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Building on the previous work, Brigham reserachers have published preclinical evidence that using gene therapy to deliver a functional copy of PSEN1 may someday be able to treat FAD." /> <link rel="canonical" href="https://www.brighamhealthonamission.org/2024/03/26/proof-of-concept-presenilin-based-gene-therapy-targets-early-onset-alzheimer-s-disease-carrying-psen-mutations/" /> <meta property="og:locale" content="en_US" /> <meta property="og:type" content="article" /> <meta property="og:title" content="Presenilin Gene Therapy Early-onset Alzheimer's Disease PSEN Mutation" /> <meta property="og:description" content="Mutations in human presenilin genes (PSEN1 and PSEN2) are the major cause of early-onset familial Alzheimer's disease (FAD). Building on the previous work, Brigham reserachers have published preclinical evidence that using gene therapy to deliver a functional copy of PSEN1 may someday be able to treat FAD." /> <meta property="og:url" content="https://www.brighamhealthonamission.org/2024/03/26/proof-of-concept-presenilin-based-gene-therapy-targets-early-onset-alzheimer-s-disease-carrying-psen-mutations/" /> <meta property="og:site_name" content="Brigham On a Mission" /> <meta property="article:publisher" content="https://www.facebook.com/BrighamandWomensHospital" /> <meta property="article:published_time" content="2024-03-26T13:35:28+00:00" /> <meta name="author" content="Faith Reidenbach" /> <meta name="twitter:card" content="summary_large_image" /> <meta name="twitter:creator" content="@BrighamWomens" /> <meta name="twitter:site" content="@BrighamWomens" /> <meta name="twitter:label1" content="Written by" /> <meta name="twitter:data1" content="Faith Reidenbach" /> <meta name="twitter:label2" content="Est. reading time" /> <meta name="twitter:data2" content="3 minutes" /> <script type="application/ld+json" class="yoast-schema-graph">{"@context":"https://schema.org","@graph":[{"@type":"Article","@id":"https://www.brighamhealthonamission.org/2024/03/26/proof-of-concept-presenilin-based-gene-therapy-targets-early-onset-alzheimer-s-disease-carrying-psen-mutations/#article","isPartOf":{"@id":"https://www.brighamhealthonamission.org/2024/03/26/proof-of-concept-presenilin-based-gene-therapy-targets-early-onset-alzheimer-s-disease-carrying-psen-mutations/"},"author":{"name":"Faith Reidenbach","@id":"https://www.brighamhealthonamission.org/#/schema/person/4b9967d6f8b443d2bfc1f5771e91574c"},"headline":"Proof of Concept: Presenilin-based Gene Therapy Targets Early-onset Alzheimer’s Disease Carrying PSEN Mutations","datePublished":"2024-03-26T13:35:28+00:00","mainEntityOfPage":{"@id":"https://www.brighamhealthonamission.org/2024/03/26/proof-of-concept-presenilin-based-gene-therapy-targets-early-onset-alzheimer-s-disease-carrying-psen-mutations/"},"wordCount":479,"commentCount":0,"publisher":{"@id":"https://www.brighamhealthonamission.org/#organization"},"image":{"@id":"https://www.brighamhealthonamission.org/2024/03/26/proof-of-concept-presenilin-based-gene-therapy-targets-early-onset-alzheimer-s-disease-carrying-psen-mutations/#primaryimage"},"thumbnailUrl":"https://www.brighamhealthonamission.org/wp-content/uploads/2024/03/brain-and-dna-as-genes-l-2.jpg","articleSection":["Neurology & Neurosurgery"],"inLanguage":"en-US","potentialAction":[{"@type":"CommentAction","name":"Comment","target":["https://www.brighamhealthonamission.org/2024/03/26/proof-of-concept-presenilin-based-gene-therapy-targets-early-onset-alzheimer-s-disease-carrying-psen-mutations/#respond"]}]},{"@type":"WebPage","@id":"https://www.brighamhealthonamission.org/2024/03/26/proof-of-concept-presenilin-based-gene-therapy-targets-early-onset-alzheimer-s-disease-carrying-psen-mutations/","url":"https://www.brighamhealthonamission.org/2024/03/26/proof-of-concept-presenilin-based-gene-therapy-targets-early-onset-alzheimer-s-disease-carrying-psen-mutations/","name":"Presenilin Gene Therapy Early-onset Alzheimer's Disease PSEN Mutation","isPartOf":{"@id":"https://www.brighamhealthonamission.org/#website"},"primaryImageOfPage":{"@id":"https://www.brighamhealthonamission.org/2024/03/26/proof-of-concept-presenilin-based-gene-therapy-targets-early-onset-alzheimer-s-disease-carrying-psen-mutations/#primaryimage"},"image":{"@id":"https://www.brighamhealthonamission.org/2024/03/26/proof-of-concept-presenilin-based-gene-therapy-targets-early-onset-alzheimer-s-disease-carrying-psen-mutations/#primaryimage"},"thumbnailUrl":"https://www.brighamhealthonamission.org/wp-content/uploads/2024/03/brain-and-dna-as-genes-l-2.jpg","datePublished":"2024-03-26T13:35:28+00:00","description":"Mutations in human presenilin genes (PSEN1 and PSEN2) are the major cause of early-onset familial Alzheimer's disease (FAD). 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class="post-7679 post type-post status-publish format-standard has-post-thumbnail hentry category-neurology-neurosurgery"> <header class="entry-header"> <h1 class="entry-title textcenter-xs">Proof of Concept: Presenilin-based Gene Therapy Targets Early-onset Alzheimer’s Disease Carrying PSEN Mutations</h1> <div class="entry-thumbnail"> <img width="300" height="225" src="https://www.brighamhealthonamission.org/wp-content/uploads/2024/03/brain-and-dna-as-genes-l-2.jpg" class="attachment-full size-full wp-post-image" alt="" decoding="async" fetchpriority="high" /> </div> </header> <div class="entry-content"> <p>In 2007, researchers from Mass General Brigham proposed in the <a href="https://www.pnas.org/doi/full/10.1073/pnas.0608332104" target="_blank" rel="noopener noreferrer"><em>Proceedings of the National Academy of Sciences</em></a> that loss of presenilin function underlies memory impairment and neurodegeneration in familial Alzheimer’s disease (FAD). Presenilin is the catalytic subunit of 纬-secretase, which cleaves the amyloid precursor protein and other transmembrane proteins.</p> <p>The “presenilin hypothesis” was based on studies of mice in which presenilin genes were selectively inactivated in the adult cerebral cortex. The animals developed age-related, progressive neurodegeneration characterized by hallmarks of AD neuropathology, including synaptic loss, neuronal cell death, astrogliosis, and tau hyperphosphorylation.</p> <p>Mutations in human presenilin genes <em>(PSEN1 and PSEN2) </em>are the major cause of early-onset familial Alzheimer’s disease. Building on the previous work, <a href="https://shenlab.bwh.harvard.edu/paola-montenegro/" target="_blank" rel="noopener noreferrer">Paola Montenegro, PhD</a>, formerly a research fellow in the <a href="https://shenlab.bwh.harvard.edu/" target="_blank" rel="noopener noreferrer">Shen Laboratory for Molecular Neurobiology</a> in the <a href="https://www.brighamandwomens.org/neurology" target="_blank" rel="noopener noreferrer">Department of Neurology</a> at Brigham and Women’s Hospital, <a href="https://brain.harvard.edu/?people=jie-shen" target="_blank" rel="noopener noreferrer">Jie Shen, PhD</a>, principal of the Shen Lab and part of the <a href="https://brain.harvard.edu/about/" target="_blank" rel="noopener noreferrer">Harvard Brain Science Initiative</a>, and colleagues have published preclinical evidence that using gene therapy to deliver a functional copy of<em> PSEN1</em> may someday be able to treat FAD. Their report appears in a new paper in the <a href="https://www.pnas.org/doi/10.1073/pnas.2306714120" target="_blank" rel="noopener noreferrer"><em>Proceedings of the National Academy of Sciences</em></a><em>.</em></p> <h2>Methods</h2> <p>The researchers tested the use of adeno-associated virus 9 (AAV9) to deliver wild-type human presenilin-1 (hPS1) to four different sets of <em>Psen-</em>mutant mice. AAVs are often used as carriers of transgenes because of their neuronal tropism, stable transgene expression, and low immune responses. The AAV9 serotype is particularly attractive because it can achieve widespread gene expression in the central nervous system.</p> <h2>Key Results</h2> <p>The principal findings were:</p> <ul> <li>Despite low to moderate levels of hPS1 expressed from the AAV9 vector, hPS1 expression was sustained over time and rescued impaired 纬-secretase activity in the cerebral cortex of mice that lacked presenilin.</li> </ul> <ul> <li>Impaired 纬-secretase activity was also rescued in mice expressing the <em>Psen1</em> L435F mutation, the alteration that most severely reduces 纬-secretase activity; these mice are genetically analogous to patients with FAD who carry the same mutation.</li> </ul> <ul> <li>Introduction of hPS1 alleviated short- and long-term synaptic plasticity impairments and memory deficits exhibited by <em>Psen-</em>mutant mice.</li> </ul> <ul> <li>hPS1 expression ameliorated neurodegeneration in aged <em>Psen-</em>mutant mice, as shown by reversal of cortical neuronal loss and elevated microgliosis and astrogliosis.</li> </ul> <h2>The Path Forward</h2> <p>These results are exciting proof-of-concept preclinical data for the use of gene therapy for patients with FAD who carry <em>PSEN</em> mutations. However, many technical challenges to clinical translation remain. One example is the much larger cerebral cortex in humans; the gene delivery vehicle will need to be capable of broader transduction and distribution.</p> <p>Fortunately, recently developed AAV9 capsids have shown robust delivery across the blood鈥揵rain barrier and widespread CNS transduction in nonhuman primates after noninvasive intravenous administration. 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