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.).

Long-term outcomes of autologous vein bypass for repair of upper and lower extremity major arterial trauma.

OBJECTIVE: Autologous vein is the preferred bypass conduit for extremity arterial injuries owing to superior patency and low infection risk; however, long-term data on outcomes in civilians are limited. Our goal was to assess short- and long-term outcomes of autologous vein bypass for upper and lower extremity arterial trauma. METHODS: A retrospective review was performed of patients with major extremity arterial injuries (2001-2019) at a level I trauma center. Demographics, injury and intervention details, and outcomes were recorded. Primary outcomes were primary patency at 1 year and 3 years. Secondary outcomes were limb function at 6 months, major amputation, and mortality. Multivariable analysis determined risk factors for functional impairment. RESULTS: There were 107 extremity arterial injuries (31.8% upper and 68.2% lower) treated with autologous vein bypass. Mechanism was penetrating in 77% of cases, of which 79.3% were due to firearms. The most frequently injured vessels were the common and superficial femoral (38%), popliteal (30%), and brachial arteries (29%). For upper extremity trauma, concomitant nerve and orthopedic injuries were found in 15 (44.1%) and 11 (32.4%) cases, respectively. For lower extremities, concomitant nerve injuries were found in 10 (13.7%) cases, and orthopedic injuries in 31 (42.5%). Great saphenous vein was the conduit in 96% of cases. Immediate intraoperative bypass revision occurred in 9.3% of patients, most commonly for graft thrombosis. The in-hospital return to operating room rate was 15.9%, with graft thrombosis (47.1%) and wound infections (23.5%) being the most common reasons. The median follow-up was 3.6 years. Kaplan-Meier analysis showed 92% primary patency at 1 year and 90% at 3 years. At 6 months, 36.1% of patients had functional impairment. Of patients with functional impairment at 6 months, 62.9% had concomitant nerve and 60% concomitant orthopedic injuries. Of those with nerve injury, 91.7% had functional impairment, compared with 17.8% without nerve injury (P < .001). Of patients with orthopedic injuries, 51.2% had functional impairment, vs 25% of those without orthopedic injuries (P = .01). On multivariable analysis, concomitant nerve injury (odds ratio, 127.4; 95% confidence interval, 17-957; P <. 001) and immediate intraoperative revision (odds ratio, 11.03; 95% confidence interval, 1.27-95.55; P = .029) were associated with functional impairment. CONCLUSIONS: Autologous vein bypass for major extremity arterial trauma is durable; however, many patients have long-term limb dysfunction associated with concomitant nerve injury and immediate intraoperative bypass revision. These factors may allow clinicians to identify patients at higher risk for functional impairment, to outline patient expectations and direct rehabilitation efforts toward improving functional outcomes.

Higher stroke risk after carotid endarterectomy and transcarotid artery revascularization is associated with relative surgeon volume ratio.

OBJECTIVE: Adoption of transcarotid artery revascularization (TCAR) by surgeons has been variable, with some still performing traditional carotid endarterectomy (CEA), whereas others have shifted to mostly TCAR. Our goal was to evaluate the association of relative surgeon volume of CEA to TCAR with perioperative outcomes. METHODS: The Vascular Quality Initiative CEA and carotid artery stent registries were analyzed from 2021 to 2023 for symptomatic and asymptomatic interventions. Surgeons participating in both registries were categorized in the following CEA to CEA+TCAR volume percentage ratios: 0.25 (majority TCAR), 0.26 to 0.50 (more TCAR), 0.51 to 0.75 (more CEA), and 0.76 to 1.00 (majority CEA). Primary outcomes were rates of perioperative ipsilateral stroke, death, cranial nerve injury, and return to the operating room for bleeding. RESULTS: There were 50,189 patients who underwent primary carotid revascularization (64.3% CEA and 35.7% TCAR). CEA patients were younger (71.1 vs 73.5 years, P < .001), with more symptomatic cases, less coronary artery disease, diabetes, and lower antiplatelet and statin use (all P < .001). TCAR patients had lower rates of smoking, obesity, and dialysis or renal transplant (all P < .001). Postoperative stroke after CEA was significantly impacted by the operator CEA to TCAR volume ratio (P = .04), with surgeons who perform majority TCAR and more TCAR having higher postoperative ipsilateral stroke (majority TCAR odds ratio [OR]: 2.15, 95% confidence interval [CI]: 1.16-3.96, P = .01; more TCAR OR: 1.42, 95% CI: 1.02-1.96, P = .04), as compared with those who perform majority CEA. Similarly, postoperative stroke after TCAR was significantly impacted by the CEA to TCAR volume ratio (P = .02), with surgeons who perform majority CEA and more CEA having higher stroke (majority CEA OR: 1.51, 95% CI: 1.00-2.27, P = .05; more CEA OR: 1.50, 95% CI: 1.14-2.00, P = .004), as compared with those who perform majority TCAR. There was no association between surgeon ratio and perioperative death, cranial nerve injury, and return to the operating room for bleeding for either procedure. CONCLUSIONS: The relative surgeon CEA to TCAR ratio is significantly associated with perioperative stroke rate. Surgeons who perform a majority of one procedure have a higher stroke rate in the other. Surgeons offering both operations should maintain a balanced practice and have a low threshold to collaborate as needed.