Pardridge William M
Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
Front Aging Neurosci. 2020 Jan 10;11:373. doi: 10.3389/fnagi.2019.00373. eCollection 2019.
Alzheimer's disease (AD) and treatment of the brain in aging require the development of new biologic drugs, such as recombinant proteins or gene therapies. Biologics are large molecule therapeutics that do not cross the blood-brain barrier (BBB). BBB drug delivery is the limiting factor in the future development of new therapeutics for the brain. The delivery of recombinant protein or gene medicines to the brain is a binary process: either the brain drug developer re-engineers the biologic with BBB drug delivery technology, or goes forward with brain drug development in the absence of a BBB delivery platform. The presence of BBB delivery technology allows for engineering the therapeutic to enable entry into the brain across the BBB from blood. Brain drug development may still take place in the absence of BBB delivery technology, but with a reliance on approaches that have rarely led to FDA approval, e.g., CSF injection, stem cells, small molecules, and others. CSF injection of drug is the most widely practiced approach to brain delivery that bypasses the BBB. However, drug injection into the CSF results in limited drug penetration to the brain parenchyma, owing to the rapid export of CSF from the brain to blood. A CSF injection of a drug is equivalent to a slow intravenous (IV) infusion of the pharmaceutical. Given the profound effect the existence of the BBB has on brain drug development, future drug or gene development for the brain will be accelerated by future advances in BBB delivery technology in parallel with new drug discovery.
阿尔茨海默病（AD）以及衰老大脑的治疗需要开发新的生物药物，如重组蛋白或基因疗法。生物制剂是大分子治疗药物，无法穿过血脑屏障（BBB）。血脑屏障药物递送是未来大脑新疗法开发的限制因素。将重组蛋白或基因药物递送至大脑是一个二元过程：要么大脑药物开发者利用血脑屏障药物递送技术对生物制剂进行重新设计，要么在没有血脑屏障递送平台的情况下推进大脑药物开发。血脑屏障递送技术的存在使得能够对治疗药物进行工程改造，使其能够从血液穿过血脑屏障进入大脑。在没有血脑屏障递送技术的情况下，大脑药物开发仍可能进行，但依赖的方法很少能获得美国食品药品监督管理局（FDA）的批准，例如脑脊液注射、干细胞、小分子等。向脑脊液中注射药物是绕过血脑屏障的最广泛应用的大脑给药方法。然而，向脑脊液中注射药物导致药物向脑实质的渗透有限，这是因为脑脊液会迅速从大脑排出到血液中。向脑脊液中注射药物相当于缓慢静脉输注药物。鉴于血脑屏障的存在对大脑药物开发有深远影响，未来血脑屏障递送技术的进步与新药物发现并行，将加速未来大脑药物或基因的开发。
