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Spinal bulbar muscular atrophy (SBMA) is a rare, X-linked inherited neuromuscular disease, caused by a CAG repeat expansion in the first exon of the androgen receptor gene, that affects males. Symptoms begin with hand tremors and lower proximal muscle weakness and slowly progress to dysphagia, dysarthria, and dysphonia. The 6-minute walk test (6MWT) and timed up and go (TUG) are used to assess motor capacity in people with SBMA. The 6MWT measures the distance (m) walked in 6 minutes and the TUG measures the time (s) it takes an individual to stand up, walk 3m, turn around, and sit down. Wearable sensors could be used in future therapeutic SBMA trials to objectively analyze gait and balance. This study aims to describe the wearable sensors' ability to measure motor capacity from the baseline instrumented-6MWT (i-6MWT) and -TUG (i-TUG) in individuals with SBMA. This study had 18 male participants with a mean age of 61.8 ± 6.68 years — 4 healthy controls (H), 5 with SBMA who did not use assistive devices (S), and 8 with SBMA who used assistive devices (SD). All 18 individuals participated in the i-6MWT. For the i-6MWT, the distance (m) walked ranged from: (H) 477-653, (S) 400-584, and (SD) 236-373. The i-6MWT percent norms ranged from: (H) 81.5-122, (S) 80.3-108, and (SD) 42.5-68.4. Cadence (steps/min) ranged from: published norms (N) 103-133, (H) 109 – 140, (S) 103-133, and (SD) 74.8-119. Gait speed (m/s) ranged from: (N) 1.04-1.64, (H) 1.22-1.67, (S) 1.05-1.56, and (SD) 0.60-0.99. Only participants with SBMA completed the i-TUG. i-TUG duration (s) ranged from: published norms (N) 6.28-11.6, (S) 5.09-8.98, and (SD) 8.91-27.9. Turn velocity ranged from: (N) 158 – 322, (S) 188 – 305, and (SD) 85.4-239. Stand to sit duration(s) ranged from: (N) 0.49-1.06, (S) 0.49-0.80, and (SD) 0.56-1.15. Longitudinal studies examining the i-6MWT and i-TUG in larger sample sizes are needed to validate the use of wearable sensors as an effective outcome measure for SBMA clinical trials. [ABSTRACT FROM AUTHOR]

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 x 1013 total vector genomes (vg) (in 2 participants), 1.2 x 1014 vg (in 4), 1.8 x 1014 vg (in 5), and 3.5 x 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 x 1013-vg dose, 3.23 percentage points (95% credible interval, -1.27 to 7.65) with the 1.2 x 1014-vg dose, 5.32 percentage points (95% credible interval, 1.07 to 9.57) with the 1.8 x 1014-vg dose, and 3.43 percentage points (95% credible interval, -1.89 to 8.82) with the 3.5 x 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.) [ABSTRACT FROM AUTHOR]

Congenital muscular dystrophies (CMDs) are congenital onset muscular dystrophies with laminin alpha-2 (LAMA2) and collagen VI (COL6)-related dystrophies (RD) being the most common subtypes. Symptoms include hypotonia, progressive muscle weakness, respiratory insufficiency and joint contractures. With multiple promising therapies in development for LAMA2-RD and COL6-RD, the validation of motor outcome measures in young children is essential, given their likely inclusion in future clinical trials. The Motor Function Measure-20 (MFM20) is a 20-item standardized scale used to measure motor function and has been validated in children 2-6 years of age with congenital muscle diseases. The Neuromuscular Gross Motor Outcome (NM GRO) is a 50-item scale, developed by Nationwide Children's Hospital for use in patients from birth onward. The goal of the scale is to assess motor function across the years and reduce the burden of testing. Initial validation studies have been completed in individuals with spinal muscular atrophy (SMA), a motor neuron disease. This exploratory analysis aims to compare MFM20 and NM GRO assessments from the baseline visit of CMD participants younger than 6 years of age. MFM20 and NM GRO were administered to 14 participants: 5 with LAMA2-RD (35.7%) and 9 with COL6-RD (64.3%). Of the 14 participants, 11 were male with the mean age of 3.84 ± 1.11 years. Using Spearman's rank correlation, there was a statistically significant correlation between the MFM20 percentage and NM GRO score (ρ = 0.97, p < 0.001). When individually examining each subgroup, both the COL6-RD group and LAMA2-RD retained statistical significance between the MFM20 percentage and NM GRO score (ρ = 0.94, p < 0.001) and (ρ = 0.87, p = 0.05), respectively. Additional studies, with a larger sample size, are needed to validate the NM GRO as a comprehensive assessment tool for patients with LAMA2-RD and COL6-RD. [ABSTRACT FROM AUTHOR]

Reactivation of Human Endogenous Retrovirus K (HERV-K), subtype HML-2, has been associated with pathophysiology of amyotrophic lateral sclerosis (ALS). We aimed to assess the efficacy of antiretroviral therapy in inhibiting HML-2 in patients with ALS and a possible association between the change in HML-2 levels and clinical outcomes. We studied the effect of 24-weeks antiretroviral combination therapy with abacavir, lamivudine, and dolutegravir on HML-2 levels in 29 ALS patients. HML-2 levels decreased progressively over 24 weeks (P = 0.001) and rebounded within a week of stopping medications (P = 0.02). The majority of participants (82%), defined as "responders", experienced a decrease in HML-2 at week 24 of treatment compared to the pre-treatment levels. Differences in the evolution of some of the clinical outcomes could be seen between responders and non-responders: FVC decreased 23.69% (SE = 11.34) in non-responders and 12.71% (SE = 8.28) in responders. NPI score decreased 91.95% (SE = 6.32) in non-responders and 53.05% (SE = 10.06) in responders (P = 0.01). Thus, participants with a virological response to treatment showed a trend for slower progression of the illness. These findings further support the possible involvement of HML-2 in the clinical course of the disease. [Display omitted] • Antiretroviral therapy for 24 weeks decreased HERV-K (HML-2) levels in most patients with ALS. • A rebound in HML-2 levels occurred after discontinuation of the antiretroviral drugs. • Patients that had an antiviral effect against HML-2 showed a trend for slower progression in several clinical parameters. [ABSTRACT FROM AUTHOR]

Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease of the central, peripheral and autonomic nervous systems caused by deficiency or complete loss-of-function of gigaxonin, leading to accumulation of intermediate filaments. GAN clinically manifests with progressive axonal sensorimotor, orthopedic complications, CNS involvement, and optic neuropathy, and in its more aggressive form leads to respiratory failure with death by the third decade of life. There are no approved therapies for the treatment of GAN. We have evaluated participants with GAN in an ongoing natural history study (NCT01568658). Additionally, a first-in-human intrathecal (IT) AAV9-mediated gene transfer trial for GAN (NCT02362438) is ongoing. This is an ongoing single site, phase I/II, open-label, dose-escalation, non-randomized trial with lead-in data from the GAN natural history data. Fourteen trial participants (6-14 years of age) have received a single IT dose of scAAV9-JeT-GANopt, ranging from 3.5e13 to 3.5e14 total vector genomes by dot blot, with concomitant immunomodulation. Cross-sectional and longitudinal ophthalmologic data are presented, including best corrected visual acuity (LogMAR) and retinal nerve fiber layer thickness as measured by optical coherence tomography (OCT) (SD-OCT: Cirrus HD-OC) from participants with GAN in natural history and in participants following gene transfer. Participants with GAN, especially those with a more aggressive form of the disease, frequently have abnormalities in average RNFL thickness (defined as < 80 μm) and progressive decline in visual acuity. Prior to gene transfer, 9 participants (64%) had abnormal RNFL thickness at baseline in the right (OD) and left eye (OS) (range: 56 - 100 μm). In follow up to 6 years, we observe trends towards stabilization in visual acuity as assessed by slope post gene transfer as compared to lead in natural history data. Concomitant trends in RNFL measurements following gene transfer were reviewed, taking into account the measurable range of RNFL thickness. Potential stabilization in visual acuity over long term follow up suggests an impact at the level of the optic nerve with IT administration of AAV9 mediated gene transfer in GAN at the vector genome doses administered in this trial. [ABSTRACT FROM AUTHOR]

Giant axonal neuropathy (GAN) is a rare and fatal pediatric neurodegenerative disorder affecting the central and peripheral nervous system. Recessive variants in the GAN gene cause dysfunction of gigaxonin, a cytoskeletal regulatory protein, leading to progressive sensorimotor and optic neuropathy, CNS involvement and respiratory failure with death by the second to third decade of life. We are conducting a first-in-human intrathecal (IT) AAV9-mediated gene transfer trial for GAN (NCT02362438). This is an ongoing single site, phase I, non-randomized, open label dose escalation trial with lead-in and GAN natural history data serving for comparison. Fourteen GAN participants ages 6 years to 14 years old have received a single IT dose of scAAV9-JeT-GANopt (ranging from 3.5x1013 vector genomes (vg) to 3.5x1014 vg total dose) with concomitant immunomodulation protocols. Safety is the primary outcome measure with follow-up data spanning 24-72 months post gene transfer. Secondary outcome measures include the motor function measure (MFM)-32, nerve conduction studies, and nerve pathology. Here we review safety and immunologic findings related to dose, genotype, baseline AAV9 seropositivity, and the use of T-cell immune modulation. We present preliminary efficacy results on change in MFM-32 at one year post gene transfer compared to lead-in and our GAN natural history data as well as MFM-32 trajectories in long-term follow-up. Neurophysiologic (CMAP and SNAP amplitude) and nerve pathology findings are also reviewed. This study highlights the overall safety and feasibility of an intrathecal route of AAV9 based gene transfer and demonstrates the ability of IT gene transfer to positively modify the expected rate of decline and progression in GAN. Importantly, this study serves as proof of concept for IT gene transfer with targeted immune modulation as a successful strategy for gene replacement in disorders affecting the central and peripheral nervous system. [ABSTRACT FROM AUTHOR]