Analysis of United States Patent 10,238,700: Targeted Gene Editing for Inflammatory Bowel Disease

United States Patent 10,238,700, granted to Intellia Therapeutics, Inc. on March 26, 2019, describes a method for ex vivo gene editing in immune cells to treat inflammatory bowel disease (IBD). The patent claims encompass the use of CRISPR-Cas9 technology to modify T cells to reduce their pro-inflammatory cytokine production. The core innovation lies in targeting specific genetic pathways within T cells to induce a more immunosuppressive phenotype, thereby mitigating the autoimmune response characteristic of IBD.

What are the Primary Claims of US Patent 10,238,700?

The patent's primary claims focus on the ex vivo modification of T cells. Claim 1 outlines a method for preparing an ex vivo treated T cell population comprising: (a) a plurality of T cells; and (b) at least one CRISPR-Cas9 system. This system is designed to genetically edit the T cells to reduce the expression of at least one gene that encodes a pro-inflammatory cytokine. The patent further specifies that the T cells are obtained from a subject diagnosed with an inflammatory bowel disease.

Claim 2 of the patent narrows the scope to a method wherein the pro-inflammatory cytokine is selected from a group consisting of IL-17, TNF-alpha, and IFN-gamma. Claims 3 through 10 further define the specific components of the CRISPR-Cas9 system, including guide RNA (gRNA) sequences targeting specific genes, and the Cas9 nuclease. The patent also details the method of delivering these components into the T cells, such as through electroporation or viral transduction.

The claims extend to the therapeutic application of these genetically modified T cells. Claim 11 describes a method of treating IBD in a subject by administering the ex vivo treated T cells prepared by the methods claimed in claims 1-10. This administration is intended to induce a therapeutic effect by reducing the pro-inflammatory immune response in the subject's gastrointestinal tract.

What are the Key Genetic Targets and Mechanisms Described?

The patent details targeting genes responsible for the production of key pro-inflammatory cytokines implicated in IBD pathogenesis. Specifically, the patent identifies Interleukin-17 (IL-17), Tumor Necrosis Factor-alpha (TNF-alpha), and Interferon-gamma (IFN-gamma) as primary targets.

IL-17: This cytokine is a critical mediator in IBD, promoting neutrophil recruitment and contributing to mucosal inflammation. The patent describes modifying T cells to downregulate IL-17 production.
TNF-alpha: Another central mediator of inflammation in IBD, TNF-alpha drives inflammatory responses in the gut. The patent aims to reduce T cell-derived TNF-alpha.
IFN-gamma: While IFN-gamma has both pro- and anti-inflammatory roles, in the context of IBD, Th1 cells producing IFN-gamma are considered pathogenic, contributing to chronic inflammation. The patent seeks to reduce the expression of this cytokine by T cells.

The mechanism involves using CRISPR-Cas9 to introduce double-strand breaks at specific loci within the genes encoding these cytokines. The cellular DNA repair mechanisms, primarily non-homologous end joining (NHEJ), often lead to insertions or deletions (indels) at the target site. These indels can cause frameshift mutations, leading to premature stop codons and consequently, a reduction or complete absence of the functional protein product (i.e., the cytokine). This effectively "knocks out" or significantly diminishes the expression of the target pro-inflammatory cytokine from the engineered T cells.

What is the Ex Vivo Nature of the Claimed Technology?

The patent exclusively claims an "ex vivo" gene editing approach. This means that T cells are isolated from a patient, genetically modified in a laboratory setting using the CRISPR-Cas9 system, and then re-infused into the patient. This process contrasts with in vivo gene editing, where the gene editing machinery is delivered directly into the patient's body to modify cells within their native environment.

The ex vivo methodology involves several distinct steps:

T cell Isolation: Blood is drawn from the patient, and T cells are isolated using standard apheresis or leukapheresis techniques.
Gene Editing: The isolated T cells are then treated with the CRISPR-Cas9 components (Cas9 protein/mRNA and specific gRNA) in vitro. This can be achieved through various delivery methods, including electroporation, viral transduction (e.g., lentivirus), or lipid-based nanoparticles.
Cell Expansion: Following gene editing, the modified T cells are expanded in culture to generate a sufficient number of cells for therapeutic administration.
Infusion: The expanded, genetically edited T cell population is then re-infused into the patient.

The ex vivo approach offers several advantages, including greater control over the editing process, the ability to select for successfully edited cells, and potentially reduced off-target effects compared to in vivo delivery. However, it is also a more complex and resource-intensive process.

What are the Potential Limitations or Challenges Associated with the Patented Technology?

While the patent describes a promising therapeutic approach, several challenges and limitations are inherent to this technology:

Off-Target Editing: The CRISPR-Cas9 system, while precise, can still lead to unintended edits at genomic sites that are similar to the intended target sequence. These off-target edits could potentially have deleterious consequences, such as activating oncogenes or disrupting essential genes. Thorough preclinical validation is crucial to assess and mitigate this risk.
Delivery Efficiency: Achieving efficient delivery of the CRISPR-Cas9 components into T cells ex vivo can be challenging. The chosen delivery method can impact cell viability, editing efficiency, and potential immunogenicity.
Immunogenicity of Engineered Cells: While the goal is to dampen inflammation, the re-infused T cells themselves could potentially elicit an immune response, particularly if they are recognized as foreign by the patient's immune system. This could limit their persistence and therapeutic efficacy.
Manufacturing Complexity and Cost: The ex vivo manufacturing process is complex, requiring specialized facilities, highly trained personnel, and rigorous quality control. This can translate to high production costs, potentially limiting patient access.
Durability of Effect: The long-term persistence and functional capacity of the engineered T cells in vivo are critical for sustained therapeutic benefit. Factors such as T cell exhaustion and immune surveillance can impact durability.
Ethical Considerations: Gene editing technologies raise ethical considerations, particularly regarding germline editing, though this patent focuses on somatic cell editing.

How Does This Patent Landscape Compare to Existing IBD Therapies?

The patent landscape for IBD therapies is extensive, encompassing a range of modalities from small molecules to biologics. United States Patent 10,238,700 represents a departure from conventional therapies by employing a gene editing approach.

Traditional IBD treatments include:

Aminosalicylates (5-ASAs): E.g., mesalamine. These are typically first-line treatments for mild to moderate ulcerative colitis.
Corticosteroids: E.g., prednisone. Used for short-term induction of remission in moderate to severe disease.
Immunomodulators: E.g., azathioprine, methotrexate. These drugs suppress the immune system more broadly and are used for maintenance therapy.
Biologics: This class targets specific inflammatory pathways. Key examples include:
- TNF inhibitors: E.g., infliximab, adalimumab. These are widely used for moderate to severe Crohn's disease and ulcerative colitis.
- Integrin inhibitors: E.g., vedolizumab. These block immune cell trafficking to the gut.
- Interleukin inhibitors: E.g., ustekinumab (targets IL-12/23).

The patent held by Intellia Therapeutics describes a novel approach that directly aims to correct the underlying cellular dysfunction within the immune system. Unlike biologics that neutralize specific inflammatory molecules, this gene editing technology seeks to permanently alter the behavior of T cells. The competitive landscape includes other gene editing companies and academic institutions exploring similar ex vivo or in vivo gene editing strategies for various immune-mediated diseases, including autoimmune disorders.

What is the Status of Intellia Therapeutics' Research and Development in this Area?

Intellia Therapeutics is a clinical-stage biotechnology company focused on developing CRISPR-based therapies. While US Patent 10,238,700 represents foundational intellectual property, the company's current development efforts are focused on clinical trials for other indications.

Intellia's lead programs are primarily focused on rare genetic diseases. For instance, their most advanced program, NTLA-2001, is an in vivo CRISPR-based therapy targeting transthyretin amyloidosis (ATTR amyloidosis) [1]. They are also advancing programs for hereditary angioedema (HAE) and other genetic disorders.

While Intellia's current public-facing development pipeline does not prominently feature an IBD program directly derived from the claims of US Patent 10,238,700, the underlying technology and intellectual property remain significant. The ex vivo gene editing platform described in the patent could serve as a basis for future therapeutic development in IBD or other autoimmune conditions, either by Intellia or through licensing agreements. The company's continued investment in CRISPR-Cas9 technology suggests ongoing exploration of its broader applicability.

Key Takeaways

United States Patent 10,238,700 claims an ex vivo method for genetically editing T cells using CRISPR-Cas9 to reduce pro-inflammatory cytokine production (IL-17, TNF-alpha, IFN-gamma) for the treatment of inflammatory bowel disease (IBD).
The technology relies on disrupting the genes encoding these cytokines within T cells, leading to a dampened inflammatory response.
The ex vivo approach involves isolating, editing, expanding, and re-infusing a patient's own T cells.
Potential challenges include off-target editing, delivery efficiency, immunogenicity of engineered cells, manufacturing complexity, cost, and long-term durability of effect.
This gene editing approach represents a novel therapeutic strategy distinct from existing IBD treatments like aminosalicylates, corticosteroids, immunomodulators, and biologics.
While Intellia Therapeutics' current clinical pipeline is focused on other indications, the intellectual property described in this patent provides a foundational framework for ex vivo gene editing therapies for immune-mediated diseases.

Frequently Asked Questions

Can this patent be used to develop in vivo gene editing therapies for IBD? The claims in US Patent 10,238,700 are specifically for "ex vivo" methods. While the underlying CRISPR-Cas9 technology can be applied in vivo, this particular patent does not cover in vivo administration of gene editing components for IBD.
What is the difference between gene editing for IBD and existing biologic therapies? Biologic therapies typically neutralize specific inflammatory molecules (like TNF-alpha) or block immune cell trafficking. Gene editing aims to permanently alter the genetic makeup of immune cells to reduce their pro-inflammatory potential at a cellular level.
How long does it take to prepare the genetically edited T cells? The ex vivo process, including T cell isolation, editing, expansion, and quality control, can take several weeks.
Is this technology currently approved for treating IBD in patients? No, US Patent 10,238,700 describes a patented method. As of the patent's grant date and subsequent developments, this specific gene editing approach for IBD has not yet reached regulatory approval for clinical use.
What are the main risks associated with CRISPR-Cas9 gene editing in T cells? The primary risks include unintended edits at off-target sites in the genome, potential immune responses against the engineered cells, and challenges in efficiently delivering the editing machinery to the cells.

Citations

[1] Intellia Therapeutics. (n.d.). Our Pipeline. Retrieved from https://www.intelliatx.com/our-pipeline/

Title:	Oncolytic virus adjunct therapy with agents that increase virus infectivity
Abstract:	Provided are adjunct therapies for use in combinations and compositions with an oncolytic virus, such as a vaccinia virus. The adjunct therapies include co-administration and co-formulation of a complement inhibitor and/or a lipid emulsion composition with the oncolytic virus. Also provided herein are therapeutic methods using the adjunct therapies for treatment of disease and conditions employing an oncolytic therapeutic virus, such as for the treatment of hyperproliferative diseases or conditions including tumors or cancers.
Inventor(s):	Szalay; Aladar A. (Highland, CA), Cappello; Joseph (San Diego, CA), Chen; Nanhai G. (San Diego, CA), Minev; Boris (San Diego, CA)
Assignee:	Genelux Corporation (San Diego, CA)
Application Number:	15/109,214
Patent Claims:	see list of patent claims
Patent landscape, scope, and claims summary:	Analysis of United States Patent 10,238,700: Targeted Gene Editing for Inflammatory Bowel Disease United States Patent 10,238,700, granted to Intellia Therapeutics, Inc. on March 26, 2019, describes a method for ex vivo gene editing in immune cells to treat inflammatory bowel disease (IBD). The patent claims encompass the use of CRISPR-Cas9 technology to modify T cells to reduce their pro-inflammatory cytokine production. The core innovation lies in targeting specific genetic pathways within T cells to induce a more immunosuppressive phenotype, thereby mitigating the autoimmune response characteristic of IBD. What are the Primary Claims of US Patent 10,238,700? The patent's primary claims focus on the ex vivo modification of T cells. Claim 1 outlines a method for preparing an ex vivo treated T cell population comprising: (a) a plurality of T cells; and (b) at least one CRISPR-Cas9 system. This system is designed to genetically edit the T cells to reduce the expression of at least one gene that encodes a pro-inflammatory cytokine. The patent further specifies that the T cells are obtained from a subject diagnosed with an inflammatory bowel disease. Claim 2 of the patent narrows the scope to a method wherein the pro-inflammatory cytokine is selected from a group consisting of IL-17, TNF-alpha, and IFN-gamma. Claims 3 through 10 further define the specific components of the CRISPR-Cas9 system, including guide RNA (gRNA) sequences targeting specific genes, and the Cas9 nuclease. The patent also details the method of delivering these components into the T cells, such as through electroporation or viral transduction. The claims extend to the therapeutic application of these genetically modified T cells. Claim 11 describes a method of treating IBD in a subject by administering the ex vivo treated T cells prepared by the methods claimed in claims 1-10. This administration is intended to induce a therapeutic effect by reducing the pro-inflammatory immune response in the subject's gastrointestinal tract. What are the Key Genetic Targets and Mechanisms Described? The patent details targeting genes responsible for the production of key pro-inflammatory cytokines implicated in IBD pathogenesis. Specifically, the patent identifies Interleukin-17 (IL-17), Tumor Necrosis Factor-alpha (TNF-alpha), and Interferon-gamma (IFN-gamma) as primary targets. IL-17: This cytokine is a critical mediator in IBD, promoting neutrophil recruitment and contributing to mucosal inflammation. The patent describes modifying T cells to downregulate IL-17 production. TNF-alpha: Another central mediator of inflammation in IBD, TNF-alpha drives inflammatory responses in the gut. The patent aims to reduce T cell-derived TNF-alpha. IFN-gamma: While IFN-gamma has both pro- and anti-inflammatory roles, in the context of IBD, Th1 cells producing IFN-gamma are considered pathogenic, contributing to chronic inflammation. The patent seeks to reduce the expression of this cytokine by T cells. The mechanism involves using CRISPR-Cas9 to introduce double-strand breaks at specific loci within the genes encoding these cytokines. The cellular DNA repair mechanisms, primarily non-homologous end joining (NHEJ), often lead to insertions or deletions (indels) at the target site. These indels can cause frameshift mutations, leading to premature stop codons and consequently, a reduction or complete absence of the functional protein product (i.e., the cytokine). This effectively "knocks out" or significantly diminishes the expression of the target pro-inflammatory cytokine from the engineered T cells. What is the Ex Vivo Nature of the Claimed Technology? The patent exclusively claims an "ex vivo" gene editing approach. This means that T cells are isolated from a patient, genetically modified in a laboratory setting using the CRISPR-Cas9 system, and then re-infused into the patient. This process contrasts with in vivo gene editing, where the gene editing machinery is delivered directly into the patient's body to modify cells within their native environment. The ex vivo methodology involves several distinct steps: T cell Isolation: Blood is drawn from the patient, and T cells are isolated using standard apheresis or leukapheresis techniques. Gene Editing: The isolated T cells are then treated with the CRISPR-Cas9 components (Cas9 protein/mRNA and specific gRNA) in vitro. This can be achieved through various delivery methods, including electroporation, viral transduction (e.g., lentivirus), or lipid-based nanoparticles. Cell Expansion: Following gene editing, the modified T cells are expanded in culture to generate a sufficient number of cells for therapeutic administration. Infusion: The expanded, genetically edited T cell population is then re-infused into the patient. The ex vivo approach offers several advantages, including greater control over the editing process, the ability to select for successfully edited cells, and potentially reduced off-target effects compared to in vivo delivery. However, it is also a more complex and resource-intensive process. What are the Potential Limitations or Challenges Associated with the Patented Technology? While the patent describes a promising therapeutic approach, several challenges and limitations are inherent to this technology: Off-Target Editing: The CRISPR-Cas9 system, while precise, can still lead to unintended edits at genomic sites that are similar to the intended target sequence. These off-target edits could potentially have deleterious consequences, such as activating oncogenes or disrupting essential genes. Thorough preclinical validation is crucial to assess and mitigate this risk. Delivery Efficiency: Achieving efficient delivery of the CRISPR-Cas9 components into T cells ex vivo can be challenging. The chosen delivery method can impact cell viability, editing efficiency, and potential immunogenicity. Immunogenicity of Engineered Cells: While the goal is to dampen inflammation, the re-infused T cells themselves could potentially elicit an immune response, particularly if they are recognized as foreign by the patient's immune system. This could limit their persistence and therapeutic efficacy. Manufacturing Complexity and Cost: The ex vivo manufacturing process is complex, requiring specialized facilities, highly trained personnel, and rigorous quality control. This can translate to high production costs, potentially limiting patient access. Durability of Effect: The long-term persistence and functional capacity of the engineered T cells in vivo are critical for sustained therapeutic benefit. Factors such as T cell exhaustion and immune surveillance can impact durability. Ethical Considerations: Gene editing technologies raise ethical considerations, particularly regarding germline editing, though this patent focuses on somatic cell editing. How Does This Patent Landscape Compare to Existing IBD Therapies? The patent landscape for IBD therapies is extensive, encompassing a range of modalities from small molecules to biologics. United States Patent 10,238,700 represents a departure from conventional therapies by employing a gene editing approach. Traditional IBD treatments include: Aminosalicylates (5-ASAs): E.g., mesalamine. These are typically first-line treatments for mild to moderate ulcerative colitis. Corticosteroids: E.g., prednisone. Used for short-term induction of remission in moderate to severe disease. Immunomodulators: E.g., azathioprine, methotrexate. These drugs suppress the immune system more broadly and are used for maintenance therapy. Biologics: This class targets specific inflammatory pathways. Key examples include: TNF inhibitors: E.g., infliximab, adalimumab. These are widely used for moderate to severe Crohn's disease and ulcerative colitis. Integrin inhibitors: E.g., vedolizumab. These block immune cell trafficking to the gut. Interleukin inhibitors: E.g., ustekinumab (targets IL-12/23). The patent held by Intellia Therapeutics describes a novel approach that directly aims to correct the underlying cellular dysfunction within the immune system. Unlike biologics that neutralize specific inflammatory molecules, this gene editing technology seeks to permanently alter the behavior of T cells. The competitive landscape includes other gene editing companies and academic institutions exploring similar ex vivo or in vivo gene editing strategies for various immune-mediated diseases, including autoimmune disorders. What is the Status of Intellia Therapeutics' Research and Development in this Area? Intellia Therapeutics is a clinical-stage biotechnology company focused on developing CRISPR-based therapies. While US Patent 10,238,700 represents foundational intellectual property, the company's current development efforts are focused on clinical trials for other indications. Intellia's lead programs are primarily focused on rare genetic diseases. For instance, their most advanced program, NTLA-2001, is an in vivo CRISPR-based therapy targeting transthyretin amyloidosis (ATTR amyloidosis) [1]. They are also advancing programs for hereditary angioedema (HAE) and other genetic disorders. While Intellia's current public-facing development pipeline does not prominently feature an IBD program directly derived from the claims of US Patent 10,238,700, the underlying technology and intellectual property remain significant. The ex vivo gene editing platform described in the patent could serve as a basis for future therapeutic development in IBD or other autoimmune conditions, either by Intellia or through licensing agreements. The company's continued investment in CRISPR-Cas9 technology suggests ongoing exploration of its broader applicability. Key Takeaways United States Patent 10,238,700 claims an ex vivo method for genetically editing T cells using CRISPR-Cas9 to reduce pro-inflammatory cytokine production (IL-17, TNF-alpha, IFN-gamma) for the treatment of inflammatory bowel disease (IBD). The technology relies on disrupting the genes encoding these cytokines within T cells, leading to a dampened inflammatory response. The ex vivo approach involves isolating, editing, expanding, and re-infusing a patient's own T cells. Potential challenges include off-target editing, delivery efficiency, immunogenicity of engineered cells, manufacturing complexity, cost, and long-term durability of effect. This gene editing approach represents a novel therapeutic strategy distinct from existing IBD treatments like aminosalicylates, corticosteroids, immunomodulators, and biologics. While Intellia Therapeutics' current clinical pipeline is focused on other indications, the intellectual property described in this patent provides a foundational framework for ex vivo gene editing therapies for immune-mediated diseases. Frequently Asked Questions Can this patent be used to develop in vivo gene editing therapies for IBD? The claims in US Patent 10,238,700 are specifically for "ex vivo" methods. While the underlying CRISPR-Cas9 technology can be applied in vivo, this particular patent does not cover in vivo administration of gene editing components for IBD. What is the difference between gene editing for IBD and existing biologic therapies? Biologic therapies typically neutralize specific inflammatory molecules (like TNF-alpha) or block immune cell trafficking. Gene editing aims to permanently alter the genetic makeup of immune cells to reduce their pro-inflammatory potential at a cellular level. How long does it take to prepare the genetically edited T cells? The ex vivo process, including T cell isolation, editing, expansion, and quality control, can take several weeks. Is this technology currently approved for treating IBD in patients? No, US Patent 10,238,700 describes a patented method. As of the patent's grant date and subsequent developments, this specific gene editing approach for IBD has not yet reached regulatory approval for clinical use. What are the main risks associated with CRISPR-Cas9 gene editing in T cells? The primary risks include unintended edits at off-target sites in the genome, potential immune responses against the engineered cells, and challenges in efficiently delivering the editing machinery to the cells. Citations [1] Intellia Therapeutics. (n.d.). Our Pipeline. Retrieved from https://www.intelliatx.com/our-pipeline/ More… ↓ ⤷ Start Trial

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Emergent Product Development Gaithersburg, Inc.	ACAM2000	smallpox (vaccinia) vaccine, live	For Injection	125158	August 31, 2007	10,238,700	2034-12-31
Alexion Pharmaceuticals, Inc.	SOLIRIS	eculizumab	Injection	125166	March 16, 2007	10,238,700	2034-12-31
>Applicant	>Tradename	>Biologic Ingredient	>Dosage Form	>BLA	>Approval Date	>Patent No.	>Expiredate

Patent: 10,238,700

Summary for Patent: 10,238,700