Deiva Kumaran, Ausseil Jérôme, de Bournonville Stéphanie, Zérah Michel, Husson Béatrice, Gougeon Marie-Lise, Poirier-Beaudouin Béatrice, Zafeiriou Dimitrios, Parenti Giancarlo, Heard Jean-Michel, Tardieu Marc
Pediatric Neurology Department, Université Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Saclay, Site Bicêtre, Le Kremlin-Bicêtre, France.
Service de Biochimie, Institut Fédératif de Biologie, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
Hum Gene Ther. 2021 Oct;32(19-20):1251-1259. doi: 10.1089/hum.2021.135.
We report the safety (primary endpoint) and efficacy (secondary endpoint) of a novel intracerebral gene therapy at 5.5 years of follow-up in children with Sanfilippo B. An uncontrolled, phase 1/2 clinical trial was performed in four patients aged 20, 26, 30, and 53 months. Treatment consisted of 16 intracerebral and cerebellar deposits of a recombinant adeno-associated viral vector encoding human α-N-acetylglucosaminidase (rAAV2/5-hNAGLU) plus immunosuppression. An intermediate report at 30 months was previously published. Thirty treatment-emergent adverse events were reported between 30 and 66 months after surgery, including three classified as severe with no serious drug reactions. At 5.5 years, NAGLU activity was persistently detected in the lumbar cerebrospinal fluid (18% of unaffected control level). Circulating T cells reacting against NAGLU peptides were present, indicating a lack of acquired tolerance. Patients 2, 3, and 4 showed progressive brain atrophy and neurocognitive evolution that did not differ from untreated Sanfilippo A/B children. Patient 1, enrolled at 20 months of age, had a milder disease with normal brain imaging and a significantly better cognitive outcome than the three other patients and untreated patients, although not equivalent to normal children. After 5.5 years, the primary endpoint of this study was achieved with a good safety profile of the proposed treatment. We have also observed sustained enzyme production in the brain and absence of immunological tolerance. Cognitive benefit was not confirmed in the three oldest patients. Milder disease in the youngest patient supports further investigations of adeno-associated vector-mediated intracerebral gene therapy in Sanfilippo B.
我们报告了在患有桑菲利波综合征B型的儿童中进行的一项新型脑内基因治疗在5.5年随访期内的安全性（主要终点）和疗效（次要终点）。在4名年龄分别为20、26、30和53个月的患者中进行了一项非对照的1/2期临床试验。治疗包括在脑内和小脑进行16次注射重组腺相关病毒载体，该载体编码人α-N-乙酰氨基葡萄糖苷酶（rAAV2/5-hNAGLU）并联合免疫抑制。之前已发表了30个月时的中期报告。在术后30至66个月期间报告了30例治疗中出现的不良事件，其中3例被分类为严重不良事件，无严重药物反应。在5.5岁时，在腰椎脑脊液中持续检测到NAGLU活性（为未受影响对照水平的18%）。存在针对NAGLU肽段的循环T细胞，表明缺乏获得性耐受。患者2、3和4表现出进行性脑萎缩和神经认知进展，与未治疗的桑菲利波A/B型儿童无异。患者1在20个月时入组，病情较轻，脑成像正常，与其他三名患者及未治疗患者相比，认知结局明显更好，尽管与正常儿童不等同。5.5年后，本研究的主要终点得以实现，所提议治疗的安全性良好。我们还观察到脑内持续产生酶且不存在免疫耐受。在三名年龄较大的患者中未证实有认知益处。最年幼患者病情较轻，这支持进一步研究腺相关病毒载体介导的脑内基因治疗在桑菲利波综合征B型中的应用。
