Moser Center for Leukodystrophies, Kennedy Krieger Institute, Baltimore, MD, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Neurotherapeutics. 2023 Jan;20(1):272-283. doi: 10.1007/s13311-022-01311-x. Epub 2022 Oct 7.
X-linked adrenoleukodystrophy (ALD) is a genetic disorder that presents neurologically as either a rapid and fatal cerebral demyelinating disease in childhood (childhood cerebral adrenoleukodystrophy; ccALD) or slow degeneration of the spinal cord in adulthood (adrenomyeloneuropathy; AMN). All forms of ALD result from mutations in the ATP Binding Cassette Subfamily D Member (ABCD) 1 gene, encoding a peroxisomal transporter responsible for the import of very long chain fatty acids (VLCFA) and results mechanistically in a complex array of dysfunction, including endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction, and inflammation. Few therapeutic options exist for these patients; however, an additional peroxisomal transport protein (ABCD2) has been successfully targeted previously for compensation of dysfunctional ABCD1. 4-Phenylbutyrate (4PBA), a potent activator of the ABCD1 homolog ABCD2, is FDA approved, but use for ALD has been stymied by a short half-life and thus a need for unfeasibly high doses. We conjugated 4PBA to hydroxyl polyamidoamine (PAMAM) dendrimers (D-4PBA) to a create a long-lasting and intracellularly targeted approach which crosses the blood-brain barrier to upregulate Abcd2 and its downstream pathways. Across two studies, Abcd1 knockout mice administered D-4PBA long term showed neurobehavioral improvement and increased Abcd2 expression. Furthermore, when the conjugate was administered early, significant reduction of VLCFA and improved survival of spinal cord neurons was observed. Taken together, these data show improved efficacy of D-4PBA compared to previous studies of free 4PBA alone, and promise for D-4PBA in the treatment of complex and chronic neurodegenerative diseases using a dendrimer delivery platform that has shown successes in recent clinical trials. While recovery in our studies was partial, combined therapies on the dendrimer platform may offer a safe and complete strategy for treatment of ALD.
X 连锁肾上腺脑白质营养不良（ALD）是一种遗传性疾病，在临床上表现为儿童期快速致命的脑脱髓鞘疾病（儿童脑肾上腺脑白质营养不良；ccALD）或成年期脊髓缓慢退化（肾上腺脑脊髓神经病；AMN）。所有形式的 ALD 都是由于 ATP 结合盒亚家族 D 成员（ABCD）1 基因突变引起的，该基因编码一种过氧化物酶体转运蛋白，负责长链脂肪酸（VLCFA）的输入，其机制是导致一系列复杂的功能障碍，包括内质网应激、氧化应激、线粒体功能障碍和炎症。这些患者的治疗选择很少；然而，以前已经成功地针对功能失调的 ABCD1 靶向另一种过氧化物酶体转运蛋白（ABCD2）。4-苯丁酸（4PBA）是 ABCD1 同源物 ABCD2 的有效激活剂，已获得 FDA 批准，但由于半衰期短，因此需要高剂量，因此在 ALD 中的应用受到阻碍。我们将 4PBA 与羟基聚酰胺胺（PAMAM）树枝状大分子（D-4PBA）缀合，以创建一种持久的和细胞内靶向的方法，该方法可穿过血脑屏障上调 Abcd2 及其下游途径。在两项研究中，长期给予 D-4PBA 的 Abcd1 敲除小鼠表现出神经行为改善和 Abcd2 表达增加。此外，当给予早期时，观察到 VLCFA 显著减少和脊髓神经元存活改善。总之，与以前单独使用游离 4PBA 的研究相比，这些数据表明 D-4PBA 的疗效得到了改善，并为使用树枝状大分子递送平台治疗复杂和慢性神经退行性疾病提供了希望，该平台在最近的临床试验中取得了成功。虽然我们的研究中的恢复是部分的，但在树枝状大分子平台上的联合治疗可能为 ALD 的治疗提供一种安全有效的完全策略。
