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したがって、本明細書には、微小管結合タンパク質タウ(MAPT)遺伝子の遺伝子モジュレーターであって、MAPT遺伝子中の少なくとも12個のヌクレオチドの標的部位に結合するDNA結合ドメイン、および機能性ドメイン(例えば、転写制御ドメイン(抑制ドメインまたは活性化ドメインなど)またはヌクレアーゼドメイン)を含む遺伝子モジュレーターが記載されている。ジンクフィンガータンパク質(ZFP)、TAL-エフェクタードメインタンパク質(TALE)、単鎖ガイドRNA(CRISPR系の)、およびアルゴノートタンパク質などを含むが、これらに限定されない、任意のDNA結合ドメインを使用することができる。本明細書に記載のような遺伝子モジュレーター(または同じまたは異なるポリヌクレオチドにあるその1つまたは複数の成分)をコードするウイルスおよび非ウイルス遺伝子送達ビヒクル(例えば、mRNA、プラスミド、AAVベクター、レンチウイルスベクター、Adベクターとして)を含む、1つまたは複数のポリヌクレオチドも提供される。ある特定の実施形態では、遺伝子送達ビヒクルは、AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV8、AAV8.2、AAV9、AAV rh10、当技術分野で公知のAAVベクター変異体(例えば、米国特許第9,585,971号および米国特許仮出願第62/503,121号)を含む、これらベクターの偽型(例えば、AAV2/8、AAV2/5、AAV2/6、AAV2/9などとして)を含むが、これらに限定されないAVVベクターを含む。遺伝子モジュレーターの1つまたは複数、1つまたは複数のポリヌクレオチド、および/または1つまたは複数の遺伝子送達ビヒクルを含む医薬組成物ならびに単離細胞も提供される。また、本発明は、それを必要とする対象のMAPT発現を調節するための方法および使用であって、本明細書に記載のような、1つまたは複数のポリヌクレオチド、1つまたは複数の遺伝子送達ビヒクル、および/または医薬組成物を対象に提供することによることを含む方法および使用を提供する。ある特定の実施形態では、本明細書に記載の組成物は、タウオパチーを処置および/または予防するため(例えば、対象におけるタウの量を低減することにより)を含む、対象のMAPT発現を抑制するために使用される。本明細書に記載の組成物は、脳(前頭皮質、前部皮質、後部皮質、海馬、脳幹、線条体、視床、中脳、小脳を含むが、これらに限定されない)および脊髄(腰部、胸部、および頚部領域を含むが、これらに限定されない)のタウレベルを持続的な期間(6か月から1年またはそれよりも長期間)にわたって低減する。本明細書に記載の組成物は、脳室内、髄腔内、頭蓋内、静脈内、眼窩的(後眼窩的(RO))、および/またはクモ膜下槽内投与を含むが、これらに限定されない、任意の投与手段により対象に提供することができる。また、本明細書に記載の組成物(例えば、遺伝子モジュレーター、ポリヌクレオチド、医薬組成物、および/または細胞)の1つまたは複数ならびにこれら組成物を使用するための説明書を含むキットが提供される。
Accordingly, provided herein are gene modulators of the microtubule-associated protein tau (MAPT) gene, wherein the DNA-binding domain binds to a target site of at least 12 nucleotides in the MAPT gene, and a functional domain (e.g., Gene modulators containing transcriptional regulatory domains (such as repression or activation domains or nuclease domains) have been described. Any DNA binding domain can be used, including but not limited to zinc finger proteins (ZFPs), TAL-effector domain proteins (TALEs), single-stranded guide RNAs (of the CRISPR system), Argonaute proteins, and the like. can. Viral and non-viral gene delivery vehicles (e.g., mRNA, plasmids, AAV vectors, lentiviral vectors) encoding gene modulators (or one or more components thereof on the same or different polynucleotides) as described herein , as an Ad vector) are also provided. In certain embodiments, the gene delivery vehicle is AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV8, AAV8.2, AAV9, AAV rh10, AAV vector variants known in the art (e.g., US Pat. 9,585,971 and U.S. Provisional Patent Application No. 62/503,121). Including, but not limited to, AVV vectors. Also provided are pharmaceutical compositions and isolated cells comprising one or more of the gene modulators, one or more polynucleotides, and/or one or more gene delivery vehicles. The invention also provides methods and uses for modulating MAPT expression in a subject in need thereof, comprising one or more polynucleotides, one or more genes, as described herein. Methods and uses are provided, including by providing a delivery vehicle, and/or a pharmaceutical composition to a subject. In certain embodiments, the compositions described herein suppress MAPT expression in a subject, including to treat and/or prevent tauopathy (e.g., by reducing the amount of tau in the subject). used for The compositions described herein may be used in the brain (including but not limited to frontal cortex, anterior cortex, posterior cortex, hippocampus, brainstem, striatum, thalamus, midbrain, cerebellum) and spinal cord (lumbar, It reduces tau levels over a sustained period of time (6 months to 1 year or longer), including but not limited to the chest and neck regions. Compositions described herein include, but are not limited to, intracerebroventricular, intrathecal , intracranial, intravenous, orbital (retroorbital (RO)), and/or intracisternal administration. can be provided to the subject by any means of administration, not Also provided are kits comprising one or more of the compositions (e.g., gene modulators, polynucleotides, pharmaceutical compositions, and/or cells) described herein and instructions for using these compositions. be.
したがって、他の態様では、本明細書には、対象のタウオパチー(例えば、AD)を予防および/または処置するための方法であって、1つまたは複数のAAVベクターを使用して、タウ対立遺伝子のリプレッサーを対象に投与することを含む方法が記載されている。ある特定の実施形態では、リプレッサーをコードするAAVは、脳室内、髄腔内、またはクモ膜下槽内送達を含むが、それらに限定されない、任意の送達方法により、CNS(脳および/またはCSF)に投与される。他の実施形態では、リプレッサーをコードするAAVは、対象の実質組織(例えば、海馬および/または嗅内皮質)に直接投与される。他の実施形態では、リプレッサーをコードするAAVは、静脈内(IV)投与される。本明細書に記載の方法のいずれかでは、投与は、1回(単回投与)で行われてもよく、または複数回(投与間に任意の時間をおいて)行われてもよい。複数回投与される場合、同じまたは異なる投薬量および/または送達ビヒクルの投与モードを使用することができる(例えば、異なるAAVベクターが、IVおよび/またはICVで投与される)。上記方法としては、対象での、例えばADを有する対象のADニューロンでのタウの凝集を低減する(例えば、タウ凝集のNFT特徴を低減する)ための方法;ニューロンまたはニューロンの集団(例えば、ADニューロンまたはADニューロンの集団)のアポトーシスを低減するための方法;神経過興奮を低減するための方法;アミロイドベータ誘導性毒性(例えば、シナプス喪失および/または神経炎性ジストロフィー)を低減するための方法;および/またはAD対象の1つまたは複数の認知機能の喪失を低減するための方法が挙げられ、すべては、上記方法を受けていない対象との比較、または上記方法を受ける前の対象自身との比較である。したがって、本明細書に記載の方法は、以下のもの:神経毒性、グリオーシス、変性神経突起、脊椎喪失、興奮毒性、皮質および海馬の収縮、樹状タウ蓄積、認知(例えば、げっ歯動物モデルにおける放射状アーム迷路およびモリス水迷路、恐怖条件付けなど)、および/または運動障害の1つまたは複数を含む、タウオパチーのバイオマーカーおよび/または症状の低減をもたらす。
Thus, in another aspect, provided herein is a method for preventing and/or treating tauopathy (e.g., AD) in a subject, comprising using one or more AAV vectors, tau allele are described, comprising administering to a subject a repressor of In certain embodiments, the AAV encoding the repressor is delivered to the CNS (brain and/or CSF). In other embodiments, AAV encoding a repressor is administered directly to a subject's parenchyma (eg, hippocampus and/or entorhinal cortex). In other embodiments, the AAV encoding the repressor is administered intravenously (IV). In any of the methods described herein, administration may be performed once (single dose) or multiple times (with any time between administrations). If multiple doses are administered, the same or different dosages and/or delivery vehicle modes of administration can be used (eg, different AAV vectors administered IV and/or ICV). Methods for reducing tau aggregation (e.g., reducing the NFT characteristic of tau aggregation) in a subject, e.g., in AD neurons of a subject with AD; methods for reducing apoptosis of neurons or populations of AD neurons); methods for reducing neuronal excitability; methods for reducing amyloid beta-induced toxicity (e.g., synaptic loss and/or neuritic dystrophy) and/or methods for reducing loss of one or more cognitive functions in an AD subject, all in comparison to a subject not receiving the method, or to the subject himself before undergoing the method. This is a comparison of Thus, the methods described herein include: neurotoxicity, gliosis, degenerative neurites, spinal loss, excitotoxicity, cortical and hippocampal contraction, dendritic tau accumulation, cognition (e.g., in rodent models). resulting in reduced biomarkers and/or symptoms of tauopathy, including one or more of radial arm maze and Morris water maze, fear conditioning, etc.), and/or movement disorders.
また、本明細書に記載のようなタウモジュレーターの成分を含むおよび/またはタウモ
ジュレーター(またはその成分)をコードするAAVタウモジュレーター(例えば、リプレッサー)および/またはポリヌクレオチドの1つまたは複数を含むキットが提供される。キットは、細胞(例えば、ニューロン)、(例えば、例えばCSFにおいてタウタンパク質を検出および/または定量化するための)試薬、および/または本明細書に記載のような方法を含むその使用のための説明書をさらに含んでいてもよい。
特定の実施形態では、例えば、以下が提供される:
(項目1)
微小管結合タンパク質タウ(MAPT)遺伝子の遺伝子モジュレーターであって、
該MAPT遺伝子の少なくとも12個のヌクレオチドの標的部位に結合するDNA結合ドメイン、および
転写制御ドメインまたはヌクレアーゼドメイン
を含む遺伝子モジュレーター。
(項目2)
前記DNA結合ドメインが、ジンクフィンガータンパク質(ZFP)、TAL-エフェクタードメインタンパク質(TALE)、または単鎖ガイドRNAを含む、項目1に記載の遺伝子モジュレーター。
(項目3)
前記転写制御ドメインが、抑制ドメインまたは活性化ドメインを含む、項目1または項目2に記載の遺伝子モジュレーター。
(項目4)
項目1から3のいずれかに記載の遺伝子モジュレーターをコードするポリヌクレオチド。
(項目5)
項目4に記載のポリヌクレオチドを含む遺伝子送達ビヒクル。
(項目6)
AAVベクターを含む、項目5に記載の遺伝子送達ビヒクル。
(項目7)
項目1から3に記載の1つまたは複数の遺伝子モジュレーター、項目4に記載の1つまたは複数のポリヌクレオチド、および/または項目5または6に記載の1つまたは複数の遺伝子送達ビヒクルを含む医薬組成物。
(項目8)
前記遺伝子モジュレーターが、ヌクレアーゼドメインを含み、該遺伝子モジュレーターが、前記MAPT遺伝子を切断する、項目7に記載の医薬組成物。
(項目9)
切断された前記MAPT遺伝子に組み込まれるドナー分子をさらに含む、項目8に記載の医薬組成物。
(項目10)
項目1から3に記載の1つまたは複数の遺伝子モジュレーター、項目4に記載の1つまたは複数のポリヌクレオチド、項目5または6に記載の1つまたは複数の遺伝子送達ビヒクル、および/または項目7から9のいずれかに記載の医薬組成物を含む単離細胞。
(項目11)
対象のMAPT発現を調節するための、項目1から3に記載の1つまたは複数の遺伝子モジュレーター、項目4に記載の1つまたは複数のポリヌクレオチド、項目5または6に記載の1つまたは複数の遺伝子送達ビヒクル、および/または項目7から9のいずれかに記載の医薬組成物の使用。
(項目12)
MAPT発現が抑制される、項目11に記載の使用。
(項目13)
前記対象への投与が、脳室内、髄腔内、頭蓋内、静脈内、後眼窩的、またはクモ膜下槽内である、項目11または12に記載の使用。
(項目14)
前記対象中のMAPT発現の抑制が、タウオパチーを処置および/または予防する、項目11から13のいずれかに記載の使用。
(項目15)
前記対象中のタウの量が低減される、項目11から14のいずれかに記載の使用。
(項目16)
項目1から3に記載の1つまたは複数の遺伝子モジュレーター、項目4に記載の1つまたは複数のポリヌクレオチド、項目5または6に記載の1つまたは複数の遺伝子送達ビヒクル、項目7から9のいずれかに記載の医薬組成物、および/または使用のための指示を含むキット。
Also, one or more of the AAV tau modulators (e.g., repressors) and/or polynucleotides comprising and/or encoding a tau modulator (or a component thereof) as described herein. Kits are provided that include. The kit includes cells (e.g., neurons), reagents (e.g., for detecting and/or quantifying tau protein in CSF), and/or methods for its use as described herein. Instructions may also be included.
In certain embodiments, for example, the following are provided:
(Item 1)
A gene modulator of the microtubule-associated protein tau (MAPT) gene,
A gene modulator comprising a DNA binding domain that binds to a target site of at least 12 nucleotides of said MAPT gene, and a transcriptional regulatory or nuclease domain.
(Item 2)
2. The gene modulator of item 1, wherein said DNA binding domain comprises a zinc finger protein (ZFP), a TAL-effector domain protein (TALE), or a single-stranded guide RNA.
(Item 3)
3. The gene modulator of item 1 or item 2, wherein said transcriptional control domain comprises a repression domain or an activation domain.
(Item 4)
A polynucleotide encoding the gene modulator of any of items 1-3.
(Item 5)
A gene delivery vehicle comprising the polynucleotide of item 4.
(Item 6)
6. The gene delivery vehicle of item 5, comprising an AAV vector.
(Item 7)
A pharmaceutical composition comprising one or more gene modulators according to items 1 to 3, one or more polynucleotides according to item 4, and/or one or more gene delivery vehicles according to items 5 or 6. thing.
(Item 8)
8. The pharmaceutical composition of item 7, wherein said gene modulator comprises a nuclease domain and said gene modulator cleaves said MAPT gene.
(Item 9)
9. Pharmaceutical composition according to item 8, further comprising a donor molecule that integrates into said truncated MAPT gene.
(Item 10)
one or more gene modulators according to items 1 to 3, one or more polynucleotides according to item 4, one or more gene delivery vehicles according to items 5 or 6, and/or from item 7 10. An isolated cell comprising the pharmaceutical composition according to any one of 9.
(Item 11)
one or more gene modulators according to items 1 to 3, one or more polynucleotides according to item 4, one or more according to items 5 or 6, for modulating MAPT expression in a subject Use of a gene delivery vehicle and/or a pharmaceutical composition according to any of items 7-9.
(Item 12)
12. Use according to item 11, wherein MAPT expression is suppressed.
(Item 13)
13. Use according to item 11 or 12, wherein administration to said subject is intracerebroventricular, intrathecal , intracranial, intravenous, retroorbital, or intracisternal.
(Item 14)
14. Use according to any of items 11 to 13, wherein suppression of MAPT expression in said subject treats and/or prevents tauopathy.
(Item 15)
15. Use according to any of items 11-14, wherein the amount of tau in said subject is reduced.
(Item 16)
one or more gene modulators according to items 1 to 3, one or more polynucleotides according to item 4, one or more gene delivery vehicles according to items 5 or 6, any of items 7 to 9 A kit comprising a pharmaceutical composition as described above and/or instructions for use.
遺伝子治療ベクターは、下記に記載のように、典型的には全身性投与(例えば、静脈内、腹腔内、筋肉内、皮下、髄腔内、クモ膜下槽内、脳室内、または海馬、皮質、線条体などの脳の任意の領域内を含む脳内への直接注射を含む頭蓋内注入)または局所塗布により個々の患者に投与することによりin vivo送達することができる。あるいは、ベクターを、個々の患者から外植された細胞(例えば、リンパ球、骨髄穿刺液、組織生検)または万能供血者造血幹細胞などの細胞にex vivoで送達し、その後、通常はベクターが組み込まれた細胞を選択した後で、細胞を患者に再移植してもよい。
Gene therapy vectors are typically administered systemically (e.g., intravenously, intraperitoneally, intramuscularly, subcutaneously, intrathecally, intrathecally , intracerebroventricularly, or hippocampally, cortically, etc.), as described below. , intracranial injection, including direct injection into the brain, including within any region of the brain such as the striatum) or by topical application to individual patients. Alternatively, vectors are delivered ex vivo to cells such as explanted cells from individual patients (e.g., lymphocytes, bone marrow aspirates, tissue biopsies) or universal hematopoietic donor hematopoietic stem cells, after which the vectors are usually delivered. After selecting the integrated cells, the cells may be re-implanted into the patient.
ある特定の実施形態では、本明細書に記載のような組成物(例えば、ポリヌクレオチドおよび/またはタンパク質)は、直接的にin vivo送達される。組成物(細胞、ポリヌクレオチド、および/またはタンパク質)は、脳または脊髄への直接注射を含むが、それらに限定されず、中枢神経系(CNS)に直接投与することができる。これらに限定されないが、海馬、黒質、マイネルト基底核(NBM)、線条体、および/または皮質を含む、脳の1つまたは複数の区域を標的とすることができる。CNS送達の代わりにまたはそれに加えて、組成物は、全身性投与してもよい(例えば、静脈内、腹腔内、心臓内、筋肉内、皮下、髄腔内、クモ膜下槽内、脳室内、および/または頭蓋内注入)。本明細書に記載のような組成物を対象に直接的に送達する(CNSに直接を含む)ための方法および組成物としては、これに限定されないが、針アセンブリによる直接注射(例えば、定位注射)が挙げられる。そのような方法は、例えば、脳への組成物(発現ベクターを含む)の送達に関する米国特許第7,837,668号および第8,092,429号、ならびに米国特許出願公開第2006/0239966号に記載されており、これらの文献は、参照によりそれらの全体が本明細書に組み込まれる。
In certain embodiments, compositions (eg, polynucleotides and/or proteins) as described herein are delivered directly in vivo. Compositions (cells, polynucleotides, and/or proteins) can be administered directly to the central nervous system (CNS), including, but not limited to, direct injection into the brain or spinal cord. One or more areas of the brain can be targeted including, but not limited to, hippocampus, substantia nigra, Meynert nucleus basalis (NBM), striatum, and/or cortex. Alternatively or in addition to CNS delivery, the composition may be administered systemically (e.g., intravenous, intraperitoneal, intracardiac, intramuscular, subcutaneous, intrathecal , intracisternal, intracerebroventricular , and/or intracranial injection). Methods and compositions for delivering compositions as described herein directly to a subject (including directly to the CNS) include, but are not limited to, direct injection via a needle assembly (e.g., stereotaxic injection). ). Such methods are described, for example, in US Pat. , which are incorporated herein by reference in their entireties.
Claims (36)
該MAPT遺伝子内の配列番号1~6、33、および44~45のいずれかの少なくとも12個のヌクレオチドの標的部位に結合するジンクフィンガータンパク質(ZFP)DNA結合ドメインであって、ここで、該ZFP DNA結合ドメインが
cgACAGAAGGCGAGgacagaagaggaca(配列番号1)、
ccGTTGCGCCTGATtGATGCCcagctcc(配列番号2)、
gtGGCGGAGACTGAGAGcgcgcgcggcc(配列番号3)、
ctTCTGTCGATTATCAGgtaagcgccgc(配列番号4)、
ctGGTGGGtGGCGGAGACTGAgagcgcg(配列番号5)、
tgGTGCTGGAGCTGGTGGGTggcggaga(配列番号6)、
agGGGCGGGCAGCGaggcctgggcgggc(配列番号33)、
cgGCAGAAGGTGGGcGGTGGCggcggcg(配列番号44)、および、
gcGGCGGCgGCAGAAGGTGGGcggtggc(配列番号45)
から選択されるヌクレオチド配列中の大文字のヌクレオチドに結合する、ZFP DNA結合ドメイン、ならびに、
転写制御ドメインまたはヌクレアーゼドメイン
を含む遺伝子モジュレーターであって、該MAPT遺伝子の発現を抑制する、遺伝子モジュレーター。 A gene modulator of the microtubule-associated protein tau (MAPT) gene, comprising:
A zinc finger protein (ZFP) DNA binding domain that binds to a target site of at least 12 nucleotides of any of SEQ ID NOS: 1-6, 33, and 44-45 within said MAPT gene, wherein said ZFP DNA binding domain
cgACAGAAGGCGAGgacagaagaggaca (SEQ ID NO: 1),
ccGTTGCGCCTGATtGATGCCcagctcc (SEQ ID NO: 2),
gtGGCGGAGACTGAGAGcgcgcgcggcc (SEQ ID NO: 3),
ctTCTGTCGATTATCAGgtaagcgccgc (SEQ ID NO: 4),
ctGGTGGGtGGCGGAGACTGAgagcgcg (SEQ ID NO: 5),
tgGTGCTGGAGCTGGTGGGTggcggaga (SEQ ID NO: 6),
agGGGCGGGCAGCGagggcctggcgggc (SEQ ID NO: 33),
cgGCAGAAGGTGGGcGGTGGCggcggcg (SEQ ID NO: 44), and
gcGGCGGCgGCAGAAGGTGGGcggtggc (SEQ ID NO: 45)
a ZFP DNA binding domain that binds to capitalized nucleotides in a nucleotide sequence selected from and
A gene modulator comprising a transcriptional regulatory domain or a nuclease domain , wherein the gene modulator suppresses expression of said MAPT gene .
ここで、各配列の配列番号は、括弧内に示される、遺伝子モジュレーター。 2. The gene modulator of claim 1, wherein said ZFP DNA binding domain comprises 4, 5, or 6 zinc finger domains, each zinc finger domain comprising a recognition helix region, said ZFP DNA binding domain comprises recognition helix regions in the order F1-F4, F1-F5, or F1-F6 shown in one row of the table below;
Gene modulators, where the SEQ ID NO of each sequence is shown in brackets.
36. The composition or pharmaceutical composition of any one of claims 32-35 , wherein said subject is a human.
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