotype of newly developed GAN rat models.Materials and Methods: Microscopic examination of eyes at various timepoints.Results: We noted the unexpected finding of progressive and extensive degeneration of rod and cone photoreceptor (PR) cells in the retinas of GAN rat models.Conclusion: This PR-cell loss in rat models of GAN raises the possibility that PR-cell loss may contribute to the visual impairment observed in human GAN. The intrathecal viral vector employed in the ongoing Phase I gene therapy clinical trial for the treatment of children with GAN was not specifically designed to address PR-cell degeneration. If GAN-associated PR-cell loss is present and clinically significant in humans, then future treatment protocols for GAN may need to include a gene transfer approach or combinatorial treatment strategy that also targets retinal PR cells.