Compositions and methods for predicting response to Anti-cancer agents

Abstract

Provided herein are methods of treating cancer in a subject comprising administering an anti-OPA1 agent and an anti-cancer agent. Also provided herein are methods of treating cancer in a subject with reduced levels of OPA1.

Description

[0001] Attorney Docket No. : UCH-42525

[0002] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0003] COMPOSITIONS AND METHODS FOR PREDICTING RESPONSE TO ANTICANCER AGENTS

[0004] RELATED APPLICATIONS

[0005] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 779,623, filed March 28, 2025, the contents of which are incorporated herein by reference in their entirety.

[0006] GOVERNMENT SUPPORT

[0007] This invention was made with government support under CA208642 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0008] BACKGROUND

[0009] Cytotoxic chemotherapeutic agents are often conjugated to antibodies, creating antibody drug conjugates (ADCs). Treatment with ADCs causes tumor cell apoptosis, which leads to eventual tumor cell death and effective anti-cancer treatment. There are currently many ADCs with cytotoxic chemotherapy payloads that are FDA approved for the treatment of human cancers, as well as a large number of similar ADCs currently under clinical development.

[0010] However, despite these approved and developmental ADCs, the majority of patients receiving ADCs do not respond to therapy, leading to a significant unmet need for more effective patient selection to enhance precision of cancer therapeutics.

[0011] SUMMARY

[0012] Provided herein are methods of treating cancer in a subject comprising administering an anti-OPAl agent and an anti-cancer agent. Further provided herein are methods of reducing levels of OPA1 in a subject comprising administering an anti-OPAl agent.

[0013] Also provided herein are methods of treating cancer in a subject comprising administering an anti-cancer agent to the subject. In some embodiments, the subject has reduced levels of OPAl. In some embodiments, the subject has reduced mitochondrial membrane potential. In some embodiments, the subject has reduced mitochondrial length or mitochondrial area. In some embodiments, the subject has increased mitochondrial fragmentation, reduced mitochondrial cristae organization, and / or reduced mitochondrial cristae density.Attorney Docket No. : UCH-42525

[0014] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0015] In some aspects, the present disclosure provides methods of treating cancer comprising administering an anti-cancer agent to a subject, wherein the subject has reduced levels of OPA1 relative to a reference level.

[0016] In some aspects, the present disclosure provides methods of treating cancer comprising administering an anti-cancer agent to a subject, wherein the subject has reduced mitochondrial membrane potential relative to a reference level.

[0017] In some aspects, the present disclosure provides methods of treating cancer in a subject comprising administering an anti-cancer agent to the subject, wherein the subject has reduced mitochondrial length or mitochondrial area relative to a reference level.

[0018] In some aspects, the present disclosure provides methods of treating cancer in a subject comprising administering an anti-cancer agent to the subject, wherein the subject has increased mitochondrial fragmentation, reduced mitochondrial cristae organization, and / or reduced mitochondrial cristae density relative to a reference level.

[0019] BRIEF DESCRIPTION OF THE FIGURES FIGs. 1A-G show mitochondrial structure and A significantly predict cisplatin sensitivity in cancer cells. FIG. 1A shows TMRE staining of cancer cell lines. FIG. IB shows cell death following lOpM cisplatin treatment. FIG. 1C shows Pearson’s correlation of cell death vs. AT in cisplatin treated cancer cell lines from FIGs. 1A-B. FIG. ID and FIG. IE show confocal imaging of mitochondrial networks in cisplatin-sensitive (Cis-S) vs. resistant (Cis-R) cell lines. Fragmented mitochondria with Type II & III open cristae shown in the inset of FIG. ID. FIGs. 1F-G show fused mitochondrial fragmentation by circularity and AT in cristae in Cis-R vs. Cis-S cells. P-values represent statistical analysis by student t-test.

[0020] FIGs. 2A-I show that OPA1 regulates mitochondrial structure and governs response to ADC induced apoptosis. FIG. 2A shows super-resolution STED microscopy images of H1975 sgOPAl vs. control sgNT cancer cells. FIG. 2B shows a violin plot of mitochondrial length (in pm) in H1975 cells. FIG. 2C shows a violin plot of mitochondrial circularity. FIG.

[0021] 2D shows a violin plot of mitochondrial cristae density per mitochondria. FIG. 2E shows immunoblots of H1975 parental, sgNT, or sgOPAl cancer cell lines. Blots were probed for the indicated antibodies. FIG. 2F shows apoptosis measured by caspase 3 / 7 gio in H1975 sgNT vs. sgOPAl cell lines treated with vehicle, Topi (0.5pM), TROP2 antibody (300pg / mL), TROP2-TopI (300pg / mL) or positive apoptosis control, staurosporine for 72hrs.Attorney Docket No. : UCH-42525

[0022] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0023] FIG. 2G shows immunoblots of lysates of H1975 cells treated with DMSO or lOpM Venetoclax (Ventclx) for 24hrs; lysates were probed with the indicated antibodies. FIG. 2H shows representative confocal microscopy images of H1975 cells treated with DMSO or lOpM Venetoclax (Ventclx) for 24hrs. FIG. 21 shows apoptosis measured by caspase 3 / 7 gio in Hl 975 treated for 72hrs with Veh, Topi, TROP2, TROP2-TopI, Ventclx, or the combination of TROP2-TopI + Ventclx. One-way Anova with Dunnett’s Multiple comparison or Tukey test performed on graphs. N=13-15 mitochondria per group imaged. P-values represented as **** PO.OOOl, ** P<0.01, *P<0.5 as significant and >0.5 not significant (n.s.).

[0024] FIGs. 3A-G show OPA1 expression and mitochondrial structure as biomarkers of ADC response. FIG. 3A shows immunoblots from patient-derived xenografts (PDXs) derived from TROP2-TopI treated patients and classified as Resistant (R) vs. Sensitive (S). Immunoblots probed with the indicated antibodies. Bolded box highlights OPA1 protein expression in sensitive tumors. FIG. 3B shows IF staining of FFPE tumor samples from PDXs 76-S (Sensitive) vs. 38-R (Resistant). Representative images of MTC02 and DAPI staining represented in i) and ii) and mitochondrial network tracing in iii) and iv). FIG. 3C shows quantification of mitochondrial length (pm) of the samples in FIG. 3B. FIG. 3D shows quantification of mitochondrial area (pm2) of the samples in FIG. 3B. FIG. 3E shows analysis of mitochondrial networks from patient 54 repeat biopsies (1BX, 2BX) who exhibited TROP2-TopI sensitivity, followed by resistance. Representative images from IF stained FFPE 1BX and 2BX tumors stained for MTC02 and DAPI in i) and ii) and mitochondrial network tracing shown in iii) and iv). FIG. 3F shows quantification of mitochondrial length (pm) of the samples in FIG. 3E. FIG. 3G shows quantification of mitochondrial area (pm2) of the samples in FIG. 3E. Student t-test performed on graphs. **** indicate a p-value less than 0.0001.

[0025] FIGs. 4A-B show OPA1 knockdown sensitizes Hl 975 mouse lung tumor xenografts to Dato-DXd. FIG. 4A shows the percent change in tumor volume shown from Day 0 (time of treatment) to Day 21 in Hl 975 sgNT control mouse lung tumor xenografts; mice were then injected with either vehicle or a single dose of Dato-DXd (5mg / kg / iv). FIG. 4B shows the percent change in tumor volume shown from Day 0 (time of treatment) to Day 21 in H1975 sgOPAl knockdown mouse lung tumor xenografts; mice were then injected with either vehicle or a single dose of Dato-DXd (5mg / kg / iv). Student t-tests were performed on the graphs.Attorney Docket No. : UCH-42525

[0026] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0027] DETAILED DESCRIPTION

[0028] Provided herein are compositions and methods for treating cancer. Also provided herein are methods for evaluating mitochondrial phenotypes (e.g., OPA1 levels) as a predictive biomarker of response to an anti-cancer agent.

[0029] In some aspects, the present disclosure provides methods of reducing levels of OPA1 in a subject comprising administering an anti-OPAl agent.

[0030] In some embodiments, the methods further comprise treating cancer in the subject by administering an anti-cancer agent.

[0031] In some aspects, the present disclosure provides methods of treating cancer in a subject comprising administering an anti-OPAl agent and an anti-cancer agent.

[0032] In some embodiments, levels of OPA1 in the subject are reduced relative to a reference level.

[0033] In some embodiments, the anti-OPAl agent is a small molecule, a polypeptide (e.g., an OPA1 -specific PROTAC), an inhibitory oligonucleotide, or a gene-editing agent. In some embodiments, the anti-OPAl agent is a BH3 mimetic e.g., venetoclax or navitoclax), preferably wherein the BH3 mimetic is venetoclax. In some embodiments, the anti-OPAl agent is an inhibitory oligonucleotide specific for OPAL In some embodiments, the inhibitory oligonucleotide is selected from siRNA, shRNA, and antisense RNA, or is a polynucleotide that encodes a molecule selected from siRNA, shRNA, and antisense RNA. In some embodiments, the anti-OPAl agent is a gene editing agent that edits a gene encoding OPA1 or reduces the amount or activity of RNA encoding OPAL In some embodiments, the gene editing agent is a CRISPR-Cas system with a sgRNA targeting OPAL In some embodiments, the sgRNA targeting OPA1 is encoded by a nucleic acid that comprises a sequence that has at least about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the sgRNA targeting OPA1 is encoded by a nucleic acid that comprises a sequence of SEQ ID NO: 1. In some embodiments, the sgRNA targeting OPA1 is encoded by a nucleic acid that comprises a sequence of SEQ ID NO: 2.

[0034] In some aspects, the present disclosure provides methods of treating cancer comprising administering an anti-cancer agent to a subject, wherein the subject has reduced levels of OPA1 relative to a reference level.Attorney Docket No. : UCH-42525

[0035] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0036] In some embodiments, the levels of OPA1 are measured in mitochondria. In some embodiments, the levels of OPA1 comprise the levels of the OPA1-L isoform. In some embodiments, the levels of OPA1 comprise the levels of the total OPA1 protein. In some embodiments, the subject has reduced levels of OPA1 in the cancer relative to a reference level. In some embodiments, the levels of OPA1 are measured in a subject sample.

[0037] In some aspects, the present disclosure provides methods of treating cancer comprising administering an anti-cancer agent to a subject, wherein the subject has reduced mitochondrial membrane potential relative to a reference level. In some embodiments, the subject has reduced mitochondrial membrane potential in the cancer relative to a reference level. In some embodiments, the mitochondrial membrane potential is measured in a subject sample.

[0038] In some aspects, the present disclosure provides methods of treating cancer in a subject comprising administering an anti-cancer agent to the subject, wherein the subject has reduced mitochondrial length or mitochondrial area relative to a reference level.

[0039] In some embodiments, the subject has reduced mitochondrial length or mitochondrial area in the cancer relative to a reference level. In some embodiments, the reduced mitochondrial length or mitochondrial area is measured in a subject sample.

[0040] In some aspects, the present disclosure provides methods of treating cancer in a subject comprising administering an anti-cancer agent to the subject, wherein the subject has increased mitochondrial fragmentation, reduced mitochondrial cristae organization, and / or reduced mitochondrial cristae density relative to a reference level.

[0041] In some embodiments, the subject has increased mitochondrial fragmentation, reduced mitochondrial cristae organization, and / or reduced mitochondrial cristae density in the cancer relative to a reference level. In some embodiments, the increased mitochondrial fragmentation, reduced mitochondrial cristae organization, and / or reduced mitochondrial cristae density is measured in a subject sample. In some embodiments, the subject sample comprises at least one of peripheral blood, plasma, serum, or cancer tissue (e.g., a tumor xenograft or a tumor biopsy). In some embodiments, the reference level is a value obtained from a subject or a plurality of subjects that do not have cancer. In some embodiments, the reference level is measured from a reference sample. In some embodiments, the reference sample comprises at least one of peripheral blood, plasma, serum, or cancer tissue (e.g., a tumor xenograft or a tumor biopsy). In some embodiments, the reference sample is of the same or comparable tissue type as the subject sample. In some embodiments, the referenceAttorney Docket No. : UCH-42525

[0042] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0043] sample is a plurality of cells or a tissue that does not exhibit the same phenotype as the subject sample. In some embodiments, the reference sample comprises non-cancerous tissue from the subject. In some embodiments, the reference sample is obtained from a subject or a plurality of subjects that do not have cancer.

[0044] In some embodiments, the anti-cancer agent is a small molecule. In some embodiments, the anti-cancer agent is a topoisomerase inhibitor. In some embodiments, the anti-cancer agent is cisplatin, carboplatin, or DXd. In some embodiments, the anti-cancer agent is an antibody. In some embodiments, the anti-cancer agent is an anti-TROP2 antibody. In some embodiments, the anti-cancer agent is an antibody-drug conjugate. In some embodiments, the anti-cancer agent is a TROP2 antibody conjugated to a topoisomerase inhibitor. In some embodiments, the anti-cancer agent is datopotamab deruxtecan (Dato-DXd).

[0045] In some embodiments, the cancer is a tumor. In some embodiments, the cancer is nonsmall cell lung cancer (NSCLC). In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is breast cancer, urothelial cancer, kidney cancer, head and neck cancer, lung cancer, mesothelioma, ovarian cancer, cervical cancer, gastric cancer, colorectal cancer, pancreatic cancer, testicular cancer, endometrial cancer, esophageal cancer, brain cancer, bone cancer, leukemia, lymphoma, multiple myeloma, testicular cancer, oral cancer, gallbladder cancer, uterine cancer, vaginal cancer, vulvar cancer, cervical cancer, penile cancer, prostate cancer, anal or rectal cancer, endocrine tumors, Hodgkin’s lymphoma, nonHodgkin’s lymphoma, retinoblastoma, or sarcoma.

[0046] Mitochondria regulate cellular processes that include bioenergetics, metabolism and programmed cell death (apoptosis). The mitochondria are dynamic organelles that exist in filamentous tubule networks, capable of remodeling their architecture in response to cellular stresses that include cytotoxic chemotherapy, such as ADCs with cytotoxic payloads (e.g., Topoisomerase I inhibitors). Healthy mitochondria possess inner membranes that fold into highly organized cristae to support bioenergetic function. Specifically, mitochondrial networks undergo fusion of the outer mitochondrial membrane (OMM) and remodel cristae within the inner mitochondrial membrane (IMM) into well-organized folds as they become resistant to cytotoxic chemotherapy. Critical to maintenance of cristae architecture is the mitochondrial fusion protein Optic atrophy gene 1 (OPA1), which exists in two isoforms -long (L) and short (S) form. Specifically, the expression of the OPA1-L and OPAl-S isoforms dictates cristae architecture, such that the expression of OPA1-L supportsAttorney Docket No. : UCH-42525

[0047] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0048] closed / active cristae, while reduced 0PA1-L leads to open / inactive cristae with reduced mitochondrial activity. Importantly, reduced 0PA1-L levels in tumors, and the resultant disorganization of cristae, lead to apoptotic priming resulting in therapeutic sensitivity to cytotoxic therapies, such as ADCs.

[0049] The present disclosure shows that tumors with reduced protein levels of 0PA1 are highly sensitive to cytotoxic chemotherapy, including cytotoxic chemotherapy payloads conjugated to antibody drug conjugates. Further, 0PA1 expression levels in tumors can predict for clinical benefit from cytotoxic chemotherapy, such as cytotoxic chemotherapy payloads conjugated to antibody drug conjugates. Importantly, by using 0PA1 expression levels in tumors to select patients for treatment with cytotoxic chemotherapy, including cytotoxic chemotherapy payloads conjugated to antibody drug conjugates, significant improvement in human health can be achieved by allowing improved precision in patient selection for such therapies. As such, 0PA1 evaluation can be used as a therapeutic biomarker to select cancer patients for cytotoxic chemotherapies, including antibody drug conjugates with cytotoxic chemotherapy payloads, such as topoisomerase I inhibitors. Use of these biomarkers improves precision in patient selection, increasing the likelihood of therapeutic benefit of cytotoxic chemotherapy in the selected patients.

[0050] Provided herein are methods of treating cancer in a subject comprising administering an anti-cancer agent. Also provided herein are methods of treating cancer in a subject comprising administering an anti-OPAl agent and an anti-cancer agent.

[0051] In certain embodiments, the subject has reduced levels of 0PA1 relative to a reference level. In some embodiments, the subject has reduced mitochondrial membrane potential (AT) relative to a reference level. In some embodiments, the subject has reduced mitochondrial length or mitochondrial area relative to a reference level. In some embodiments, the subject has increased mitochondrial fragmentation relative to a reference level. In some embodiments, the subject has reduced mitochondrial cristae organization relative to a reference level. In some embodiments, the subject has reduced mitochondrial cristae density relative to a reference level.

[0052] Further provided herein are methods of reducing levels of 0PA1 in a subject comprising administering an anti-OPAl agent. In some embodiments, the levels of 0PA1 are reduced relative to a reference level. In some embodiments, the subject has cancer and the method further comprises treating cancer in the subject by administering an anti-cancer agent.Attorney Docket No. : UCH-42525

[0053] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0054] In another aspect, provided herein are methods of treating cancer comprising administering an anti-cancer agent to a subject, wherein the subject has reduced levels of OPA1 relative to a reference level. In some embodiments, the levels of OPA1, which resides in the mitochondria are measured in mitochondria. In some embodiments, the levels of OPA1 comprise the levels of the OPA1-L isoform. In some embodiments, the levels of OPA1 comprise the levels of the total OPA1 protein. In some embodiments, the subject has reduced levels of OPA1 in the cancer relative to a reference level. In some embodiments, the levels of OPA1 are measured in a subject sample.

[0055] In another aspect, provided herein are methods of treating cancer comprising administering an anti-cancer agent to a subject, wherein the subject has reduced mitochondrial membrane potential (AT) relative to a reference level. In some embodiments, the subject has reduced mitochondrial membrane potential in the cancer relative to a reference level. In some embodiments, the mitochondrial membrane potential is measured in a subject sample.

[0056] In another aspect, provided herein are methods of treating cancer in a subject comprising administering an anti-cancer agent to the subject, wherein the subject has reduced mitochondrial length or mitochondrial area relative to a reference level. In some embodiments, the subject has reduced mitochondrial length or mitochondrial area in the cancer relative to a reference level. In some embodiments, the reduced mitochondrial length or mitochondrial area is measured in a subject sample.

[0057] In another aspect, provided herein are methods of treating cancer in a subject comprising administering an anti-cancer agent to the subject, wherein the subject has increased mitochondrial fragmentation relative to a reference level. In some embodiments, the subject has increased mitochondrial fragmentation in the cancer relative to a reference level. In some embodiments, the increased mitochondrial fragmentation is measured in a subject sample.

[0058] In another aspect, provided herein are methods of treating cancer in a subject comprising administering an anti-cancer agent to the subject, wherein the subject has reduced mitochondrial cristae density relative to a reference level. In some embodiments, the subject has reduced mitochondrial cristae density in the cancer relative to a reference level. In some embodiments, the increased mitochondrial cristae density is measured in a subject sample.Attorney Docket No. : UCH-42525

[0059] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0060] Sample and Reference Level Measurements

[0061] In some embodiments, the subject sample comprises at least one of peripheral blood, plasma, serum, or cancer tissue (e.g., a tumor xenograft or a tumor biopsy). In some embodiments, the reference level is a value obtained from a subject or a plurality of subjects that do not have cancer. In some embodiments, the reference level is measured from a reference sample. In some embodiments, the reference sample comprises at least one of peripheral blood, plasma, serum, or cancer tissue (e.g., a tumor xenograft or a tumor biopsy). In some embodiments, the reference sample is of the same or comparable tissue type as the subject sample. In some embodiments, the reference sample is a plurality of cells or a tissue that does not exhibit the same phenotype as the subject sample. In some embodiments, the reference sample comprises non-cancerous tissue from the subject. In some embodiments, the reference sample is obtained from a subject or a plurality of subjects that do not have cancer.

[0062] To measure the levels of a protein e.g., OPA1) in a sample (e.g., a subject sample or reference sample), a variety of biochemical and molecular biology techniques can be used. An amount, expression, or activity of a target protein in a sample can be determined by, for instance, densitometry, Western blotting, an enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), immunofluorescence (IF), and / or mass spectrometry (e.g., proteomics). In some embodiments, the levels of a protein can be measured by densitometry. In some embodiments, the levels of a protein can be normalized to levels of a control (e.g., Actin, Vinculin, or TOM20). In some embodiments, the reference level of OPA1 represents a ratio of OPA1-L expression to TOM20 expression. In some embodiments, the ratio of OPA1-L expression to TOM20 expression is between about 0.8 and 1.2 (e.g., about 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.1, 1.15, or 1.2), most preferably 1.

[0063] Mitochondrial membrane potential can be assessed with several techniques. In some embodiments, determining the mitochondrial membrane potential comprises staining a sample (e.g., a sample comprising cells) a fluorescent dye (e.g., tetramethylrhodamine ethyl ester [TMRE], tetramethylrhodamine methyl ester [TMRM], or JC-1 dye), followed by a fluorescence measurement. In some embodiments, the fluorescent dye is TMRE. After staining, fluorescence can be measured, for instance, by flow cytometry, by fluorescence microscopy, or on a fluorescence plate reader, wherein the fluorescence intensity correlates with the mitochondrial membrane potential. In other embodiments, determining the mitochondrial membrane potential comprises exposing a sample (e.g., a sample comprising cells) to a radiotracer (e.g.,18F-BnTP), followed by imaging. In some embodiments, theAttorney Docket No. : UCH-42525

[0064] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0065] imaging is PET / CT imaging. In some embodiments, the mitochondrial membrane potential is determined using the percent injected dose of radiotracer per gram (%ID / g) (i.e., radiotracer uptake), wherein increased radiotracer uptake indicates increased mitochondrial membrane potential. In some embodiments, the percent injected dose of radiotracer per gram is measured in cancerous tissue, optionally where radiotracer uptake is normalized to uptake in noncancerous tissue. In some embodiments, the reference level of percent injected dose of radiotracer per gram is between about 0.4 and 0.8, most preferably wherein the reference level is 0.6.

[0066] Mitochondrial length, mitochondrial area, mitochondrial fragmentation, mitochondrial cristae organization, and / or mitochondrial density can be assessed through imaging (e.g., confocal microscopy). In some embodiments, the imaging comprises 2D Airyscan / STED microscopy and / or 3D SBEM imaging. In some embodiments, determining mitochondrial length, area, or fragmentation comprises fixing, permeabilizing, and / or staining a sample (e.g., a sample comprising cells) before performing imaging. In some embodiments, dyes are used to stain the mitochondria and provide contrast for imaging.

[0067] In some embodiments, the reference level of mitochondrial area is between about 0.75 and about 1.2 pm2. In some embodiments, the reference level of mitochondrial area is about 0.75, about 0.8, about 0.85, about 0.9, about 0.95, about 1.0, about 1.05, about 1.1, about 1.15, or about 1.2 pm2. In some embodiments, the reference level of mitochondrial area is about 1 pm2.

[0068] In some embodiments, the reference level of mitochondrial length is between about 1.25 and about 2.25 pm. In some embodiments, the reference level of mitochondrial length is about 1.25, about 1.3, about 1.35, about 1.4, about 1.45, about 1.5, about 1.55, about 1.6, about 1.65, about 1.7, about 1.75, about 1.8, about 1.85, about 1.9, about 1.95, about 2, about 2.05, about 2.1, about 2.15, about 2.2, or about 2.25 pm. In some embodiments, the reference level of mitochondrial length is about 1.75 pm.

[0069] Cancers

[0070] In some embodiments, the cancer is a tumor (e.g., a solid tumor or liquid tumor). In some embodiments, the cancer is breast cancer, urothelial cancer, kidney cancer, head & neck cancer, lung cancer, mesothelioma, gynecological cancer (e.g., cervical cancer, ovarian cancer, endometrial cancer, uterine cancer, vaginal cancer, vulvar cancer), gastric cancer, colorectal cancer, pancreatic cancer, testicular cancer, esophageal cancer, brain cancer, boneAttorney Docket No. : UCH-42525

[0071] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0072] cancer, leukemia, lymphoma, multiple myeloma, testicular cancer, oral cancer, gallbladder cancer, penile cancer, prostate cancer, anal or rectal cancer, endocrine tumors, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, retinoblastoma, or sarcoma. In some embodiments, the cancer is lung cancer (e.g., NSCLC or SCLC). In some embodiments, the cancer is nonsmall cell lung cancer (NSCLC). In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is HER2 -negative.

[0073] Anti-OPAl Agents

[0074] In some embodiments, the anti-OPAl agent is a small molecule, a polypeptide, an inhibitory oligonucleotide, or a gene-editing agent. In some embodiments, the anti-OPAl agent is a BH3 mimetic (e.g., venetoclax or navitoclax). In some embodiments, the anti-OPAl agent is venetoclax. In some embodiments, the anti-OPAl agent is an alexidine derivative (e.g., alexidine dihydrochloride, alexidine hydrochloride, bisguanides such as chlorhexidine or PHMB, or modified alexidine compounds). In other embodiments, the anti-OPAl agent is an OPA1 -specific proteolysis targeting chimera (PROTAC). In some embodiments, the anti-OPAl agent is an inhibitory oligonucleotide specific for OPAL In some embodiments, the inhibitory oligonucleotide is selected from siRNA, shRNA, and antisense RNA, or a polynucleotide that encodes a molecule selected from siRNA, shRNA, and antisense RNA. In some embodiments, the anti-OPAl agent is a gene editing agent that edits a gene encoding OP Al or reduces the amount or activity of RNA encoding OPAL In some embodiments, the gene editing agent is a CRISPR-Cas system with a sgRNA targeting OPAL In some embodiments, the sgRNA targeting OPA1 is encoded by a nucleic acid that comprises a sequence that has at least about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to SEQ ID NO: 1. In some embodiments, the sgRNA targeting OPA1 is encoded by a nucleic acid that comprises a sequence of SEQ ID NO: 1. In some embodiments, the sgRNA targeting OPA1 is encoded by a nucleic acid that comprises a sequence that has at least about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to SEQ ID NO: 2. In some embodiments, the sgRNA targeting OPA1 is encoded by a nucleic acid that comprises a sequence of SEQ ID NO: 2.Attorney Docket No. : UCH-42525

[0075] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0076] Anti-Cancer Agents

[0077] In some embodiments, the anti-cancer agent is a small molecule. In some embodiments, the anti-cancer agent is a topoisomerase inhibitor. In some embodiments, the anti-cancer agent is cisplatin, carboplatin, or DXd.

[0078] In some embodiments, the anti-cancer agent is an antibody. In some embodiments, the anti-cancer agent is an anti-TROP2 antibody. In some embodiments, the anti-cancer agent comprises a chemotherapeutic agent.

[0079] In some embodiments, the anti-cancer agent comprises antibody-drug conjugates (ADCs). In some embodiments, antibody-drug conjugates comprise an antibody conjugated to a payload molecule. In some embodiments, the payload molecule comprises a chemotherapeutic agent (e.g., a topoisomerase inhibitor). In some embodiments, the anticancer agent is a TROP2 antibody conjugated to a topoisomerase inhibitor. In some embodiments, the anti-cancer agent is datopotamab deruxtecan (Dato-DXd). In some embodiments, the anti-cancer agent is traztuzumab-deruxtecan, datopotamab deruxtecan, patritumab deruxtecan, sacituzumab govitecan, DB1303, DB1305, DB1310, DB1311, ifinatamab deruxtecan, ABBV-400, or MK-2870. In some embodiments, the anti-cancer agent comprises an antibody-drug conjugate selected from gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, moxetumomab pasudotox, polatuzumab vedotin-piiq, enfortumab vedotin, trastuzumab deruxtecan, sacituzumab govitecan, belantamab mafodotin-blmf, loncastuximab tesirine-lpyl, tisotumab vedotin-tftv, mirvetuximab soravtansine, and datopotamab deruxtecan.

[0080] As used herein, the term “chemotherapeutic agent,” consistent with its use in the art, refers to one or more agents known, or having characteristics known to, treat or contribute to the treatment of cancer. In particular, chemotherapeutic agents include pro-apoptotic, cytostatic, and / or cytotoxic agents. In some embodiments, a chemotherapeutic agent can be or include alkylating agents, anthracyclines, cytoskeletal disruptors (e.g. microtubule targeting moieties such as taxanes, maytansine, and analogs thereof, of), epothilones, histone deacetylase inhibitors HDACs), topoisomerase inhibitors e.g., inhibitors of topoisomerase I and / or topoisomerase II), kinase inhibitors, nucleotide analogs or nucleotide precursor analogs, peptide antibiotics, platinum-based agents, retinoids, vinca alkaloids, and / or analogs that share a relevant anti-proliferative activity. In some embodiments, a chemotherapeutic agent can be or include of Actinomycin, All-trans retinoic acid, an Auiristatin, Azacitidine, Azathioprine, Bleomycin, Bortezomib, Carboplatin, Capecitabine, Cisplatin, Chlorambucil,Attorney Docket No. : UCH-42525

[0081] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0082] Cyclophosphamide, Curcumin, Cytarabine, Daunorubicin, Docetaxel, Doxifluridine, Doxorubicin, Epirubicin, Epothilone, Etoposide, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Imatinib, Irinotecan, Maytansine and / or analogs thereof (e.g. DM1), Mechlorethamine, Mercaptopurine, Methotrexate, Mitoxantrone, a Maytansinoid, Oxaliplatin, Paclitaxel, Pemetrexed, Teniposide, Tioguanine, Topotecan, Valrubicin, Vinblastine, Vincristine, Vindesine, Vinorelbine, or a combination thereof. In some embodiments, a chemotherapeutic agent can be utilized in the context of an antibody-drug conjugate. In some embodiments, a chemotherapeutic agent is one found in an antibody-drug conjugate selected from hLLl -doxorubicin, hRS7-SN-38, hMN-14-SN-38, hLL2-SN-38, hA20-SN-38, hPAM4-SN-38, hLLl-SN-38, hRS7-Pro-2-P-Dox, hMN-14-Pro-2-P-Dox, hLL2-Pro-2-P-Dox, hA20-Pro-2-P-Dox, hPAM4-Pro-2-P-Dox, hLLl-Pro-2-P-Dox, P4 / D10-doxorubicin, gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, glembatumomab vedotin, SAR3419, SAR566658, BIIB015, BT062, SGN-75, SGN-CD19A, AMG-172, AMG-595, BAY-94-9343, ASG-5ME, ASG-22ME, ASG-16M8F, MDX-1203, MLN-0264, anti-PSMA ADC, RG-7450, RG-7458, RG-7593, RG-7596, RG-7598, RG-7599, RG-7600, RG-7636, ABT-414, IMGN-853, IMGN-529, vorsetuzumab mafodotin, and lorvotuzumab mertansine. In some embodiments, a chemotherapeutic agent can be or include of farnesyl-thiosalicylic acid (FTS), 4-(4-Chloro-2-methylphenoxy)-N-hydroxybutanamide (CMH), estradiol (E2), tetramethoxystilbene (TMS), 6-tocatrienol, salinomycin, or curcumin.

[0083] Interfering Nucleic Acid Agents

[0084] In certain embodiments, interfering nucleic acid molecules that selectively target OPA1 are used in methods described herein. Interfering nucleic acids generally include a sequence of cyclic subunits, each bearing a base-pairing moiety, linked by intersubunit linkages that allow the base-pairing moieties to hybridize to a target sequence in a nucleic acid (typically an RNA) by Watson-Crick base pairing, to form a nucleic acid: oligomer heteroduplex within the target sequence. Interfering RNA molecules include, but are not limited to, antisense molecules, siRNA molecules, single-stranded siRNA molecules, miRNA molecules and shRNA molecules.

[0085] Typically an interfering nucleic acid molecule comprising at least 17, 18, 19, 20, 21, 22 or 23 nucleotides of the complement of the target mRNA sequence is sufficient to mediate inhibition of a target transcript. Exemplary mRNA target sequences are included in Table 1.Attorney Docket No. : UCH-42525

[0086] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0087] Perfect complementarity is not necessary. In some embodiments, the interfering nucleic acid contains a 1, 2 or 3 nucleotide mismatch with the target sequence. In some embodiments, the interfering nucleic acid molecule is double-stranded RNA. The double-stranded RNA molecule may have a 2 nucleotide 3’ overhang. If the interfering nucleic acid molecule is expressed in a cell from a construct, for example from a hairpin molecule or from an inverted repeat of the desired sequence, then the endogenous cellular machinery will create the overhangs. In some embodiments, the two RNA strands are connected via a hairpin structure, forming a shRNA molecule. shRNA molecules can contain hairpins derived from microRNA molecules. For example, an RNAi vector can be constructed by cloning the interfering RNA sequence into a pCAG-miR30 construct containing the hairpin from the miR30 miRNA. RNA interference molecules may include DNA residues, as well as RNA residues.

[0088] Interfering nucleic acid molecules provided herein can contain RNA bases, non-RNA bases or a mixture of RNA bases and non-RNA bases. For example, interfering nucleic acid molecules provided herein can be primarily composed of RNA bases but can also contain DNA bases or non-naturally occurring nucleotides.

[0089] The interfering nucleic acids can employ a variety of oligonucleotide chemistries. Examples of oligonucleotide chemistries include, without limitation, peptide nucleic acid (PNA), linked nucleic acid (LNA), phosphorothioate, 2’0-Me-modified oligonucleotides, and morpholino chemistries, including combinations of any of the foregoing. In general, PNA and LNA chemistries can utilize shorter targeting sequences because of their relatively high target binding strength relative to 2’0-Me oligonucleotides. Phosphorothioate and 2’0-Me-modified chemistries are often combined to generate 2’0-Me-modified oligonucleotides having a phosphorothioate backbone. See, e.g., PCT Publication Nos. WO / 2013 / 112053 and WO / 2009 / 008725, incorporated by reference in their entireties.

[0090] Peptide nucleic acids (PNAs) are analogs of DNA in which the backbone is structurally homomorphous with a deoxyribose backbone, consisting of N-(2-aminoethyl) glycine units to which pyrimidine or purine bases are attached. PNAs containing natural pyrimidine and purine bases hybridize to complementary oligonucleotides obeying Watson-Crick base-pairing rules, and mimic DNA in terms of base pair recognition (Egholm, Buchardt et al. 1993). The backbone of PNAs is formed by peptide bonds rather than phosphodiester bonds, making them well-suited for antisense applications. The backbone is uncharged, resulting in PNA / DNA or PNA / RNA duplexes that exhibit greater than normal thermal stability. PNAs are not recognized by nucleases or proteases.Attorney Docket No. : UCH-42525

[0091] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0092] Despite a radical structural change to the natural structure, PNAs are capable of sequence-specific binding in a helix form to DNA or RNA. Characteristics of PNAs include a high binding affinity to complementary DNA or RNA, a destabilizing effect caused by single-base mismatch, resistance to nucleases and proteases, hybridization with DNA or RNA independent of salt concentration and triplex formation with homopurine DNA.

[0093] PANAGENE.TM. has developed its proprietary Bts PNA monomers (Bts; benzothiazole-2-sulfonyl group) and proprietary oligomerization process. The PNA oligomerization using Bts PNA monomers is composed of repetitive cycles of deprotection, coupling and capping. PNAs can be produced synthetically using any technique known in the art. See, e.g., U.S. Pat. Nos. 6,969,766, 7,211,668, 7,022,851, 7,125,994, 7,145,006 and 7,179,896. See also U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262 for the preparation of PNAs. Further teaching of PNA compounds can be found in Nielsen et al., Science, 254:1497-1500, 1991. Each of the foregoing is incorporated by reference in its entirety.

[0094] Interfering nucleic acids may also contain “locked nucleic acid” subunits (LNAs). “LNAs” are a member of a class of modifications called bridged nucleic acid (BNA). BNA is characterized by a covalent linkage that locks the conformation of the ribose ring in a C30-endo (northern) sugar pucker. For LNA, the bridge is composed of a methylene between the 2’-0 and the 4’-C positions. LNA enhances backbone preorganization and base stacking to increase hybridization and thermal stability.

[0095] The structures of LNAs can be found, for example, in Wengel, et al., Chemical Communications (1998) 455; Tetrahedron (1998) 54:3607, and Accounts of Chem. Research (1999) 32:301); Obika, et al., Tetrahedron Letters (1997) 38:8735; (1998) 39:5401, and Bioorganic Medicinal Chemistry (2008) 16:9230. Compounds provided herein may incorporate one or more LNAs; in some cases, the compounds may be entirely composed of LNAs. Methods for the synthesis of individual LNA nucleoside subunits and their incorporation into oligonucleotides are described, for example, in U.S. Pat. Nos. 7,572,582, 7,569,575, 7,084,125, 7,060,809, 7,053,207, 7,034,133, 6,794,499, and 6,670,461, each of which is incorporated by reference in its entirety. Typical intersubunit linkers include phosphodiester and phosphorothioate moieties; alternatively, non-phosphorous containing linkers may be employed. One embodiment is an LNA containing compound where each LNA subunit is separated by a DNA subunit. Certain compounds are composed of alternating LNA and DNA subunits where the intersubunit linker is phosphorothioate.Attorney Docket No. : UCH-42525

[0096] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0097] “Phosphorothioates” (or S-oligos) are a variant of normal DNA in which one of the nonbridging oxygens is replaced by a sulfur. The sulfurization of the internucleotide bond reduces the action of endo-and exonucleases including 5’ to 3’ and 3’ to 5’ DNA POL 1 exonuclease, nucleases SI and Pl, RNases, serum nucleases and snake venom phosphodiesterase. Phosphorothioates are made by two principal routes: by the action of a solution of elemental sulfur in carbon disulfide on a hydrogen phosphonate, or by the method of sulfurizing phosphite triesters with either tetraethylthiuram disulfide (TETD) or 3H-1, 2-bensodithiol-3-one 1, 1-dioxide (BDTD) (see, e.g., Iyer et al., J. Org. Chem. 55, 4693-4699, 1990). The latter methods avoid the problem of elemental sulfur’s insolubility in most organic solvents and the toxicity of carbon disulfide. The TETD and BDTD methods also yield higher purity phosphorothioates.

[0098] “2’0-Me oligonucleotides” molecules carry a methyl group at the 2’ -OH residue of the ribose molecule. 2’-O-Me-RNAs show the same (or similar) behavior as DNA, but are protected against nuclease degradation. 2’-O-Me-RNAs can also be combined with phosphothioate oligonucleotides (PTOs) for further stabilization. 2’0-Me oligonucleotides (phosphodiester or phosphothioate) can be synthesized according to routine techniques in the art (see, e.g., Yoo et al., Nucleic Acids Res. 32:2008-16, 2004).

[0099] The interfering nucleic acids described herein may be contacted with a cell or administered to an organism (e.g., a human). Alternatively, constructs and / or vectors encoding the interfering RNA molecules may be contacted with or introduced into a cell or organism. In certain embodiments, a viral, retroviral or lentiviral vector is used. In some embodiments, the vector has a tropism for cardiac tissue. In some embodiments the vector is an adeno-associated virus.

[0100] In some embodiments, the interfering nucleic acid molecule is a siRNA molecule. Such siRNA molecules should include a region of sufficient homology to the target region, and be of sufficient length in terms of nucleotides, such that the siRNA molecule down-regulate target RNA. The term “ribonucleotide” or “nucleotide” can, in the case of a modified RNA or nucleotide surrogate, also refer to a modified nucleotide, or surrogate replacement moiety at one or more positions. It is not necessary that there be perfect complementarity between the siRNA molecule and the target, but the correspondence must be sufficient to enable the siRNA molecule to direct sequence-specific silencing, such as by RNAi cleavage of the target RNA. In some embodiments, the sense strand need only be sufficientlyAttorney Docket No. : UCH-42525

[0101] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0102] complementary with the antisense strand to maintain the overall double-strand character of the molecule.

[0103] In addition, an siRNA molecule may be modified or include nucleoside surrogates. Single stranded regions of an siRNA molecule may be modified or include nucleoside surrogates, e.g., the unpaired region or regions of a hairpin structure, e.g., a region which links two complementary regions, can have modifications or nucleoside surrogates.

[0104] Modification to stabilize one or more 3'- or 5 '-terminus of an siRNA molecule, e.g., against exonucleases, or to favor the antisense siRNA agent to enter into RISC are also useful.

[0105] Modifications can include C3 (or C6, C7, Cl 2) amino linkers, thiol linkers, carboxyl linkers, non-nucleotidic spacers (C3, C6, C9, Cl 2, abasic, tri ethylene glycol, hexaethylene glycol), special biotin or fluorescein reagents that come as phosphoramidites and that have another DMT-protected hydroxyl group, allowing multiple couplings during RNA synthesis.

[0106] Each strand of an siRNA molecule can be equal to or less than 35, 30, 25, 24, 23, 22, 21, or 20 nucleotides in length. In some embodiments, the strand is at least 19 nucleotides in length. For example, each strand can be between 21 and 25 nucleotides in length. In some embodiments, siRNA agents have a duplex region of 17, 18, 19, 29, 21, 22, 23, 24, or 25 nucleotide pairs, and one or more overhangs, such as one or two 3' overhangs, of 2-3 nucleotides.

[0107] A “small hairpin RNA” or “short hairpin RNA” or “shRNA” includes a short RNA sequence that makes a tight hairpin turn that can be used to silence gene expression via RNA interference. The shRNAs provided herein may be chemically synthesized or transcribed from a transcriptional cassette in a DNA plasmid. The shRNA hairpin structure is cleaved by the cellular machinery into siRNA, which is then bound to the RNA-induced silencing complex (RISC).

[0108] In some embodiments, shRNAs are about 15-60, 15-50, or 15-40 (duplex) nucleotides in length, about 15-30, 15-25, or 19-25 (duplex) nucleotides in length, or are about 20-24, 21- 22, or 21-23 (duplex) nucleotides in length (e.g., each complementary sequence of the double-stranded shRNA is 15-60, 15-50, 15-40, 15-30, 15-25, or 19-25 nucleotides in length, or about 20-24, 21-22, or 21-23 nucleotides in length, and the double-stranded shRNA is about 15-60, 15-50, 15-40, 15-30, 15-25, or 19-25 base pairs in length, or about 18-22, 19-20, or 19-21 base pairs in length). shRNA duplexes may comprise 3’ overhangs of about 1 to about 4 nucleotides or about 2 to about 3 nucleotides on the antisense strand and / or 5’-phosphate termini on the sense strand. In some embodiments, the shRNA comprises a senseAttorney Docket No. : UCH-42525

[0109] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0110] strand and / or antisense strand sequence of from about 15 to about 60 nucleotides in length (e.g., about 15-60, 15-55, 15-50, 15-45, 15-40, 15-35, 15-30, or 15-25 nucleotides in length), or from about 19 to about 40 nucleotides in length (e.g., about 19-40, 19-35, 19-30, or 19-25 nucleotides in length), or from about 19 to about 23 nucleotides in length e.g., 19, 20, 21, 22, or 23 nucleotides in length).

[0111] Non-limiting examples of shRNA include a double-stranded polynucleotide molecule assembled from a single-stranded molecule, where the sense and antisense regions are linked by a nucleic acid-based or non-nucleic acid-based linker; and a double-stranded polynucleotide molecule with a hairpin secondary structure having self-complementary sense and antisense regions. In some embodiments, the sense and antisense strands of the shRNA are linked by a loop structure comprising from about 1 to about 25 nucleotides, from about 2 to about 20 nucleotides, from about 4 to about 15 nucleotides, from about 5 to about 12 nucleotides, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more nucleotides.

[0112] Additional embodiments related to the shRNAs, as well as methods of designing and synthesizing such shRNAs, are described in U.S. patent application publication number 2011 / 0071208, the disclosure of which is herein incorporated by reference in its entirety for all purposes.

[0113] In some embodiments, provided herein are micro RNAs (miRNAs). miRNAs represent a large group of small RNAs produced naturally in organisms, some of which regulate the expression of target genes. miRNAs are formed from an approximately 70 nucleotide single-stranded hairpin precursor transcript by Dicer. miRNAs are not translated into proteins, but instead bind to specific messenger RNAs, thereby blocking translation. In some instances, miRNAs base-pair imprecisely with their targets to inhibit translation.

[0114] In some embodiments, antisense oligonucleotide compounds are provided herein. In certain embodiments, the degree of complementarity between the target sequence and antisense targeting sequence is sufficient to form a stable duplex. The region of complementarity of the antisense oligonucleotides with the target RNA sequence may be as short as 8-11 bases, but can be 12-15 bases or more, e.g., 10-40 bases, 12-30 bases, 12-25 bases, 15-25 bases, 12-20 bases, or 15-20 bases, including all integers in between these ranges. An antisense oligonucleotide of about 14-15 bases is generally long enough to have a unique complementary sequence.Attorney Docket No. : UCH-42525

[0115] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0116] In certain embodiments, antisense oligonucleotides may be 100% complementary to the target sequence, or may include mismatches, e.g., to improve selective targeting of allele containing the disease-associated mutation, as long as a heteroduplex formed between the oligonucleotide and target sequence is sufficiently stable to withstand the action of cellular nucleases and other modes of degradation which may occur in vivo. Hence, certain oligonucleotides may have about or at least about 70% sequence complementarity, e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence complementarity, between the oligonucleotide and the target sequence. Oligonucleotide backbones that are less susceptible to cleavage by nucleases are discussed herein.

[0117] Mismatches, if present, are typically less destabilizing toward the end regions of the hybrid duplex than in the middle. The number of mismatches allowed will depend on the length of the oligonucleotide, the percentage of G:C base pairs in the duplex, and the position of the mismatch(es) in the duplex, according to well understood principles of duplex stability.

[0118] Interfering nucleic acid molecules can be prepared, for example, by chemical synthesis, in vitro transcription, or digestion of long dsRNA by Rnase III or Dicer. These can be introduced into cells by transfection, electroporation, or other methods known in the art. See Hannon, GJ, 2002, RNA Interference, Nature 418: 244-251; Bernstein E et al., 2002, The rest is silence. RNA 7: 1509-1521; Hutvagner G et al., RNAi: Nature abhors a double-strand. Curr. Opin. Genetics & Development 12: 225-232; Brummelkamp, 2002, A system for stable expression of short interfering RNAs in mammalian cells. Science 296: 550-553; Lee NS, Dohjima T, Bauer G, Li H, Li M-J, Ehsani A, Salvaterra P, and Rossi J. (2002). Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells. Nature Biotechnol. 20:500-505; Miyagishi M, and Taira K. (2002). U6-promoter-driven siRNAs with four uridine 3' overhangs efficiently suppress targeted gene expression in mammalian cells. Nature Biotechnol. 20:497-500; Paddison PJ, Caudy AA, Bernstein E, Hannon GJ, and Conklin DS. (2002). Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes & Dev. 16:948-958; Paul CP, Good PD, Winer I, and Engelke DR. (2002). Effective expression of small interfering RNA in human cells. Nature Biotechnol. 20:505-508; Sui G, Soohoo C, Affar E-B, Gay F, Shi Y, Forrester WC, and Shi Y. (2002). A DNA vector-based RNAi technology to suppress gene expression in mammalian cells. Proc. Natl. Acad. Sci. USA 99(6):5515-5520; Yu J-Y, DeRuiter SL, and Turner DL. (2002). RNAAttorney Docket No. : UCH-42525

[0119] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0120] interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells. Proc. Natl. Acad. Sci. USA 99(9):6047-6052.

[0121] In the present methods, an interfering nucleic acid molecule or an interfering nucleic acid encoding polynucleotide can be administered to the subject, for example, as naked nucleic acid, in combination with a delivery reagent, and / or as a nucleic acid comprising sequences that express an interfering nucleic acid molecule. In some embodiments the nucleic acid comprising sequences that express the interfering nucleic acid molecules are delivered within vectors, e.g. plasmid, viral and bacterial vectors. Any nucleic acid delivery method known in the art can be used in the methods described herein. Suitable delivery reagents include, but are not limited to, e.g., the Minis Transit TKO lipophilic reagent; lipofectin; lipofectamine; cellfectin; polycations (e.g., polylysine), atelocollagen, nanoplexes and liposomes. The use of atelocollagen as a delivery vehicle for nucleic acid molecules is described in Minakuchi et al. Nucleic Acids Res., 32(13):el09 (2004); Hanai et al. Ann NY Acad Sci., 1082:9-17 (2006); and Kawata et al. Mol Cancer Then, 7(9):2904-12 (2008); each of which is incorporated herein in their entirety. Exemplary interfering nucleic acid delivery systems are provided in U.S. Patent Nos. 8,283,461, 8,313,772, 8,501,930. 8,426,554, 8,268,798 and 8,324,366, each of which is hereby incorporated by reference in its entirety.

[0122] In some embodiments of the methods described herein, liposomes are used to deliver an inhibitory oligonucleotide to a subject. Liposomes suitable for use in the methods described herein can be formed from standard vesicle-forming lipids, which generally include neutral or negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally guided by consideration of factors such as the desired liposome size and half-life of the liposomes in the blood stream. A variety of methods are known for preparing liposomes, for example, as described in Szoka etal. (1980), Ann. Rev. Biophys. Bioeng. 9:467; and U.S. Pat. Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369, the entire disclosures of which are herein incorporated by reference.

[0123] The liposomes for use in the present methods can also be modified so as to avoid clearance by the mononuclear macrophage system ("MMS") and reticuloendothelial system ("RES"). Such modified liposomes have opsonization-inhibition moieties on the surface or incorporated into the liposome structure.

[0124] Opsonization-inhibiting moieties for use in preparing the liposomes described herein are typically large hydrophilic polymers that are bound to the liposome membrane. As used herein, an opsonization inhibiting moiety is “bound” to a liposome membrane when it isAttorney Docket No. : UCH-42525

[0125] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0126] chemically or physically attached to the membrane, e.g., by the intercalation of a lipid-soluble anchor into the membrane itself, or by binding directly to active groups of membrane lipids. These opsonization-inhibiting hydrophilic polymers form a protective surface layer that significantly decreases the uptake of the liposomes by the MMS and RES; e.g., as described in U.S. Pat. No. 4,920,016, the entire disclosure of which is herein incorporated by reference.

[0127] In some embodiments, opsonization inhibiting moieties suitable for modifying liposomes are water-soluble polymers with a number-average molecular weight from about 500 to about 40,000 daltons, or from about 2,000 to about 20,000 daltons. Such polymers include polyethylene glycol (PEG) or polypropylene glycol (PPG) derivatives; e.g., methoxy PEG or PPG, and PEG or PPG stearate; synthetic polymers such as polyacrylamide or poly N-vinyl pyrrolidone; linear, branched, or dendrimeric polyamidoamines; polyacrylic acids; polyalcohols, e.g., polyvinylalcohol and polyxylitol to which carboxylic or amino groups are chemically linked, as well as gangliosides, such as ganglioside GM1. Copolymers of PEG, methoxy PEG, or methoxy PPG, or derivatives thereof, are also suitable. In addition, the opsonization inhibiting polymer can be a block copolymer of PEG and either a polyamino acid, polysaccharide, polyamidoamine, polyethyleneamine, or polynucleotide. The opsonization inhibiting polymers can also be natural polysaccharides containing amino acids or carboxylic acids, e.g., galacturonic acid, glucuronic acid, mannuronic acid, hyaluronic acid, pectic acid, neuraminic acid, alginic acid, carrageenan; aminated polysaccharides or oligosaccharides (linear or branched); or carboxylated polysaccharides or oligosaccharides, e.g., reacted with derivatives of carbonic acids with resultant linking of carboxylic groups. In some embodiments, the opsonization-inhibiting moiety is a PEG, PPG, or derivatives thereof. Liposomes modified with PEG or PEG-derivatives are sometimes called “PEGylated liposomes.”

[0128] Polynucleotide / Nucleic Acid Molecules

[0129] Also provided herein are nucleic acid or polynucleotide molecules that encode the antibodies, antigen binding fragments thereof and / or polypeptides described herein. The nucleic acids may be present, for example, in whole cells, in a cell lysate, or in a partially purified or substantially pure form.

[0130] Nucleic acids described herein can be obtained using standard molecular biology techniques. For example, nucleic acid molecules described herein can be cloned usingAttorney Docket No. : UCH-42525

[0131] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0132] standard PCR techniques or chemically synthesized. For antibodies obtained from an immunoglobulin gene library (e.g., using phage or yeast display techniques), nucleic acid encoding the antibody or peptide can be recovered from the library.

[0133] Nucleic acids encoding any of the proteins described herein (e.g., OPA1) are also provided herein. Such a nucleic acid may further be linked to a promoter and / or other regulatory sequences, as further described herein. Exemplary nucleic acids are those that are at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% or 100% identical to a nucleotide sequence wildtype sequence of P-catenin, such as nucleic acid sequence encoding the protein fragments described herein. Nucleic acids may also hybridize specifically, e.g., under stringent hybridization conditions, to a nucleic acid described herein or a fragment thereof. Table 1 comprises exemplary OPA1 mRNA transcripts.

[0134] Nucleic acids, e.g., those encoding a protein described above, a functional homolog thereof, or a nucleic acid intended to inhibit the production of a protein of interest e.g., siRNA, shRNA or antisense RNA, described in greater detail in this application) can be delivered to cells in culture, ex vivo, and in vivo. The delivery of nucleic acids can be by any technique known in the art including viral mediated gene transfer, liposome mediated gene transfer, direct injection into a target tissue, organ, or tumor, injection into vasculature which supplies a target tissue or organ. Exemplary mRNAs for OPA1 can be found in Table 1.

[0135] Polynucleotides can be administered in any suitable formulations known in the art. These can be as virus particles, as naked DNA, in liposomes, in complexes with polymeric carriers, etc. Polynucleotides can be administered to the arteries which feed a tissue or tumor.

[0136] Nucleic acids can be delivered in any desired vector. These include viral or non-viral vectors, including adenovirus vectors, adeno-associated virus vectors, retrovirus vectors, lentivirus vectors, and plasmid vectors. Exemplary types of viruses include HSV (herpes simplex virus), AAV (adeno associated virus), HIV (human immunodeficiency virus), BIV (bovine immunodeficiency virus), and MLV (murine leukemia virus). Nucleic acids can be administered in any desired format that provides sufficiently efficient delivery levels, including in virus particles, in liposomes, in nanoparticles, and complexed to polymers.

[0137] A polynucleotide of interest can also be combined with a condensing agent to form a gene delivery vehicle. The condensing agent may be a polycation, such as polylysine, polyarginine, polyomithine, protamine, spermine, spermidine, and putrescine. Many suitable methods for making such linkages are known in the art.Attorney Docket No. : UCH-42525

[0138] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0139] In an alternative embodiment, a polynucleotide of interest is associated with a liposome to form a gene delivery vehicle. Liposomes are small, lipid vesicles comprised of an aqueous compartment enclosed by a lipid bilayer, typically spherical or slightly elongated structures several hundred Angstroms in diameter. Under appropriate conditions, a liposome can fuse with the plasma membrane of a cell or with the membrane of an endocytic vesicle within a cell which has internalized the liposome, thereby releasing its contents into the cytoplasm. Prior to interaction with the surface of a cell, however, the liposome membrane acts as a relatively impermeable barrier which sequesters and protects its contents, for example, from degradative enzymes. Additionally, because a liposome is a synthetic structure, specially designed liposomes can be produced which incorporate desirable features. See Stryer, Biochemistry, pp. 236-240, 1975 (W.H. Freeman, San Francisco, CA); Szoka et al., Biochim. Biophys. Acta 600:1, 1980; Bayer et al., Biochim. Biophys. Acta. 550:464, 1979; Rivnay et al., Meth. Enzymol. 149:119, 1987; Wang et al., PROC. NATL. ACAD. SCI. U.S.A. 84: 7851, 1987, Plant et al., Anal. Biochem. 176:420, 1989, and U.S. Patent 4,762,915. Liposomes can encapsulate a variety of nucleic acid molecules including DNA, RNA, plasmids, and expression constructs comprising growth factor polynucleotides such those described herein.

[0140] Liposomal preparations for use in the methods described herein include cationic (positively charged), anionic (negatively charged) and neutral preparations. Cationic liposomes have been shown to mediate intracellular delivery of plasmid DNA (Feigner et al., Proc. Natl. Acad. Sci. USA 84:7413-7416, 1987), mRNA (Malone et al., Proc. Natl. Acad. Sci. USA 86:6077-6081, 1989), and purified transcription factors (Debs et al., J. Biol. Chem.

[0141] 265:10189-10192, 1990), in functional form. Cationic liposomes are readily available. For example, N[l-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA) liposomes are available under the trademark Lipofectin, from GIBCO BRL, Grand Island, NY. See also Feigner et al., Proc. Natl. Acad. Sci. USA 91: 5148-5152.87, 1994. Other commercially available liposomes include Transfectace (DDAB / DOPE) and DOTAP / DOPE (Boerhinger). Other cationic liposomes can be prepared from readily available materials using techniques well known in the art. See, e.g., Szoka et al., Proc. Natl. Acad. Sci. USA 75:4194-4198, 1978; and WO 90 / 11092 for descriptions of the synthesis of DOTAP (l,2-bis(oleoyloxy)-3-(trimethylammonio)propane) liposomes.

[0142] Similarly, anionic and neutral liposomes are readily available, such as from Avanti Polar Lipids (Birmingham, AL), or can be easily prepared using readily available materials.Attorney Docket No. : UCH-42525

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[0144] Such materials include phosphatidyl choline, cholesterol, phosphatidyl ethanolamine, dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol (DOPG), dioleoylphoshatidyl ethanolamine (DOPE), among others. These materials can also be mixed with the DOTMA and DOTAP starting materials in appropriate ratios. Methods for making liposomes using these materials are well known in the art.

[0145] CRISPR / Gene Editing

[0146] Certain embodiments disclosed herein relate to agents and methods for treating or preventing a condition (e.g., any condition, disease, disorder, or indication disclosed herein) in a subject comprising administering an agent (e.g., a gene editing agent) that edits a gene encoding OPAL Certain embodiments disclosed herein relate to agents and methods for treating or preventing a condition (e.g., any condition, disease, disorder, or indication disclosed herein) in a subject comprising administering an agent (e.g., a gene editing agent) that knocks down mRNA encoding OPAL

[0147] In some embodiments, the agent disclosed herein is an agent for genome editing (e.g., an agent used to delete at least a portion of a gene that encodes OPA1). Deletion of DNA may be performed using gene therapy to knock-out or disrupt the target gene. As used herein, a “knock-out” can be a gene knock-down or the gene can be knocked out by a mutation such as, a point mutation, an insertion, a deletion, a frameshift, or a missense mutation by techniques known in the art, including, but not limited to, retroviral gene transfer. In some embodiments, the agent is a nuclease (e.g., a zinc finger nuclease or a TALEN). Zinc-finger nucleases (ZFNs) are artificial restriction enzymes generated by fusing a zinc finger DNA-binding domain to a DNA-cleavage domain. Zinc finger domains can be engineered to target desired DNA sequences, which enable zinc-finger nucleases to target unique sequence within a complex genome. By taking advantage of endogenous DNA repair machinery, these reagents can be used to precisely alter the genomes of higher organisms. Other technologies for genome customization that can be used to knock out genes are meganucleases and TAL effector nucleases (TALENs). A TALEN is composed of a TALE DNA binding domain for sequence-specific recognition fused to the catalytic domain of an endonuclease that introduces double-strand breaks (DSB). The DNA binding domain of a TALEN is capable of targeting with high precision a large recognition site (for instance, 17 bp). Meganucleases are sequence-specific endonucleases, naturally occurring “DNA scissors,” originating from a variety of single-celled organisms such as bacteria, yeast, algae and some plant organelles.Attorney Docket No. : UCH-42525

[0148] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0149] Meganucleases have long recognition sites of between 12 and 30 base pairs. The recognition site of natural meganucleases can be modified in order to target native genomic DNA sequences (such as endogenous genes).

[0150] In another embodiment, the agent comprises a CRISPR-Cas9 guided nuclease and / or a sgRNA (Wiedenheft et al., “RNA-Guided Genetic Silencing Systems in Bacteria and Archaea,” Nature 482:331-338 (2012); Zhang et al., “Multiplex Genome Engineering Using CRISPR / Cas Systems,” Science 339(6121): 819-23 (2013); and Gaj et al., “ZFN, TALEN, and CRISPR / Cas-based Methods for Genome Engineering,” Cell 31(7):397-405 (2013), which are hereby incorporated by reference in their entirety). Like the TALENs and ZFNs, CRISPR-Cas9 interference is a genetic technique which allows for sequence-specific control of gene expression in prokaryotic and eukaryotic cells by guided nuclease doublestranded DNA cleavage. It is based on the bacterial immune system - derived CRISPR (clustered regularly interspaced palindromic repeats) pathway. In some embodiments, the agent is an sgRNA. An sgRNA combines tracrRNA and crRNA, which are separate molecules in the native CRISPR / Cas9 system, into a single RNA construct, simplifying the components needed to use CRISPR / Cas9 for genome editing. In some embodiments, the crRNA of the sgRNA has complementarity to at least a portion of a gene that encodes OPA1 (or a fragment thereof). In some embodiments, the sgRNA may target at least a portion of a gene that encodes a OPA1 protein (such as the sequences of Table 1).

[0151] Pharmaceutical Compositions

[0152] In certain embodiments, provided herein is a composition, e.g., a pharmaceutical composition, containing at least one agent described herein together with a pharmaceutically acceptable carrier. In one embodiment, the composition includes a combination of multiple (e.g., two or more) agents described herein.

[0153] As described in detail below, the pharmaceutical compositions disclosed herein may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; or (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous, intrathecal, intracerebral or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation.Attorney Docket No. : UCH-42525

[0154] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0155] Methods of preparing these formulations or compositions include the step of bringing into association an agent described herein with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association an agent described herein with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0156] Pharmaceutical compositions suitable for parenteral administration comprise one or more agents described herein in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0157] Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions include water, ethanol, dimethyl sulfoxide (DMSO), polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0158] Regardless of the route of administration selected, the agents provided herein, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions disclosed herein, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.

[0159] Definitions

[0160] As used herein, "anti-Ofi Al agent” describes an agent that reduces or decreases expression of OPA1, reduces or decreases levels of OPA1, and / or inhibits the activity of OPAL The anti-OPAl agent may act on any isoform of OPA1 (e.g., the L isoform of OPA1). The anti-OPAl agent may target DNA encoding OPA1, mRNA encoding OPA1 (such as the sequences in Table 1, or sequences that encode the polypeptides in Table 2), or OPA1 proteins (such as the sequences in Table 2).

[0161] As used herein in the specification, "a" or "an" may mean one or more. As used herein in the claim(s), when used in conjunction with the word "comprising", the words "a"Attorney Docket No. : UCH-42525

[0162] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0163] or "an" may mean one or more than one. As used herein “another” may mean at least a second or more.

[0164] As used herein, the term “about” is defined as being close to as understood by one of ordinary skill in the art. In one non-limiting embodiment, the term “about” is defined to be within 10%, preferably within 5%, more preferably within 1%, and most preferably within 0.5%.

[0165] As used herein, the term “ administering" means providing a pharmaceutical agent or composition to a subject, and includes, but is not limited to, administering by a medical professional and self-administering.

[0166] As used herein, "expression" refers individually and / or cumulatively to one or more biological process that result in production from a nucleic acid sequence of an encoded agent, such as a polypeptide. Expression specifically includes either or both of transcription and translation. In some embodiments, expression of a molecule (e.g., polypeptide) can be used to determine the level of the molecule.

[0167] As used herein with respect to a molecule such as a nucleic acid or polypeptide, “ / eve / ” is used to refer to a measure indicative of an amount, concentration, ratio, or activity of the molecule, e.g., in a particular context such as a tissue, sample, organism, or a context representative thereof. An amount can be, for example, a mass or number of molecules. A concentration can be an amount relative to a context value, e.g, per a unit of mass or volume. A ratio can be a relationship between two values, such as an experimental value and a reference control value. Activity can be a measure of a function associated with a molecule, and can in various instances be measured relative to a context value, e.g, per a unit of mass or volume. Those of skill in the art will appreciate that the metric by which a level is expressed can vary depending, e.g., on the assay and purpose. Those of skill in the art will further appreciate that metrics such as amount, concentration, ratio, and activity are often interrelated and / or qualitatively or quantitatively informative of each other.

[0168] The phrase “ pharmaceutically acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethylAttorney Docket No. : UCH-42525

[0169] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0170] cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0171] The term “preventing is art-recognized, and when used in relation to a condition, such as a local recurrence, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. A therapeutic that prevents a disorder or condition refers to a bacterium or composition that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0172] The term “prophylactic” or “therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic ( / .< ., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic (z.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0173] The term “subject” refers to a mammal, including, but not limited to, a human or nonhuman mammal, such as a bovine, equine, canine, ovine, or feline. In some embodiments, the subject is a human.

[0174] A “therapeutically effective amount” of a compound with respect to the subject method of treatment refers to an amount of the compound(s) in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment.Attorney Docket No. : UCH-42525

[0175] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0176] As used herein, the term “treating’ or “treatment’ includes reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in a manner to improve or stabilize a subject's condition. The term “treating” includes prophylactic and / or therapeutic treatments. The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the subject of one or more of the disclosed compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the subject) then the treatment is prophylactic (z.e., it protects the subject against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic (z.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0177] As used herein, the terms “modulate” or “modulation ” or “regulate” or “regulation” and “differentially regulated’ can refer to both up regulation ( / .< ., activation or stimulation, e.g., by agonizing or potentiating) and down regulation (z.e., inhibition or suppression, e.g., by antagonizing, decreasing or inhibiting), unless otherwise specified or clear from the context of a specific usage.

[0178] As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the subject, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. In certain embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. Thus, a subject who receives such treatment can benefit from a combined effect of different therapeutic compounds.

[0179] As used herein, the term “combination therapy” refers to administration to a subject of to two or more agents or regimens such that the two or more agents or regimens together treat a disease, condition, or disorder of the subject. In some embodiments, the two or more therapeutic agents or regimens can be administered simultaneously, sequentially, or in overlapping dosing regimens. Those of skill in the art will appreciate that combination therapy includes but does not require that the two agents or regimens be administered together in a single composition, nor at the same time.Attorney Docket No. : UCH-42525

[0180] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0181] As used herein, the term “antibody” refers to a polypeptide that includes one or more immunoglobulin sequence elements sufficient to confer specific binding to a particular antigen (e.g., a heavy chain variable domain, a light chain variable domain, and / or one or more CDRs). Thus, the term antibody includes, without limitation, human antibodies, nonhuman antibodies, synthetic and / or engineered antibodies, fragments thereof, and agents including the same. Antibodies can be naturally occurring immunoglobulins (e.g., generated by an organism reacting to an antigen). Synthetic, non-naturally occurring, or engineered antibodies can be produced by recombinant engineering, chemical synthesis, or other artificial systems or methodologies known to those of skill in the art.

[0182] As used herein, the term “cancer” refers to a disease, disorder, or condition in which cells exhibit relatively abnormal, uncontrolled, and / or autonomous growth, so that they display an abnormally elevated proliferation rate and / or aberrant growth phenotype characterized by a significant loss of control of cell proliferation. In some embodiments, a cancer can include one or more tumors. In some embodiments, a cancer can be or include cells that are precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and / or non-metastatic. In some embodiments, a cancer can be or include a solid tumor. In some embodiments, a cancer can be or include a hematologic tumor.

[0183] As used herein, the term “sequence identity” with respect to a nucleic acid sequence are defined as the percentage of nucleic acid residues in a candidate sequence that are identical with the nucleic acid residues in the specific nucleic acid sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN™ (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.Attorney Docket No. : UCH-42525

[0184] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0185] SQOE ID N 24:

[0186] f if if I 0102soormsoormsoorm

[0187] Table 1: Exemplary mRNAs OPA1 transcripts

[0188] Lhteng

[0189] Sequence

[0190] ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA AATTAGAAAAGCCCTTCCTAGTTCAGAAGACCTTGTAAAGTTAGCACCAGACTTTGACAAGATTGTTGAAAGCCTTAGCTTATTGAAGGA CTTTTTTACCTCAGGTTCTCCGGAAGAAACGGCGTTTAGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGTGTCAGA CAAAGAGAAAATTGACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACA AAGAATTGAGAAAATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAA GTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAA AGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTC TGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGAC ATGAAATAGAACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGA CTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGT ATCAGCAAAGCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGAC TTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAG CAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGA AAGCATTGAAGCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGA CTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAA CACGTTTTAACCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATG AAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAA CTCATGTGATTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGT GGACTGATAAACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAA GGGAAAGAGCATGATGACATATTTGATAAACTTAAAGAGGCTGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGA GGACAGCTTGAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGA AGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGA AGAATCGGACCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTAT CTTGCAAGTGATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCA TCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTA GATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTA CAAATACTGAAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTT ACTGGTAAACGCGTTCAACTGGCGGAAGACCTCAAGAAAGTTAGAGAAATTCAAGAAAAACTTGATGCTTTCATTGAAGCTCTTCATCAG GAGAAATAA ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGGTTC TCCGGAAGAAACGGCGTTTAGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGTGTCAGACAAAGAGAAAATTGACC AACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAAATTA GTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTCTCTG ATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTGGAAA TGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCTCACC ATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTTCGAA TGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGTGCTT GTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTACATG CAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAATGGAC CCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGATAAT TGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTATAAG AGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTAAGCC TTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTTGAAA CTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGAAGTT ATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGAAAAC ATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACAACTT CCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATGATGA CATATTTGATAAACTTAAAGAGGCTGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGGGTTA TTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAGGCTC GTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCAAGA ACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATGAAA TAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGAAGA CATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGGAAT GCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAAATACTGAAGTTA GGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGCGTT

[0191]

[0192] CAACTGGCGGAAGACCTCAAGAAAGTTAGAGAAATTCAAGAAAAACTTGATGCTTTCATTGAAGCTCTTCATCAGGAGAAATAAAttorney Docket No. : UCH-42525

[0193] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0194] 25 26

[0195] if if 0304soormsoorm ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA 2829 2886 CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGGTCA CAAATTGGTTAGTGAAGTCATAGGAGCTTCTGACCTACTTCTCTTGTTAGGTTCTCCGGAAGAAACGGCGTTTAGAGCAACAGATCGTGG ATCTGAAAGTGACAAGCATTTTAGAAAGGTGTCAGACAAAGAGAAAATTGACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGT ATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAAATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAG AAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTG CCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCT GGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTT GATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAG CCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATC AGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGA TGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAA AGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTT ATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAG CTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACG AGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGA ACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGG AGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAG GAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACC CTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATGATGACATATTTGATAAACTTAAAGAGGCTGTTAAGGA AGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATAT CTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACA TGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTG GAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGG AGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCT TTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGC ATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAAATACTGAAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGA AGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGCGTTCAACTGGCGGAAGACCTCAAGAAAGTTAGAGAAA TTCAAGAAAAACTTGATGCTTTCATTGAAGCTCTTCATCAGGAGAAATAA ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGGTTC TCCGGAAGAAACGGCGTTTAGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGGTCTGCTTGGTGAGCTCATTCTCTT ACAACAACAAATTCAAGAGCATGAAGAGGAAGCGCGCAGAGCCGCTGGCCAATATAGCACGAGCTATGCCCAACAGAAGCGCAAGGTG TCAGACAAAGAGAAAATTGACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGA GAACAAAGAATTGAGAAAATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATT CTGAAGTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGC TGGAAAGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGT GACTCTGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATT AAGACATGAAATAGAACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCC CTGGACTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTT TCAGTATCAGCAAAGCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTA CAGACTTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGT CCAAGCAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAG CTCTGAAAGCATTGAAGCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACC AAGTGACTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCA AAGCAACACGTTTTAACCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCT AAAAATGAAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAG AGTATCAACTCATGTGATTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCT TAAACAGTGGACTGATAAACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGA ACCGAAAGGGAAAGAGCATGATGACATATTTGATAAACTTAAAGAGGCTGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGAC TTTGCGGAGGACAGCTTGAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTAT TTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTT ATACTGGAAGAATCGGACCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCAC CCAGCTTATCTTGCAAGTGATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGA TACTTGGCATCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGG CATTTTGTAGATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGC AACAACTTACAAATACTGAAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATT AAATTGCTTACTGGTAAACGCGTTCAACTGGCGGAAGACCTCAAGAAAGTTAGAGAAATTCAAGAAAAACTTGATGCTTTCATTGAAGCT

[0196]

[0197] CTTCATCAGGAGAAATAAAttorney Docket No. : UCH-42525

[0198] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0199] 27 28

[0200] if if 0506soormsoorm ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA 2940 CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA ACTATTTTTATGTAAACACATGCACGCCGTTTCCACCTAAAGATTTTCGAGGTATAAGGATCGCATATGGTTCAAATAAGGTGTAAGGCCTATCCCTAGGAACCCTTTATCGTATCCATCATGTAGTTTTGATGTGGTATACATGCCCCGTGTAAAGGCATATAATCTGGGACAGGTGTTA AGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGTGTCAGACAAAGAGAAAATTGACCAACTTCAGGAAGAACTTCT GCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAAATTAGTATTGCAGAAAGATGAC AAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATA ATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAA TATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAG ATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTTCGAATGAGGAAAAATGTGAAA GAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTG ATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTACATGCAGAATCCTAATGCCATC ATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACC ATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCC AATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTATAAGAGAATATGAAGAAGAGT TTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCT TTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTTGAAACTGAATGGAAGAATAACT ATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTA CACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGAAAACATCTACCTTCCAGCTGCGC AGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACAACTTCCTAATAAAGCAGTAGAG GTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATGATGACATATTTGATAAACTTAA AGAGGCTGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGGGTTATTCAACACAATGCTTTGG AAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAA ATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCAAGAACAGTGTGTTCACAATGAA ACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATGAAATAACCACAGTCCGGAAGAA CCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCT AAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTT TGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAAATACTGAAGTTAGGCGATTAGAGAAAAATGTT AAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGCGTTCAACTGGCGGAAGACCTCAA GAAAGTTAGAGAAATTCAAGAAAAACTTGATGCTTTCATTGAAGCTCTTCATCAGGAGAAATAA ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGGTCA CAAATTGGTTAGTGAAGTCATAGGAGCTTCTGACCTACTTCTCTTGTTAGGTTCTCCGGAAGAAACGGCGTTTAGAGCAACAGATCGTGG ATCTGAAAGTGACAAGCATTTTAGAAAGGGTCTGCTTGGTGAGCTCATTCTCTTACAACAACAAATTCAAGAGCATGAAGAGGAAGCGC GCAGAGCCGCTGGCCAATATAGCACGAGCTATGCCCAACAGAAGCGCAAGGTGTCAGACAAAGAGAAAATTGACCAACTTCAGGAAGA ACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAAATTAGTATTGCAGAAAG ATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTCTCTGATTATGATGCCAG TTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTGGAAATGATTGCCCAAGC TCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCTCACCATGTGGCCCTATT TAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTTCGAATGAGGAAAAATG TGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGTGCTTGTTGACTTACCAG GTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTACATGCAGAATCCTAATG CCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAATGGACCCTCATGGAAGGA GAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGATAATTGAAGGAAAGCTC TTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTATAAGAGAATATGAAGA AGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTAAGCCTTGCAGTATCAG ACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTTGAAACTGAATGGAAGA ATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGAAGTTATCAGTCTGAGCC AGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGAAAACATCTACCTTCCAG CTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACAACTTCCTAATAAAGCA GTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATGATGACATATTTGATAA ACTTAAAGAGGCTGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGGGTTATTCAACACAATG CTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGGATA CTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCAAGAACAGTGTGTTCAC AATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATGAAATAACCACAGTCCG GAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGAAGACATTTTTTAAAAAC AGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGGAATGCAATGATGTGGTC TTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAAATACTGAAGTTAGGCGATTAGAGAAA AATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGCGTTCAACTGGCGGAAGA

[0201]

[0202] CCTCAAGAAAGTTAGAGAAATTCAAGAAAAACTTGATGCTTTCATTGAAGCTCTTCATCAGGAGAAATAAAttorney Docket No. : UCH-42525

[0203] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0204] 29

[0205] if if 0708soormsoorm ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA 2994 3048 CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA ACTATTTTTATGTAAACACATGCACGCCGTTTTCCCTTCACGGTGTACAAGGAAAAAGCAGCGCCTGTTGTTTAAAGAAGGTCTAAAGCCAAGCACTACGGATCGTGTATGTCATCGAAAAGAAGTTTGGATTCGAAAAGACAGCTTCTTTTAAGGACATTAAGTGTGGTACATGGGCATTGGTGAGCTCATTCTCTTACAACAACAAATTCAAGAGCATGAAGAGGAAGCGCGCAGAGCCGCTGGCCAATATAGCACGAGCTATGCCC AACAGAAGCGCAAGGTGTCAGACAAAGAGAAAATTGACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTG GAACGATTAGAAAAGGAGAACAAAGAATTGAGAAAATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAAT CTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTG GTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGAC ACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGA AGAAGATCTTGCAGCATTAAGACATGAAATAGAACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATAT CCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTG ACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATG CTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAG AGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAA CAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGC ATGCTAAAGGCACACCAAGTGACTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACA ACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGA ACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAAC AATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCA CAGTGGATATCAAGCTTAAACAGTGGACTGATAAACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTT TCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATGATGACATATTTGATAAACTTAAAGAGGCTGTTAAGGAAGAAAGTATTAAACG ACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAAT GGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACT GGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAA ATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATC CAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTT TTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACC GCAAATACTTTAAGGCAACAACTTACAAATACTGAAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGA TGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGCGTTCAACTGGCGGAAGACCTCAAGAAAGTTAGAGAAATTCAAGAAAAACTTG ATGCTTTCATTGAAGCTCTTCATCAGGAGAAATAA ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA AATTAGAAAAGCCCTTCCTAGTTCAGAAGACCTTGTAAAGTTAGCACCAGACTTTGACAAGATTGTTGAAAGCCTTAGCTTATTGAAGGA CTTTTTTACCTCAGGTCACAAATTGGTTAGTGAAGTCATAGGAGCTTCTGACCTACTTCTCTTGTTAGGTTCTCCGGAAGAAACGGCGTTT AGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGGTCTGCTTGGTGAGCTCATTCTCTTACAACAACAAATTCAAGA GCATGAAGAGGAAGCGCGCAGAGCCGCTGGCCAATATAGCACGAGCTATGCCCAACAGAAGCGCAAGGTGTCAGACAAAGAGAAAATT GACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAA ATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTC TCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTG GAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCT CACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTT CGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGT GCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTA

[0206] o CATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAAT GGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGA TAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTA TAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTA AGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTT GAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGA AGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGA AAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACA ACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATG ATGACATATTTGATAAACTTAAAGAGGCTGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGG GTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAG GCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCA AGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATG AAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGA AGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGG AATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAAATACTGAAG TTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGC

[0207]

[0208] GTTCAACTGGCGGAAGACCTCAAGAAAGTTAGAGAAATTCAAGAAAAACTTGATGCTTTCATTGAAGCTCTTCATCAGGAGAAATAAAttorney Docket No. : UCH-42525

[0209] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0210] f if I 0910soormsoorm ATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGGTTCTCCGGAAGAA 2514 2511 ACGGCGTTTAGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGGTCTGCTTGGTGAGCTCATTCTCTTACAACAACAA ATTCAAGAGCATGAAGAGGAAGCGCGCAGAGCCGCTGGCCAATATAGCACGAGCTATGCCCAACAGAAGCGCAAGGTGTCAGACAAAG AGAAAATTGACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAA TTGAGAAAATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTT GATGTTCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACT AGTGTGTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGT GAAGGTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAA ATAGAACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACA GAGGATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAG CAAAGCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGT CAGTCAAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGA TTCAGCAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCA TTGAAGCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACA AGAAATTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGT TTTAACCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAAT CCTTGATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCA TGTGATTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGAC TGATAAACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGA AAGAGCATGATGACATATTTGATAAACTTAAAGAGGCTGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGAC AGCTTGAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAG GCTCTGCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAA TCGGACCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTG CAAGTGATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAA GTTTATAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATT CTGAGTTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAA ATACTGAAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACT GGTAAACGCGTTCAACTGGCGGAAGACCTCAAGAAAGTTAGAGAAATTCAAGAAAAACTTGATGCTTTCATTGAAGCTCTTCATCAGGA GAAATAA ATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAAAATTAGAAAA GCCCTTCCTAGTTCAGAAGACCTTGTAAAGTTAGCACCAGACTTTGACAAGATTGTTGAAAGCCTTAGCTTATTGAAGGACTTTTTTACCT CAGGTTCTCCGGAAGAAACGGCGTTTAGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGTGTCAGACAAAGAGAAA ATTGACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAG AAAATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGT TCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGT GTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAG GTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAG AACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGG ATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAA GCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTC AAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAG CAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAA GCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAA TTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAA CCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTG ATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGA TTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATA AACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGAAAGAG CATGATGACATATTTGATAAACTTAAAGAGGCTGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGACAGCTT GAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAGGCTCT GCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAATCGGA CCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTGCAAGT GATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAAGTTTA TAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATTCTGAG TTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAAATACTG AAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACTGGTAAA CGCGTTCAACTGGCGGAAGACCTCAAGAAAGTTAGAGAAATTCAAGAAAAACTTGATGCTTTCATTGAAGCTCTTCATCAGGAGAAATA

[0211]

[0212] AAttorney Docket No. : UCH-42525

[0213] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0214] if XIsoorm ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA 3144 3090 CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA ACTATTTTTATGTAAACACATGCACGCCGTTTCCACCTAAAAATTTTCGAGGTATAAGGATCGCATATGGTTCAAATAAGGTGTAAGGCCTATCCCTAGGAACCCTTTATCGTATCCATCATGTAGTTTTGATGTGGTATACATGCCCCGTGTAAAGGCATATAATCTGGGACAGGTGTTA AGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGGTCTGCTTGGTGAGCTCATTCTCTTACAACAACAAATTCAAGA GCATGAAGAGGAAGCGCGCAGAGCCGCTGGCCAATATAGCACGAGCTATGCCCAACAGAAGCGCAAGGTGTCAGACAAAGAGAAAATT GACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAA ATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTC TCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTG GAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCT CACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTT CGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGT GCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTA CATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAAT GGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGA TAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTA TAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTA AGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTT GAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGA AGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGA AAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACA ACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATG ATGACATATTTGATAAACTTAAAGAGGCCGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGG GTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAG GCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCA AGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATG AAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGA AGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGG AATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAAATACTGAAG TTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGC GTTCAACTGGCGGAAGACCTCATAACAGATATTTTCCCAAGTAACCTACTGCTGGTTGTGATGCTGAGGGACATTTCATGGGACTGCATG GTCGTTGCTCATCGTGATACCATCCTCAGTGGTTGGGGGATTCACAGTGAATTCTCATATCCTGTAACTATGCATCATGGATCTATCATCT GA ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA AATTAGAAAAGCCCTTCCTAGTTCAGAAGACCTTGTAAAGTTAGCACCAGACTTTGACAAGATTGTTGAAAGCCTTAGCTTATTGAAGGA CTTTTTTACCTCAGGTTCTCCGGAAGAAACGGCGTTTAGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGGTCTGCT TGGTGAGCTCATTCTCTTACAACAACAAATTCAAGAGCATGAAGAGGAAGCGCGCAGAGCCGCTGGCCAATATAGCACGAGCTATGCCC AACAGAAGCGCAAGGTGTCAGACAAAGAGAAAATTGACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTG GAACGATTAGAAAAGGAGAACAAAGAATTGAGAAAATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAAT CTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTG GTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGAC ACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGA AGAAGATCTTGCAGCATTAAGACATGAAATAGAACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATAT

[0215] j JX unoosx CCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTG ACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATG CTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAG AGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAA CAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGC ATGCTAAAGGCACACCAAGTGACTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACA ACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGA ACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAAC AATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCA CAGTGGATATCAAGCTTAAACAGTGGACTGATAAACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTT TCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATGATGACATATTTGATAAACTTAAAGAGGCTGTTAAGGAAGAAAGTATTAAACG ACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAAT GGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACT GGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAA ATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATC CAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTT TTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACC GCAAATACTTTAAGGCAACAACTTACAAATACTGAAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGA TGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGCGTTCAACTGGCGGAAGACCTCATAACAGATATTTTCCCAAGTAACCTACTGCT GGTTGTGATGCTGAGGGACATTTCATGGGACTGCATGGTCGTTGCTCATCGTGATACCATCCTCAGTGGTTGGGGGATTCACAGTGAATT

[0216]

[0217] CTCATATCCTGTAACTATGCATCATGGATCTATCATCTGAAttorney Docket No. : UCH-42525

[0218] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0219] if if X2 X3soormsoorm ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA 3080 3033 CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA ACTATTTTTATGTAAACACATGCACGCCGTTTTCCCTTCACAGTGTACAAGGAAAAAGCAGCGCCTGTTGTTTAAAGAAGGTCTAAAGCCAAGCACTACGGATCGTGTATGTCATCGAAAAGAAGTTTGGATTCGAAAAGACAGCTTCTTTTAAGGACATTAAGTGTGGTACATGGGCATTGGTGAGCTCATTCTCTTACAACAACAAATTCAAGAGCATGAAGAGGAAGCGCGCAGAGCCGCTGGCCAATATAGCACGAGCTATGCCC AACAGAAGCGCAAGGTGTCAGACAAAGAGAAAATTGACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTG GAACGATTAGAAAAGGAGAACAAAGAATTGAGAAAATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAAT CTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTG GTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGAC ACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGA AGAAGATCTTGCAGCATTAAGACATGAAATAGAACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATAT CCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTG ACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATG CTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAG

[0220] to AGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAA CAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGC ATGCTAAAGGCACACCAAGTGACTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACA ACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGA ACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAAC AATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCA CAGTGGATATCAAGCTTAAACAGTGGACTGATAAACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTT TCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATGATGACATATTTGATAAACTTAAAGAGGCCGTTAAGGAAGAAAGTATTAAACG ACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAAT GGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACT GGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAA ATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATC CAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTT TTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACC GCAAATACTTTAAGGCAACAACTTACAAATACTGAAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGA TGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGCGTTCAACTGGCGGAAGACCTCATAACAGATATTTTCCCAAGTAACCTACTGCT GGTTGTGATGCTGAGGGACATTTCATGGGACTGCATGGTCGTTGCTCATCGTGATACCATCCTCAGTGGTTGGGGGATTCACAGTGAATT CTCATATCCTGTAACTATGCATCATGGATC ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA AATTAGAAAAGCCCTTCCTAGTTCAGAAGACCTTGTAAAGTTAGCACCAGACTTTGACAAGATTGTTGAAAGCCTTAGCTTATTGAAGGA CTTTTTTACCTCAGGTCACAAATTGGTTAGTGAAGTCATAGGAGCTTCTGACCTACTTCTCTTGTTAGGTTCTCCGGAAGAAACGGCGTTT AGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGTGTCAGACAAAGAGAAAATTGACCAACTTCAGGAAGAACTTCT GCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAAATTAGTATTGCAGAAAGATGAC AAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATA ATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAA TATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAG ATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTTCGAATGAGGAAAAATGTGAAA GAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTG ATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTACATGCAGAATCCTAATGCCATC ATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACC ATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCC

[0221] co AATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTATAAGAGAATATGAAGAAGAGT TTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCT TTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTTGAAACTGAATGGAAGAATAACT ATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTA CACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGAAAACATCTACCTTCCAGCTGCGC AGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACAACTTCCTAATAAAGCAGTAGAG GTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATGATGACATATTTGATAAACTTAA AGAGGCTGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGGGTTATTCAACACAATGCTTTGG AAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAA ATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCAAGAACAGTGTGTTCACAATGAA ACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATGAAATAACCACAGTCCGGAAGAA CCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCT AAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTT TGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAAATACTGAAGTTAGGCGATTAGAGAAAAATGTT AAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGCGTTCAACTGGCGGAAGACCTCAT AACAGATATTTTCCCAAGTAACCTACTGCTGGTTGTGATGCTGAGGGACATTTCATGGGACTGCATGGTCGTTGCTCATCGTGATACCATC

[0222]

[0223] CTCAGTGGTTGGGGGATTCACAGTGAATTCTCATATCCTGTAACTATGCATCATGGATCTATCATCTGAAttorney Docket No. : UCH-42525

[0224] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0225] if if X3 X4soormsoorm ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA 3033 2982 CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA ACTATTTTTATGTAAACACATGCACGCCGTTTCCACCTAAAAATTTTCGAGGTATAAGGATCGCATATGGTTCAAATAAGGTGTAAGGCCTATCCCTAGGAACCCTTTATCGTATCCATCATGTAGTTTTGATGTGGTATACATGCCCCGTGTAAAGGCATATAATCTGGGACAGGTGTTA AGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGTGTCAGACAAAGAGAAAATTGACCAACTTCAGGAAGAACTTCT GCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAAATTAGTATTGCAGAAAGATGAC AAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATA ATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAA TATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAG ATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTTCGAATGAGGAAAAATGTGAAA GAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTG ATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTACATGCAGAATCCTAATGCCATC ATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACC ATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCC AATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTATAAGAGAATATGAAGAAGAGT TTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCT TTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTTGAAACTGAATGGAAGAATAACT ATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTA CACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGAAAACATCTACCTTCCAGCTGCGC AGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACAACTTCCTAATAAAGCAGTAGAG GTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATGATGACATATTTGATAAACTTAA AGAGGCCGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGGGTTATTCAACACAATGCTTTGG AAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAA ATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCAAGAACAGTGTGTTCACAATGAA ACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATGAAATAACCACAGTCCGGAAGAA CCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCT AAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTT TGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAAATACTGAAGTTAGGCGATTAGAGAAAAATGTT AAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGCGTTCAACTGGCGGAAGACCTCAT AACAGATATTTTCCCAAGTAACCTACTGCTGGTTGTGATGCTGAGGGACATTTCATGGGACTGCATGGTCGTTGCTCATCGTGATACCATC CTCAGTGGTTGGGGGATTCACAGTGAATTCTCATATCCTGTAACTATGCATCATGGATCTATCATCTGA ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGGTTC TCCGGAAGAAACGGCGTTTAGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGGTCTGCTTGGTGAGCTCATTCTCTT ACAACAACAAATTCAAGAGCATGAAGAGGAAGCGCGCAGAGCCGCTGGCCAATATAGCACGAGCTATGCCCAACAGAAGCGCAAGGTG TCAGACAAAGAGAAAATTGACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGA GAACAAAGAATTGAGAAAATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATT CTGAAGTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGC TGGAAAGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGT GACTCTGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATT AAGACATGAAATAGAACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCC CTGGACTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTT TCAGTATCAGCAAAGCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTA CAGACTTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGT CCAAGCAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAG CTCTGAAAGCATTGAAGCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACC AAGTGACTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCA AAGCAACACGTTTTAACCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCT AAAAATGAAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAG AGTATCAACTCATGTGATTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCT TAAACAGTGGACTGATAAACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGA ACCGAAAGGGAAAGAGCATGATGACATATTTGATAAACTTAAAGAGGCTGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGAC TTTGCGGAGGACAGCTTGAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTAT TTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTT ATACTGGAAGAATCGGACCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCAC CCAGCTTATCTTGCAAGTGATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGA TACTTGGCATCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGG CATTTTGTAGATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGC AACAACTTACAAATACTGAAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATT AAATTGCTTACTGGTAAACGCGTTCAACTGGCGGAAGACCTCATAACAGATATTTTCCCAAGTAACCTACTGCTGGTTGTGATGCTGAGG GACATTTCATGGGACTGCATGGTCGTTGCTCATCGTGATACCATCCTCAGTGGTTGGGGGATTCACAGTGAATTCTCATATCCTGTAACTA

[0226]

[0227] TGCATCATGGATCTATCATCTGAAttorney Docket No. : UCH-42525

[0228] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0229] 40

[0230] if if X4 X5soormsoorm ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA 2982 2979 CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGGTTC TCCGGAAGAAACGGCGTTTAGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGGTCTGCTTGGTGAGCTCATTCTCTT ACAACAACAAATTCAAGAGCATGAAGAGGAAGCGCGCAGAGCCGCTGGCCAATATAGCACGAGCTATGCCCAACAGAAGCGCAAGGTG TCAGACAAAGAGAAAATTGACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGA GAACAAAGAATTGAGAAAATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATT CTGAAGTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGC TGGAAAGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGT GACTCTGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATT AAGACATGAAATAGAACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCC CTGGACTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTT TCAGTATCAGCAAAGCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTA CAGACTTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGT CCAAGCAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAG CTCTGAAAGCATTGAAGCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACC AAGTGACTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCA AAGCAACACGTTTTAACCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCT AAAAATGAAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAG AGTATCAACTCATGTGATTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCT TAAACAGTGGACTGATAAACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGA ACCGAAAGGGAAAGAGCATGATGACATATTTGATAAACTTAAAGAGGCCGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGAC TTTGCGGAGGACAGCTTGAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTAT TTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTT ATACTGGAAGAATCGGACCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCAC CCAGCTTATCTTGCAAGTGATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGA TACTTGGCATCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGG CATTTTGTAGATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGC AACAACTTACAAATACTGAAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATT AAATTGCTTACTGGTAAACGCGTTCAACTGGCGGAAGACCTCATAACAGATATTTTCCCAAGTAACCTACTGCTGGTTGTGATGCTGAGG GACATTTCATGGGACTGCATGGTCGTTGCTCATCGTGATACCATCCTCAGTGGTTGGGGGATTCACAGTGAATTCTCATATCCTGTAACTA TGCATCATGGATCTATCATCTGA ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA AATTAGAAAAGCCCTTCCTAGTTCAGAAGACCTTGTAAAGTTAGCACCAGACTTTGACAAGATTGTTGAAAGCCTTAGCTTATTGAAGGA CTTTTTTACCTCAGGTTCTCCGGAAGAAACGGCGTTTAGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGTGTCAGA CAAAGAGAAAATTGACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACA AAGAATTGAGAAAATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAA GTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAA AGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTC TGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGAC ATGAAATAGAACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGA CTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGT ATCAGCAAAGCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGAC TTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAG CAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGA AAGCATTGAAGCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGA CTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAA CACGTTTTAACCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATG AAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAA CTCATGTGATTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGT GGACTGATAAACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAA GGGAAAGAGCATGATGACATATTTGATAAACTTAAAGAGGCTGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGA GGACAGCTTGAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGA AGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGA AGAATCGGACCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTAT CTTGCAAGTGATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCA TCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTA GATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTA CAAATACTGAAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTT ACTGGTAAACGCGTTCAACTGGCGGAAGACCTCATAACAGATATTTTCCCAAGTAACCTACTGCTGGTTGTGATGCTGAGGGACATTTCA TGGGACTGCATGGTCGTTGCTCATCGTGATACCATCCTCAGTGGTTGGGGGATTCACAGTGAATTCTCATATCCTGTAACTATGCATCATG

[0231]

[0232] GATCTATCATCTGAAttorney Docket No. : UCH-42525

[0233] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0234] 42

[0235] if if X5 X6soormsoorm ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA 2979 2871 CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA AATTAGAAAAGCCCTTCCTAATTCAGAAGACCTTGTAAAGTTAGCACCAGACTTTGACAAGATTGTTGAAAGCCTTAGCTTATTGAAGGA CTTTTTTACCTCAGGTTCTCCGGAAGAAACGGCGTTTAGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGTGTCAGA CAAAGAGAAAATTGACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACA AAGAATTGAGAAAATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAA GTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAA AGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTC TGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGAC ATGAAATAGAACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGA CTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGT ATCAGCAAAGCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGAC TTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAG CAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGA AAGCATTGAAGCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGA CTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAA CACGTTTTAACCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATG AAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAA CTCATGTGATTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGT GGACTGATAAACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAA GGGAAAGAGCATGATGACATATTTGATAAACTTAAAGAGGCCGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGA GGACAGCTTGAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGA AGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGA AGAATCGGACCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTAT CTTGCAAGTGATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCA TCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTA GATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTA CAAATACTGAAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTT ACTGGTAAACGCGTTCAACTGGCGGAAGACCTCATAACAGATATTTTCCCAAGTAACCTACTGCTGGTTGTGATGCTGAGGGACATTTCA TGGGACTGCATGGTCGTTGCTCATCGTGATACCATCCTCAGTGGTTGGGGGATTCACAGTGAATTCTCATATCCTGTAACTATGCATCATG GATCTATCATCTGA ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGGTTC TCCGGAAGAAACGGCGTTTAGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGTGTCAGACAAAGAGAAAATTGACC AACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAAATTA GTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTCTCTG ATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTGGAAA TGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCTCACC ATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTTCGAA TGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGTGCTT GTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTACATG CAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAATGGAC CCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGATAAT TGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTATAAG AGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTAAGCC TTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTTGAAA CTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGAAGTT ATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGAAAAC ATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACAACTT CCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATGATGA CATATTTGATAAACTTAAAGAGGCTGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGGGTTA TTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAGGCTC GTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCAAGA ACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATGAAA TAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGAAGA CATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGGAAT GCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAAATACTGAAGTTA GGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGCGTT CAACTGGCGGAAGACCTCATAACAGATATTTTCCCAAGTAACCTACTGCTGGTTGTGATGCTGAGGGACATTTCATGGGACTGCATGGTC

[0236]

[0237] GTTGCTCATCGTGATACCATCCTCAGTGGTTGGGGGATTCACAGTGAATTCTCATATCCTGTAACTATGCATCATGGATCTATCATCTGAAttorney Docket No. : UCH-42525

[0238] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0239] 44

[0240] if if X6 X7soormsoorm ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA 2871 CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGGTTC TCCGGAAGAAACGGCGTTTAGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGTGTCAGACAAAGAGAAAATTGACC AACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAAATTA GTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTCTCTG ATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTGGAAA TGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCTCACC ATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTTCGAA TGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGTGCTT GTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTACATG CAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAATGGAC CCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGATAAT TGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTATAAG AGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTAAGCC TTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTTGAAA CTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGAAGTT ATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGAAAAC ATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACAACTT CCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATGATGA CATATTTGATAAACTTAAAGAGGCCGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGGGTTA TTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAGGCTC GTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCAAGA ACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATGAAA TAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGAAGA CATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGGAAT GCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAAATACTGAAGTTA GGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGCGTT CAACTGGCGGAAGACCTCATAACAGATATTTTCCCAAGTAACCTACTGCTGGTTGTGATGCTGAGGGACATTTCATGGGACTGCATGGTC GTTGCTCATCGTGATACCATCCTCAGTGGTTGGGGGATTCACAGTGAATTCTCATATCCTGTAACTATGCATCATGGATCTATCATCTGA ATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAAAATTAGAAAA GCCCTTCCTAGTTCAGAAGACCTTGTAAAGTTAGCACCAGACTTTGACAAGATTGTTGAAAGCCTTAGCTTATTGAAGGACTTTTTTACCT CAGGTCACAAATTGGTTAGTGAAGTCATAGGAGCTTCTGACCTACTTCTCTTGTTAGGTTCTCCGGAAGAAACGGCGTTTAGAGCAACAG ATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGGTCTGCTTGGTGAGCTCATTCTCTTACAACAACAAATTCAAGAGCATGAAGAGG AAGCGCGCAGAGCCGCTGGCCAATATAGCACGAGCTATGCCCAACAGAAGCGCAAGGTGTCAGACAAAGAGAAAATTGACCAACTTCA GGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAAATTAGTATTGC AGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTCTCTGATTATGA TGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTGGAAATGATTGC CCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCTCACCATGTGGC CCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTTCGAATGAGGAA AAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGTGCTTGTTGACTT ACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTACATGCAGAATCC TAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAATGGACCCTCATGG AAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGATAATTGAAGGAA AGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTATAAGAGAATATG AAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTAAGCCTTGCAGTA

[0241] r4 TCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTTGAAACTGAATGG AAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGAAGTTATCAGTCTG AGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGAAAACATCTACCTT CCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACAACTTCCTAATAAA GCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATGATGACATATTTGA TAAACTTAAAGAGGCTGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGGGTTATTCAACACA ATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGG ATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCAAGAACAGTGTGTT CACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATGAAATAACCACAGT CCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGAAGACATTTTTTAAA AACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGGAATGCAATGATGTG GTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAAATACTGAAGTTAGGCGATTAGAG AAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGCGTTCAACTGGCGGA AGACCTCATAACAGATATTTTCCCAAGTAACCTACTGCTGGTTGTGATGCTGAGGGACATTTCATGGGACTGCATGGTCGTTGCTCATCGT

[0242]

[0243] GATACCATCCTCAGTGGTTGGGGGATTCACAGTGAATTCTCATATCCTGTAACTATGCATCATGGATCTATCATCTGAAttorney Docket No. : UCH-42525

[0244] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0245] 45 46 47

[0246] if if if X7 X8 X8soormsoormsoorm ATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAAAATTAGAAAA 2190 2190 GCCCTTCCTAATTCAGAAGACCTTGTAAAGTTAGCACCAGACTTTGACAAGATTGTTGAAAGCCTTAGCTTATTGAAGGACTTTTTTACCT CAGGTCACAAATTGGTTAGTGAAGTCATAGGAGCTTCTGACCTACTTCTCTTGTTAGGTTCTCCGGAAGAAACGGCGTTTAGAGCAACAG ATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGGTCTGCTTGGTGAGCTCATTCTCTTACAACAACAAATTCAAGAGCATGAAGAGG AAGCGCGCAGAGCCGCTGGCCAATATAGCACGAGCTATGCCCAACAGAAGCGCAAGGTGTCAGACAAAGAGAAAATTGACCAACTTCA GGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAAATTAGTATTGC AGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTCTCTGATTATGA TGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTGGAAATGATTGC CCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCTCACCATGTGGC CCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTTCGAATGAGGAA AAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGTGCTTGTTGACTT ACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTACATGCAGAATCC TAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAATGGACCCTCATGG AAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGATAATTGAAGGAA AGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTATAAGAGAATATG AAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTAAGCCTTGCAGTA

[0247] C4 TCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTTGAAACTGAATGG AAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGAAGTTATCAGTCTG AGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGAAAACATCTACCTT CCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACAACTTCCTAATAAA GCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATGATGACATATTTGA TAAACTTAAAGAGGCCGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGGGTTATTCAACACA ATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGG ATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCAAGAACAGTGTGTT CACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATGAAATAACCACAGT CCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGAAGACATTTTTTAAA AACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGGAATGCAATGATGTG GTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAAATACTGAAGTTAGGCGATTAGAG AAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGCGTTCAACTGGCGGA AGACCTCATAACAGATATTTTCCCAAGTAACCTACTGCTGGTTGTGATGCTGAGGGACATTTCATGGGACTGCATGGTCGTTGCTCATCGT GATACCATCCTCAGTGGTTGGGGGATTCACAGTGAATTCTCATATCCTGTAACTATGCATCATGGATCTATCATCTGA ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA ACTATTTTTATGTAAACACATGCACGCCGTTTCCACCTAAAGATTTTCGAGGTATAAGGATCGCATATGGTTCAAATAAGGTGTAAGGCCTATCCCTAGGAACCCTTTATCGTATCCATCATGTAGTTTTGATGTGGTATACATGCCCCGTGTAAAGGCATATAATCTGGGACAGGTGTTA AGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGGTCTGCTTGGTGAGCTCATTCTCTTACAACAACAAATTCAAGA GCATGAAGAGGAAGCGCGCAGAGCCGCTGGCCAATATAGCACGAGCTATGCCCAACAGAAGCGCAAGGTGTCAGACAAAGAGAAAATT GACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAA ATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTC TCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTG GAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCT CACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTT CGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGT GCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTA CATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAAT GGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGA TAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTA TAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTA AGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTT GAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGA AGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGA AAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACA ACTTCCTAATAAAGCAGTAGAGGTTAGGATATAA ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA AATTAGAAAAGCCCTTCCTAATTCAGAAGACCTTGTAAAGTTAGCACCAGACTTTGACAAGATTGTTGAAAGCCTTAGCTTATTGAAGGA CTTTTTTACCTCAGGTCACAAATTGGTTAGTGAAGTCATAGGAGCTTCTGACCTACTTCTCTTGTTAGGTTCTCCGGAAGAAACGGCGTTT AGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGGTCTGCTTGGTGAGCTCATTCTCTTACAACAACAAATTCAAGA GCATGAAGAGGAAGCGCGCAGAGCCGCTGGCCAATATAGCACGAGCTATGCCCAACAGAAGCGCAAGGTGTCAGACAAAGAGAAAATT GACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAA ATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTC TCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTG GAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCT CACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTT CGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGT GCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTA CATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAAT GGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGA TAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTA TAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTA AGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTT GAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGA AGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGA AAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACA

[0248]

[0249] ACTTCCTAATAAAGCAGTAGAGGTTAGGATATAAAttorney Docket No. : UCH-42525

[0250] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0251] 48 49 50

[0252] if if if X9 X 10 X 10soormsoormsoorm ATGTATTCTGAAGTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATC 2181 2085 2085 AGAGTGCTGGAAAGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCA GTTAAGGTGACTCTGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTT GCAGCATTAAGACATGAAATAGAACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGT AAAAGGCCCTGGACTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGG AAACTATTTTCAGTATCAGCAAAGCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCA GTATTGTTACAGACTTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAAT GTAGCCAGTCCAAGCAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAA GGGAACAGCTCTGAAAGCATTGAAGCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAA GGCACACCAAGTGACTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTG ATAGTTTCAAAGCAACACGTTTTAACCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTG AAAAAGCTAAAAATGAAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGT GGGAAAGAGTATCAACTCATGTGATTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATA TCAAGCTTAAACAGTGGACTGATAAACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTA TGACAGAACCGAAAGGGAAAGAGCATGATGACATATTTGATAAACTTAAAGAGGCTGTTAAGGAAGAAAGTATTAAACGACACAAGTG GAATGACTTTGCGGAGGACAGCTTGAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAG CTATTTATTTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAG AGGTGGTTATACTGGAAGAATCGGACCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGA GGAGCACCCAGCTTATCTTGCAAGTGATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGA TTAAGGATACTTGGCATCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTA CCAAAGGCATTTTGTAGATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACT TTAAGGCAACAACTTACAAATACTGAAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAA GAAGATTAAATTGCTTACTGGTAAACGCGTTCAACTGGCGGAAGACCTCATAACAGATATTTTCCCAAGTAACCTACTGCTGGTTGTGAT GCTGAGGGACATTTCATGGGACTGCATGGTCGTTGCTCATCGTGATACCATCCTCAGTGGTTGGGGGATTCACAGTGAATTCTCATATCCT GTAACTATGCATCATGGATCTATCATCTGA ATGTATTCTGAAGTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATC AGAGTGCTGGAAAGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCA GTTAAGGTGACTCTGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTT GCAGCATTAAGACATGAAATAGAACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGT AAAAGGCCCTGGACTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGG AAACTATTTTCAGTATCAGCAAAGCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCA GTATTGTTACAGACTTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAAT GTAGCCAGTCCAAGCAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAA GGGAACAGCTCTGAAAGCATTGAAGCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAA GGCACACCAAGTGACTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTG ATAGTTTCAAAGCAACACGTTTTAACCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTG AAAAAGCTAAAAATGAAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGT GGGAAAGAGTATCAACTCATGTGATTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATA TCAAGCTTAAACAGTGGACTGATAAACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTA TGACAGAACCGAAAGGGAAAGAGCATGATGACATATTTGATAAACTTAAAGAGGCTGTTAAGGAAGAAAGTATTAAACGACACAAGTG GAATGACTTTGCGGAGGACAGCTTGAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAG CTATTTATTTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAG AGGTGGTTATACTGGAAGAATCGGACCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGA GGAGCACCCAGCTTATCTTGCAAGTGATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGA TTAAGGATACTTGGCATCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTA CCAAAGGCATTTTGTAGATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACT TTAAGGCAACAACTTACAAATACTGAAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAA GAAGATTAAATTGCTTACTGGTAAACGCGTTCAACTGGCGGAAGACCTCAAGAAAGTTAGAGAAATTCAAGAAAAACTTGATGCTTTCA TTGAAGCTCTTCATCAGGAGAAATAA ATGTATTCTGAAGTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATC AGAGTGCTGGAAAGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCA GTTAAGGTGACTCTGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTT GCAGCATTAAGACATGAAATAGAACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGT AAAAGGCCCTGGACTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGG AAACTATTTTCAGTATCAGCAAAGCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCA GTATTGTTACAGACTTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAAT GTAGCCAGTCCAAGCAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAA GGGAACAGCTCTGAAAGCATTGAAGCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAA GGCACACCAAGTGACTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTG ATAGTTTCAAAGCAACACGTTTTAACCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTG AAAAAGCTAAAAATGAAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGT GGGAAAGAGTATCAACTCATGTGATTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATA TCAAGCTTAAACAGTGGACTGATAAACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTA TGACAGAACCGAAAGGGAAAGAGCATGATGACATATTTGATAAACTTAAAGAGGCCGTTAAGGAAGAAAGTATTAAACGACACAAGTG GAATGACTTTGCGGAGGACAGCTTGAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAG CTATTTATTTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAG AGGTGGTTATACTGGAAGAATCGGACCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGA GGAGCACCCAGCTTATCTTGCAAGTGATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGA TTAAGGATACTTGGCATCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTA CCAAAGGCATTTTGTAGATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACT TTAAGGCAACAACTTACAAATACTGAAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAA GAAGATTAAATTGCTTACTGGTAAACGCGTTCAACTGGCGGAAGACCTCAAGAAAGTTAGAGAAATTCAAGAAAAACTTGATGCTTTCA

[0253]

[0254] TTGAAGCTCTTCATCAGGAGAAATAAAttorney Docket No. : UCH-42525

[0255] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0256] 52

[0257] if if XI 1 X 12soormsoorm ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA 3084 3030 CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA ACTATTTTTATGTAAACACATGCACGCCGTTTCCACCTAAAAATTTTCGAGGTATAAGGATCGCATATGGTTCAAATAAGGTGTAAGGCCTATCCCTAGGAACCCTTTATCGTATCCATCATGTAGTTTTGATGTGGTATACATGCCCCGTGTAAAGGCATATAATCTGGGACAGGTGTTA AGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGGTCTGCTTGGTGAGCTCATTCTCTTACAACAACAAATTCAAGA GCATGAAGAGGAAGCGCGCAGAGCCGCTGGCCAATATAGCACGAGCTATGCCCAACAGAAGCGCAAGGTGTCAGACAAAGAGAAAATT GACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAA ATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTC TCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTG GAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCT CACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTT CGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGT GCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTA CATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAAT IT) GGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGA TAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTA TAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTA AGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTT GAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGA AGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGA AAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACA ACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATG ATGACATATTTGATAAACTTAAAGAGGCCGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGG GTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAG GCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCA AGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATG AAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGA AGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGG AATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAAATACTGAAG TTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGC GTTCAACTGGCGGAAGACCTCAAAATGTTCTTTTTCCCCAGCTCGGACTCAACACTACACACCAGGCCACCACATGGCGCCGCACCCAGC ATTGACACTTCTTTTACCTTGTCTGGGCTCTGA ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA AATTAGAAAAGCCCTTCCTAATTCAGAAGACCTTGTAAAGTTAGCACCAGACTTTGACAAGATTGTTGAAAGCCTTAGCTTATTGAAGGA CTTTTTTACCTCAGGTTCTCCGGAAGAAACGGCGTTTAGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGGTCTGCT TGGTGAGCTCATTCTCTTACAACAACAAATTCAAGAGCATGAAGAGGAAGCGCGCAGAGCCGCTGGCCAATATAGCACGAGCTATGCCC AACAGAAGCGCAAGGTGTCAGACAAAGAGAAAATTGACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTG GAACGATTAGAAAAGGAGAACAAAGAATTGAGAAAATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAAT CTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTG GTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGAC ACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGA AGAAGATCTTGCAGCATTAAGACATGAAATAGAACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATAT CCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTG ACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATG CTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAG AGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAA CAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGC ATGCTAAAGGCACACCAAGTGACTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACA ACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGA ACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAAC AATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCA CAGTGGATATCAAGCTTAAACAGTGGACTGATAAACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTT TCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATGATGACATATTTGATAAACTTAAAGAGGCCGTTAAGGAAGAAAGTATTAAACG ACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAAT GGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACT GGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAA ATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATC CAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTT TTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACC GCAAATACTTTAAGGCAACAACTTACAAATACTGAAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGA TGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGCGTTCAACTGGCGGAAGACCTCAAAATGTTCTTTTTCCCCAGCTCGGACTCAAC

[0258]

[0259] ACTACACACCAGGCCACCACATGGCGCCGCACCCAGCATTGACACTTCTTTTACCTTGTCTGGGCTCTGAAttorney Docket No. : UCH-42525

[0260] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0261] 54

[0262] if XI 3 if X14soormsoorm ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA 2973 CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA ACTATTTTTATGTAAACACATGCACGCCGTTTCCACCTAAAAATTTTCGAGGTATAAGGATCGCATATGGTTCAAATAAGGTGTAAGGCCTATCCCTAGGAACCCTTTATCGTATCCATCATGTAGTTTTGATGTGGTATACATGCCCCGTGTAAAGGCATATAATCTGGGACAGGTGTTA AGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGTGTCAGACAAAGAGAAAATTGACCAACTTCAGGAAGAACTTCT GCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAAATTAGTATTGCAGAAAGATGAC AAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATA ATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAA TATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAG ATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTTCGAATGAGGAAAAATGTGAAA GAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTG ATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTACATGCAGAATCCTAATGCCATC ATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACC ATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCC AATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTATAAGAGAATATGAAGAAGAGT TTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCT TTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTTGAAACTGAATGGAAGAATAACT ATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTA CACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGAAAACATCTACCTTCCAGCTGCGC AGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACAACTTCCTAATAAAGCAGTAGAG GTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATGATGACATATTTGATAAACTTAA AGAGGCCGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGGGTTATTCAACACAATGCTTTGG AAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAA ATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCAAGAACAGTGTGTTCACAATGAA ACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATGAAATAACCACAGTCCGGAAGAA CCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCT AAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTT TGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAAATACTGAAGTTAGGCGATTAGAGAAAAATGTT AAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGCGTTCAACTGGCGGAAGACCTCAA AATGTTCTTTTTCCCCAGCTCGGACTCAACACTACACACCAGGCCACCACATGGCGCCGCACCCAGCATTGACACTTCTTTTACCTTGTCT GGGCTCTGA ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGAGAA AATTAGAAAAGCCCTTCCTAATTCAGAAGACCTTGTAAAGTTAGCACCAGACTTTGACAAGATTGTTGAAAGCCTTAGCTTATTGAAGGA CTTTTTTACCTCAGGTTCTCCGGAAGAAACGGCGTTTAGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGTGTCAGA CAAAGAGAAAATTGACCAACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACA AAGAATTGAGAAAATTAGTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAA GTTCTTGATGTTCTCTCTGATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAA AGACTAGTGTGTTGGAAATGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTC TGAGTGAAGGTCCTCACCATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGAC ATGAAATAGAACTTCGAATGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGA CTACAGAGGATGGTGCTTGTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGT ATCAGCAAAGCTTACATGCAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGAC

[0263] o> TTGGTCAGTCAAATGGACCCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAG o> CAGGATTCAGCAGATAATTGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGA AAGCATTGAAGCTATAAGAGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGA CTACAAGAAATTTAAGCCTTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAA CACGTTTTAACCTTGAAACTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATG AAATCCTTGATGAAGTTATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAA CTCATGTGATTGAAAACATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGT GGACTGATAAACAACTTCCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAA GGGAAAGAGCATGATGACATATTTGATAAACTTAAAGAGGCCGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGA GGACAGCTTGAGGGTTATTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGA AGAGGCTCTGCAGGCTCGTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGA AGAATCGGACCCAAGAACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTAT CTTGCAAGTGATGAAATAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCA TCAAGTTTATAGAAGACATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTA GATTCTGAGTTGGAATGCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTA CAAATACTGAAGTTAGGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTT ACTGGTAAACGCGTTCAACTGGCGGAAGACCTCAAAATGTTCTTTTTCCCCAGCTCGGACTCAACACTACACACCAGGCCACCACATGGC

[0264]

[0265] GCCGCACCCAGCATTGACACTTCTTTTACCTTGTCTGGGCTCTGAAttorney Docket No. : UCH-42525

[0266] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0267] if XI 5soorm ATGTGGCGACTACGTCGGGCCGCTGTGGCCTGTGAGGTCTGCCAGTCTTTAGTGAAACACAGCTCTGGAATAAAAGGAAGTTTACCACTA CAAAAACTACATCTGGTTTCACGAAGCATTTATCATTCACATCATCCTACCTTAAAGCTTCAACGACCCCAATTAAGGACATCCTTTCAGC

[0268] 2811 AGTTCTCTTCTCTGACAAACCTTCCTTTACGTAAACTGAAATTCTCTCCAATTAAATATGGCTACCAGCCTCGCAGGAATTTTTGGCCAGC AAGATTAGCTACGAGACTCTTAAAACTTCGCTATCTCATACTAGGATCGGCTGTTGGGGGTGGCTACACAGCCAAAAAGACTTTTGATCA GTGGAAAGATATGATACCGGACCTTAGTGAATATAAATGGATTGTGCCTGACATTGTGTGGGAAATTGATGAGTATATCGATTTTGGTTC TCCGGAAGAAACGGCGTTTAGAGCAACAGATCGTGGATCTGAAAGTGACAAGCATTTTAGAAAGGTGTCAGACAAAGAGAAAATTGACC AACTTCAGGAAGAACTTCTGCACACTCAGTTGAAGTATCAGAGAATCTTGGAACGATTAGAAAAGGAGAACAAAGAATTGAGAAAATTA GTATTGCAGAAAGATGACAAAGGCATTCATCATAGAAAGCTTAAGAAATCTTTGATTGACATGTATTCTGAAGTTCTTGATGTTCTCTCTG ATTATGATGCCAGTTATAATACGCAAGATCATCTGCCACGGGTTGTTGTGGTTGGAGATCAGAGTGCTGGAAAGACTAGTGTGTTGGAAA TGATTGCCCAAGCTCGAATATTCCCAAGAGGATCTGGGGAGATGATGACACGTTCTCCAGTTAAGGTGACTCTGAGTGAAGGTCCTCACC ATGTGGCCCTATTTAAAGATAGTTCTCGGGAGTTTGATCTTACCAAAGAAGAAGATCTTGCAGCATTAAGACATGAAATAGAACTTCGAA TGAGGAAAAATGTGAAAGAAGGCTGTACCGTTAGCCCTGAGACCATATCCTTAAATGTAAAAGGCCCTGGACTACAGAGGATGGTGCTT GTTGACTTACCAGGTGTGATTAATACTGTGACATCAGGCATGGCTCCTGACACAAAGGAAACTATTTTCAGTATCAGCAAAGCTTACATG CAGAATCCTAATGCCATCATACTGTGTATTCAAGATGGATCTGTGGATGCTGAACGCAGTATTGTTACAGACTTGGTCAGTCAAATGGAC CCTCATGGAAGGAGAACCATATTCGTTTTGACCAAAGTAGACCTGGCAGAGAAAAATGTAGCCAGTCCAAGCAGGATTCAGCAGATAAT IT) TGAAGGAAAGCTCTTCCCAATGAAAGCTTTAGGTTATTTTGCTGTTGTAACAGGAAAAGGGAACAGCTCTGAAAGCATTGAAGCTATAAG IT) AGAATATGAAGAAGAGTTTTTTCAGAATTCAAAGCTCCTAAAGACAAGCATGCTAAAGGCACACCAAGTGACTACAAGAAATTTAAGCC TTGCAGTATCAGACTGCTTTTGGAAAATGGTACGAGAGTCTGTTGAACAACAGGCTGATAGTTTCAAAGCAACACGTTTTAACCTTGAAA CTGAATGGAAGAATAACTATCCTCGCCTGCGGGAACTTGACCGGAATGAACTATTTGAAAAAGCTAAAAATGAAATCCTTGATGAAGTT ATCAGTCTGAGCCAGGTTACACCAAAACATTGGGAGGAAATCCTTCAACAATCTTTGTGGGAAAGAGTATCAACTCATGTGATTGAAAAC ATCTACCTTCCAGCTGCGCAGACCATGAATTCAGGAACTTTTAACACCACAGTGGATATCAAGCTTAAACAGTGGACTGATAAACAACTT CCTAATAAAGCAGTAGAGGTTGCTTGGGAGACCCTACAAGAAGAATTTTCCCGCTTTATGACAGAACCGAAAGGGAAAGAGCATGATGA CATATTTGATAAACTTAAAGAGGCCGTTAAGGAAGAAAGTATTAAACGACACAAGTGGAATGACTTTGCGGAGGACAGCTTGAGGGTTA TTCAACACAATGCTTTGGAAGACCGATCCATATCTGATAAACAGCAATGGGATGCAGCTATTTATTTTATGGAAGAGGCTCTGCAGGCTC GTCTCAAGGATACTGAAAATGCAATTGAAAACATGGTGGGTCCAGACTGGAAAAAGAGGTGGTTATACTGGAAGAATCGGACCCAAGA ACAGTGTGTTCACAATGAAACCAAGAATGAATTGGAGAAGATGTTGAAATGTAATGAGGAGCACCCAGCTTATCTTGCAAGTGATGAAA TAACCACAGTCCGGAAGAACCTTGAATCCCGAGGAGTAGAAGTAGATCCAAGCTTGATTAAGGATACTTGGCATCAAGTTTATAGAAGA CATTTTTTAAAAACAGCTCTAAACCATTGTAACCTTTGTCGAAGAGGTTTTTATTACTACCAAAGGCATTTTGTAGATTCTGAGTTGGAAT GCAATGATGTGGTCTTGTTTTGGCGTATACAGCGCATGCTTGCTATCACCGCAAATACTTTAAGGCAACAACTTACAAATACTGAAGTTA GGCGATTAGAGAAAAATGTTAAAGAGGTATTGGAAGATTTTGCTGAAGATGGTGAGAAGAAGATTAAATTGCTTACTGGTAAACGCGTT CAACTGGCGGAAGACCTCAAAATGTTCTTTTTCCCCAGCTCGGACTCAACACTACACACCAGGCCACCACATGGCGCCGCACCCAGCATT

[0269]

[0270] GACACTTCTTTTACCTTGTCTGGGCTCTGAAttorney Docket No. : UCH-42525

[0271] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0272] | SQOE ID N:

[0273] | |f if if if if if I 0102030405soormsoormsoormsoormsoormsoorm

[0274] Table | | | | | () Lh 924 942978tengaa 2: Exemplary OPA1 protein isoforms

[0275] 11961 _ _

[0276] Sequence

[0277] MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSHHPTLKLQRPQLRTSFQQFSSLTNLPLRKLKFSPIKYGYQ PRRNFWPARLATRLLKLRYLILGSAVGGGYTAKKTFDQWKDMIPDLSEYKWIVPDIVWEIDEYIDFEKIRKALPSSEDLVKL APDFDKIVESLSLLKDFFTSGSPEETAFRATDRGSESDKHFRKVSDKEKIDQLQEELLHTQLKYQRILERLEKENKELRKLVLQ KDDKGIHHRKLKKSLIDMYSEVLDVLSDYDASYNTQDHLPRVVVVGDQSAGKTSVLEMIAQARIFPRGSGEMMTRSPVKVT LSEGPHHVALFKDSSREFDLTKEEDLAALRHEIELRMRKNVKEGCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSGMAP

[0278] o k OO DTKETIFSISKAYMQNPNAIILCIQDGSVDAERSIVTDLVSQMDPHGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKLFPMKALG k YFAVVTGKGNSSESIEAIREYEEEFFQNSKLLKTSMLKAHQVTTRNLSLAVSDCFWKMVRESVEQQADSFKATRFNLETEW KNNYPRLRELDRNELFEKAKNEILDEVISLSQVTPKHWEEILQQSLWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQWT DKQLPNKAVEVAWETLQEEFSRFMTEPKGKEHDDIFDKLKEAVKEESIKRHKWNDFAEDSLRVIQHNALEDRSISDKQQWD AAIYFMEEALQARLKDTENAIENMVGPDWKKRWLYWKNRTQEQCVHNETKNELEKMLKCNEEHPAYLASDEITTVRKNL ESRGVEVDPSLIKDTWHQVYRRHFLKTALNHCNLCRRGFYYYQRHFVDSELECNDVVLFWRIQRMLAITANTLRQQLTNTE VRRLEKNVKEVLEDFAEDGEKKIKLLTGKRVQLAEDLKKVREIQEKLDAFIEALHQEK MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSHHPTLKLQRPQLRTSFQQFSSLTNLPLRKLKFSPIKYGYQ PRRNFWPARLATRLLKLRYLILGSAVGGGYTAKKTFDQWKDMIPDLSEYKWIVPDIVWEIDEYIDFGSPEETAFRATDRGSE SDKHFRKVSDKEKIDQLQEELLHTQLKYQRILERLEKENKELRKLVLQKDDKGIHHRKLKKSLIDMYSEVLDVLSDYDASY NTQDHLPRVVVVGDQSAGKTSVLEMIAQARIFPRGSGEMMTRSPVKVTLSEGPHHVALFKDSSREFDLTKEEDLAALRHEIE LRMRKNVKEGCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSGMAPDTKETIFSISKAYMQNPNAIILCIQDGSVDAERSI VTDLVSQMDPHGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKLFPMKALGYFAVVTGKGNSSESIEAIREYEEEFFQNSKLLKT SMLKAHQVTTRNLSLAVSDCFWKMVRESVEQQADSFKATRFNLETEWKNNYPRLRELDRNELFEKAKNEILDEVISLSQVT PKHWEEILQQSLWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQWTDKQLPNKAVEVAWETLQEEFSRFMTEPKGKEH DDIFDKLKEAVKEESIKRHKWNDFAEDSLRVIQHNALEDRSISDKQQWDAAIYFMEEALQARLKDTENAIENMVGPDWKKR WLYWKNRTQEQCVHNETKNELEKMLKCNEEHPAYLASDEITTVRKNLESRGVEVDPSLIKDTWHQVYRRHFLKTALNHCN LCRRGFYYYQRHFVDSELECNDVVLFWRIQRMLAITANTLRQQLTNTEVRRLEKNVKEVLEDFAEDGEKKIKLLTGKRVQL AEDLKKVREIQEKLDAFIEALHQEK MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSHHPTLKLQRPQLRTSFQQFSSLTNLPLRKLKFSPIKYGYQ PRRNFWPARLATRLLKLRYLILGSAVGGGYTAKKTFDQWKDMIPDLSEYKWIVPDIVWEIDEYIDFGHKLVSEVIGASDLLL LLGSPEETAFRATDRGSESDKHFRKVSDKEKIDQLQEELLHTQLKYQRILERLEKENKELRKLVLQKDDKGIHHRKLKKSLID MYSEVLDVLSDYDASYNTQDHLPRVVVVGDQSAGKTSVLEMIAQARIFPRGSGEMMTRSPVKVTLSEGPHHVALFKDSSRE FDLTKEEDLAALRHEIELRMRKNVKEGCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSGMAPDTKETIFSISKAYMQNP NAIILCIQDGSVDAERSIVTDLVSQMDPHGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKLFPMKALGYFAVVTGKGNSSESIE AIREYEEEFFQNSKLLKTSMLKAHQVTTRNLSLAVSDCFWKMVRESVEQQADSFKATRFNLETEWKNNYPRLRELDRNELF EKAKNEILDEVISLSQVTPKHWEEILQQSLWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQWTDKQLPNKAVEVAWET LQEEFSRFMTEPKGKEHDDIFDKLKEAVKEESIKRHKWNDFAEDSLRVIQHNALEDRSISDKQQWDAAIYFMEEALQARLK DTENAIENMVGPDWKKRWLYWKNRTQEQCVHNETKNELEKMLKCNEEHPAYLASDEITTVRKNLESRGVEVDPSLIKDT WHQVYRRHFLKTALNHCNLCRRGFYYYQRHFVDSELECNDVVLFWRIQRMLAITANTLRQQLTNTEVRRLEKNVKEVLED FAEDGEKKIKLLTGKRVQLAEDLKKVREIQEKLDAFIEALHQEK MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSHHPTLKLQRPQLRTSFQQFSSLTNLPLRKLKFSPIKYGYQ PRRNFWPARLATRLLKLRYLILGSAVGGGYTAKKTFDQWKDMIPDLSEYKWIVPDIVWEIDEYIDFGSPEETAFRATDRGSE SDKHFRKGLLGELILLQQQIQEHEEEARRAAGQYSTSYAQQKRKVSDKEKIDQLQEELLHTQLKYQRILERLEKENKELRKL VLQKDDKGIHHRKLKKSLIDMYSEVLDVLSDYDASYNTQDHLPRVVVVGDQSAGKTSVLEMIAQARIFPRGSGEMMTRSPV KVTLSEGPHHVALFKDSSREFDLTKEEDLAALRHEIELRMRKNVKEGCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSG MAPDTKETIFSISKAYMQNPNAIILCIQDGSVDAERSIVTDLVSQMDPHGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKLFPMK ALGYFAVVTGKGNSSESIEAIREYEEEFFQNSKLLKTSMLKAHQVTTRNLSLAVSDCFWKMVRESVEQQADSFKATRFNLET EWKNNYPRLRELDRNELFEKAKNEILDEVISLSQVTPKHWEEILQQSLWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQ WTDKQLPNKAVEVAWETLQEEFSRFMTEPKGKEHDDIFDKLKEAVKEESIKRHKWNDFAEDSLRVIQHNALEDRSISDKQQ WDAAIYFMEEALQARLKDTENAIENMVGPDWKKRWLYWKNRTQEQCVHNETKNELEKMLKCNEEHPAYLASDEITTVRK NLESRGVEVDPSLIKDTWHQVYRRHFLKTALNHCNLCRRGFYYYQRHFVDSELECNDVVLFWRIQRMLAITANTLRQQLTN TEVRRLEKNVKEVLEDFAEDGEKKIKLLTGKRVQLAEDLKKVREIQEKLDAFIEALHQEK MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSHHPTLKLQRPQLRTSFQQFSSLTNLPLRKLKFSPIKYGYQ PRRNFWPARLATRLLKLRYLILGSAVGGGYTAKKTFDQWKDMIPDLSEYKWIVPDIVWEIDEYIDFEKIRKALPSSEDLVKL APDFDKIVESLSLLKDFFTSGHKLVSEVIGASDLLLLLGSPEETAFRATDRGSESDKHFRKVSDKEKIDQLQEELLHTQLKYQR ILERLEKENKELRKLVLQKDDKGIHHRKLKKSLIDMYSEVLDVLSDYDASYNTQDHLPRVVVVGDQSAGKTSVLEMIAQAR IFPRGSGEMMTRSPVKVTLSEGPHHVALFKDSSREFDLTKEEDLAALRHEIELRMRKNVKEGCTVSPETISLNVKGPGLQRM VLVDLPGVINTVTSGMAPDTKETIFSISKAYMQNPNAIILCIQDGSVDAERSIVTDLVSQMDPHGRRTIFVLTKVDLAEKNVAS PSRIQQIIEGKLFPMKALGYFAVVTGKGNSSESIEAIREYEEEFFQNSKLLKTSMLKAHQVTTRNLSLAVSDCFWKMVRESVE QQADSFKATRFNLETEWKNNYPRLRELDRNELFEKAKNEILDEVISLSQVTPKHWEEILQQSLWERVSTHVIENIYLPAAQT MNSGTFNTTVDIKLKQWTDKQLPNKAVEVAWETLQEEFSRFMTEPKGKEHDDIFDKLKEAVKEESIKRHKWNDFAEDSLR VIQHNALEDRSISDKQQWDAAIYFMEEALQARLKDTENAIENMVGPDWKKRWLYWKNRTQEQCVHNETKNELEKMLKCN EEHPAYLASDEITTVRKNLESRGVEVDPSLIKDTWHQVYRRHFLKTALNHCNLCRRGFYYYQRHFVDSELECNDVVLFWRI

[0279]

[0280] QRMLAITANTLRQQLTNTEVRRLEKNVKEVLEDFAEDGEKKIKLLTGKRVQLAEDLKKVREIQEKLDAFIEALHQEKAttorney Docket No. : UCH-42525

[0281] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0282] | | if if if if if if 0607080910 XIsoormsoormsoormsoormsoormsoorm MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSHHPTLKLQRPQLRTSFQQFSSLTNLPLRKLKFSPIKYGYQ | | | | | 979 997 1015 837 836 PRRNFWPARLATRLLKLRYLILGSAVGGGYTAKKTFDQWKDMIPDLSEYKWIVPDIVWEIDEYIDFGHKLVSEVIGASDLLL LLGSPEETAFRATDRGSESDKHFRKGLLGELILLQQQIQEHEEEARRAAGQYSTSYAQQKRKVSDKEKIDQLQEELLHTQLK YQRILERLEKENKELRKLVLQKDDKGIHHRKLKKSLIDMYSEVLDVLSDYDASYNTQDHLPRVVVVGDQSAGKTSVLEMIA QARIFPRGSGEMMTRSPVKVTLSEGPHHVALFKDSSREFDLTKEEDLAALRHEIELRMRKNVKEGCTVSPETISLNVKGPGLQ RMVLVDLPGVINTVTSGMAPDTKETIFSISKAYMQNPNAIILCIQDGSVDAERSIVTDLVSQMDPHGRRTIFVLTKVDLAEKN VASPSRIQQIIEGKLFPMKALGYFAVVTGKGNSSESIEAIREYEEEFFQNSKLLKTSMLKAHQVTTRNLSLAVSDCFWKMVRE SVEQQADSFKATRFNLETEWKNNYPRLRELDRNELFEKAKNEILDEVISLSQVTPKHWEEILQQSLWERVSTHVIENIYLPAA QTMNSGTFNTTVDIKLKQWTDKQLPNKAVEVAWETLQEEFSRFMTEPKGKEHDDIFDKLKEAVKEESIKRHKWNDFAEDS LRVIQHNALEDRSISDKQQWDAAIYFMEEALQARLKDTENAIENMVGPDWKKRWLYWKNRTQEQCVHNETKNELEKMLK CNEEHPAYLASDEITTVRKNLESRGVEVDPSLIKDTWHQVYRRHFLKTALNHCNLCRRGFYYYQRHFVDSELECNDVVLFW RIQRMLAITANTLRQQLTNTEVRRLEKNVKEVLEDFAEDGEKKIKLLTGKRVQLAEDLKKVREIQEKLDAFIEALHQEK MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSHHPTLKLQRPQLRTSFQQFSSLTNLPLRKLKFSPIKYGYQ PRRNFWPARLATRLLKLRYLILGSAVGGGYTAKKTFDQWKDMIPDLSEYKWIVPDIVWEIDEYIDFEKIRKALPSSEDLVKL APDFDKIVESLSLLKDFFTSGSPEETAFRATDRGSESDKHFRKGLLGELILLQQQIQEHEEEARRAAGQYSTSYAQQKRKVSD KEKIDQLQEELLHTQLKYQRILERLEKENKELRKLVLQKDDKGIHHRKLKKSLIDMYSEVLDVLSDYDASYNTQDHLPRVV VVGDQSAGKTSVLEMIAQARIFPRGSGEMMTRSPVKVTLSEGPHHVALFKDSSREFDLTKEEDLAALRHEIELRMRKNVKE GCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSGMAPDTKETIFSISKAYMQNPNAIILCIQDGSVDAERSIVTDLVSQMDP

[0283] o> HGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKLFPMKALGYFAVVTGKGNSSESIEAIREYEEEFFQNSKLLKTSMLKAHQVTT RNLSLAVSDCFWKMVRESVEQQADSFKATRFNLETEWKNNYPRLRELDRNELFEKAKNEILDEVISLSQVTPKHWEEILQQS LWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQWTDKQLPNKAVEVAWETLQEEFSRFMTEPKGKEHDDIFDKLKEAV KEESIKRHKWNDFAEDSLRVIQHNALEDRSISDKQQWDAAIYFMEEALQARLKDTENAIENMVGPDWKKRWLYWKNRTQ EQCVHNETKNELEKMLKCNEEHPAYLASDEITTVRKNLESRGVEVDPSLIKDTWHQVYRRHFLKTALNHCNLCRRGFYYY QRHFVDSELECNDVVLFWRIQRMLAITANTLRQQLTNTEVRRLEKNVKEVLEDFAEDGEKKIKLLTGKRVQLAEDLKKVRE IQEKLDAFIEALHQEK MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSHHPTLKLQRPQLRTSFQQFSSLTNLPLRKLKFSPIKYGYQ PRRNFWPARLATRLLKLRYLILGSAVGGGYTAKKTFDQWKDMIPDLSEYKWIVPDIVWEIDEYIDFEKIRKALPSSEDLVKL APDFDKIVESLSLLKDFFTSGHKLVSEVIGASDLLLLLGSPEETAFRATDRGSESDKHFRKGLLGELILLQQQIQEHEEEARRA AGQYSTSYAQQKRKVSDKEKIDQLQEELLHTQLKYQRILERLEKENKELRKLVLQKDDKGIHHRKLKKSLIDMYSEVLDVL SDYDASYNTQDHLPRVVVVGDQSAGKTSVLEMIAQARIFPRGSGEMMTRSPVKVTLSEGPHHVALFKDSSREFDLTKEEDL AALRHEIELRMRKNVKEGCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSGMAPDTKETIFSISKAYMQNPNAIILCIQDGS

[0284] o VDAERSIVTDLVSQMDPHGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKLFPMKALGYFAVVTGKGNSSESIEAIREYEEEFFQ NSKLLKTSMLKAHQVTTRNLSLAVSDCFWKMVRESVEQQADSFKATRFNLETEWKNNYPRLRELDRNELFEKAKNEILDE VISLSQVTPKHWEEILQQSLWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQWTDKQLPNKAVEVAWETLQEEFSRFMT EPKGKEHDDIFDKLKEAVKEESIKRHKWNDFAEDSLRVIQHNALEDRSISDKQQWDAAIYFMEEALQARLKDTENAIENMV GPDWKKRWLYWKNRTQEQCVHNETKNELEKMLKCNEEHPAYLASDEITTVRKNLESRGVEVDPSLIKDTWHQVYRRHFL KTALNHCNLCRRGFYYYQRHFVDSELECNDVVLFWRIQRMLAITANTLRQQLTNTEVRRLEKNVKEVLEDFAEDGEKKIKL LTGKRVQLAEDLKKVREIQEKLDAFIEALHQEK MIPDLSEYKWIVPDIVWEIDEYIDFGSPEETAFRATDRGSESDKHFRKGLLGELILLQQQIQEHEEEARRAAGQYSTSYAQQK RKVSDKEKIDQLQEELLHTQLKYQRILERLEKENKELRKLVLQKDDKGIHHRKLKKSLIDMYSEVLDVLSDYDASYNTQDH LPRVVVVGDQSAGKTSVLEMIAQARIFPRGSGEMMTRSPVKVTLSEGPHHVALFKDSSREFDLTKEEDLAALRHEIELRMRK NVKEGCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSGMAPDTKETIFSISKAYMQNPNAIILCIQDGSVDAERSIVTDLVS QMDPHGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKLFPMKALGYFAVVTGKGNSSESIEAIREYEEEFFQNSKLLKTSMLKA HQVTTRNLSLAVSDCFWKMVRESVEQQADSFKATRFNLETEWKNNYPRLRELDRNELFEKAKNEILDEVISLSQVTPKHWE EILQQSLWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQWTDKQLPNKAVEVAWETLQEEFSRFMTEPKGKEHDDIFDK LKEAVKEESIKRHKWNDFAEDSLRVIQHNALEDRSISDKQQWDAAIYFMEEALQARLKDTENAIENMVGPDWKKRWLYW KNRTQEQCVHNETKNELEKMLKCNEEHPAYLASDEITTVRKNLESRGVEVDPSLIKDTWHQVYRRHFLKTALNHCNLCRR GFYYYQRHFVDSELECNDVVLFWRIQRMLAITANTLRQQLTNTEVRRLEKNVKEVLEDFAEDGEKKIKLLTGKRVQLAEDL KKVREIQEKLDAFIEALHQEK MIPDLSEYKWIVPDIVWEIDEYIDFEKIRKALPSSEDLVKLAPDFDKIVESLSLLKDFFTSGSPEETAFRATDRGSESDKHFRKV SDKEKIDQLQEELLHTQLKYQRILERLEKENKELRKLVLQKDDKGIHHRKLKKSLIDMYSEVLDVLSDYDASYNTQDHLPRV VVVGDQSAGKTSVLEMIAQARIFPRGSGEMMTRSPVKVTLSEGPHHVALFKDSSREFDLTKEEDLAALRHEIELRMRKNVK EGCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSGMAPDTKETIFSISKAYMQNPNAIILCIQDGSVDAERSIVTDLVSQMD PHGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKLFPMKALGYFAVVTGKGNSSESIEAIREYEEEFFQNSKLLKTSMLKAHQVT TRNLSLAVSDCFWKMVRESVEQQADSFKATRFNLETEWKNNYPRLRELDRNELFEKAKNEILDEVISLSQVTPKHWEEILQQ SLWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQWTDKQLPNKAVEVAWETLQEEFSRFMTEPKGKEHDDIFDKLKEA VKEESIKRHKWNDFAEDSLRVIQHNALEDRSISDKQQWDAAIYFMEEALQARLKDTENAIENMVGPDWKKRWLYWKNRT QEQCVHNETKNELEKMLKCNEEHPAYLASDEITTVRKNLESRGVEVDPSLIKDTWHQVYRRHFLKTALNHCNLCRRGFYY YQRHFVDSELECNDVVLFWRIQRMLAITANTLRQQLTNTEVRRLEKNVKEVLEDFAEDGEKKIKLLTGKRVQLAEDLKKVR EIQEKLDAFIEALHQEK MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSHHPTLKLQRPQLRTSFQQFSSLTNLPLRKLKFSPIKYGYQ PRRNFWPARLATRLLKLRYLILGSAVGGGYTAKKTFDQWKDMIPDLSEYKWIVPDIVWEIDEYIDFEKIRKALPSSEDLVKL APDFDKIVESLSLLKDFFTSGHKLVSEVIGASDLLLLLGSPEETAFRATDRGSESDKHFRKGLLGELILLQQQIQEHEEEARRA AGQYSTSYAQQKRKVSDKEKIDQLQEELLHTQLKYQRILERLEKENKELRKLVLQKDDKGIHHRKLKKSLIDMYSEVLDVL SDYDASYNTQDHLPRVVVVGDQSAGKTSVLEMIAQARIFPRGSGEMMTRSPVKVTLSEGPHHVALFKDSSREFDLTKEEDL AALRHEIELRMRKNVKEGCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSGMAPDTKETIFSISKAYMQNPNAIILCIQDGS

[0285] o VDAERSIVTDLVSQMDPHGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKLFPMKALGYFAVVTGKGNSSESIEAIREYEEEFFQ NSKLLKTSMLKAHQVTTRNLSLAVSDCFWKMVRESVEQQADSFKATRFNLETEWKNNYPRLRELDRNELFEKAKNEILDE VISLSQVTPKHWEEILQQSLWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQWTDKQLPNKAVEVAWETLQEEFSRFMT EPKGKEHDDIFDKLKEAVKEESIKRHKWNDFAEDSLRVIQHNALEDRSISDKQQWDAAIYFMEEALQARLKDTENAIENMV GPDWKKRWLYWKNRTQEQCVHNETKNELEKMLKCNEEHPAYLASDEITTVRKNLESRGVEVDPSLIKDTWHQVYRRHFL KTALNHCNLCRRGFYYYQRHFVDSELECNDVVLFWRIQRMLAITANTLRQQLTNTEVRRLEKNVKEVLEDFAEDGEKKIKL

[0286]

[0287] LTGKRVQLAEDLITDIFPSNLLLVVMLRDISWDCMVVAHRDTILSGWGIHSEFSYPVTMHHGSIIAttorney Docket No. : UCH-42525

[0288] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0289] | | if if if if if if X10 X2 X3 X4 X5 X6soormsoormsoormsoormsoormsoorm MYSEVLDVLSDYDASYNTQDHLPRVVVVGDQSAGKTSVLEMIAQARIFPRGSGEMMTRSPVKVTLSEGPHHVALFKDSSRE | | I | 11 694 1029 1010 992956 _ _ FDLTKEEDLAALRHEIELRMRKNVKEGCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSGMAPDTKETIFSISKAYMQNP NAIILCIQDGSVDAERSIVTDLVSQMDPHGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKLFPMKALGYFAVVTGKGNSSESIE AIREYEEEFFQNSKLLKTSMLKAHQVTTRNLSLAVSDCFWKMVRESVEQQADSFKATRFNLETEWKNNYPRLRELDRNELF EKAKNEILDEVISLSQVTPKHWEEILQQSLWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQWTDKQLPNKAVEVAWET LQEEFSRFMTEPKGKEHDDIFDKLKEAVKEESIKRHKWNDFAEDSLRVIQHNALEDRSISDKQQWDAAIYFMEEALQARLK DTENAIENMVGPDWKKRWLYWKNRTQEQCVHNETKNELEKMLKCNEEHPAYLASDEITTVRKNLESRGVEVDPSLIKDT WHQVYRRHFLKTALNHCNLCRRGFYYYQRHFVDSELECNDVVLFWRIQRMLAITANTLRQQLTNTEVRRLEKNVKEVLED FAEDGEKKIKLLTGKRVQLAEDLKKVREIQEKLDAFIEALHQEK MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSHHPTLKLQRPQLRTSFQQFSSLTNLPLRKLKFSPIKYGYQ PRRNFWPARLATRLLKLRYLILGSAVGGGYTAKKTFDQWKDMIPDLSEYKWIVPDIVWEIDEYIDFEKIRKALPSSEDLVKL APDFDKIVESLSLLKDFFTSGSPEETAFRATDRGSESDKHFRKGLLGELILLQQQIQEHEEEARRAAGQYSTSYAQQKRKVSD KEKIDQLQEELLHTQLKYQRILERLEKENKELRKLVLQKDDKGIHHRKLKKSLIDMYSEVLDVLSDYDASYNTQDHLPRVV VVGDQSAGKTSVLEMIAQARIFPRGSGEMMTRSPVKVTLSEGPHHVALFKDSSREFDLTKEEDLAALRHEIELRMRKNVKE GCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSGMAPDTKETIFSISKAYMQNPNAIILCIQDGSVDAERSIVTDLVSQMDP HGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKLFPMKALGYFAVVTGKGNSSESIEAIREYEEEFFQNSKLLKTSMLKAHQVTT RNLSLAVSDCFWKMVRESVEQQADSFKATRFNLETEWKNNYPRLRELDRNELFEKAKNEILDEVISLSQVTPKHWEEILQQS LWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQWTDKQLPNKAVEVAWETLQEEFSRFMTEPKGKEHDDIFDKLKEAV KEESIKRHKWNDFAEDSLRVIQHNALEDRSISDKQQWDAAIYFMEEALQARLKDTENAIENMVGPDWKKRWLYWKNRTQ EQCVHNETKNELEKMLKCNEEHPAYLASDEITTVRKNLESRGVEVDPSLIKDTWHQVYRRHFLKTALNHCNLCRRGFYYY QRHFVDSELECNDVVLFWRIQRMLAITANTLRQQLTNTEVRRLEKNVKEVLEDFAEDGEKKIKLLTGKRVQLAEDLITDIFPS NLLLVVMLRDISWDCMVVAHRDTILSGWGIHSEFSYPVTMHHGSII MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSHHPTLKLQRPQLRTSFQQFSSLTNLPLRKLKFSPIKYGYQ PRRNFWPARLATRLLKLRYLILGSAVGGGYTAKKTFDQWKDMIPDLSEYKWIVPDIVWEIDEYIDFEKIRKALPSSEDLVKL APDFDKIVESLSLLKDFFTSGHKLVSEVIGASDLLLLLGSPEETAFRATDRGSESDKHFRKVSDKEKIDQLQEELLHTQLKYQR ILERLEKENKELRKLVLQKDDKGIHHRKLKKSLIDMYSEVLDVLSDYDASYNTQDHLPRVVVVGDQSAGKTSVLEMIAQAR IFPRGSGEMMTRSPVKVTLSEGPHHVALFKDSSREFDLTKEEDLAALRHEIELRMRKNVKEGCTVSPETISLNVKGPGLQRM VLVDLPGVINTVTSGMAPDTKETIFSISKAYMQNPNAIILCIQDGSVDAERSIVTDLVSQMDPHGRRTIFVLTKVDLAEKNVAS PSRIQQIIEGKLFPMKALGYFAVVTGKGNSSESIEAIREYEEEFFQNSKLLKTSMLKAHQVTTRNLSLAVSDCFWKMVRESVE QQADSFKATRFNLETEWKNNYPRLRELDRNELFEKAKNEILDEVISLSQVTPKHWEEILQQSLWERVSTHVIENIYLPAAQT MNSGTFNTTVDIKLKQWTDKQLPNKAVEVAWETLQEEFSRFMTEPKGKEHDDIFDKLKEAVKEESIKRHKWNDFAEDSLR VIQHNALEDRSISDKQQWDAAIYFMEEALQARLKDTENAIENMVGPDWKKRWLYWKNRTQEQCVHNETKNELEKMLKCN EEHPAYLASDEITTVRKNLESRGVEVDPSLIKDTWHQVYRRHFLKTALNHCNLCRRGFYYYQRHFVDSELECNDVVLFWRI QRMLAITANTLRQQLTNTEVRRLEKNVKEVLEDFAEDGEKKIKLLTGKRVQLAEDLITDIFPSNLLLVVMLRDISWDCMVVA HRDTILSGWGIHSEFSYPVTMHHGSII MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSHHPTLKLQRPQLRTSFQQFSSLTNLPLRKLKFSPIKYGYQ PRRNFWPARLATRLLKLRYLILGSAVGGGYTAKKTFDQWKDMIPDLSEYKWIVPDIVWEIDEYIDFGSPEETAFRATDRGSE SDKHFRKGLLGELILLQQQIQEHEEEARRAAGQYSTSYAQQKRKVSDKEKIDQLQEELLHTQLKYQRILERLEKENKELRKL VLQKDDKGIHHRKLKKSLIDMYSEVLDVLSDYDASYNTQDHLPRVVVVGDQSAGKTSVLEMIAQARIFPRGSGEMMTRSPV KVTLSEGPHHVALFKDSSREFDLTKEEDLAALRHEIELRMRKNVKEGCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSG MAPDTKETIFSISKAYMQNPNAIILCIQDGSVDAERSIVTDLVSQMDPHGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKLFPMK ALGYFAVVTGKGNSSESIEAIREYEEEFFQNSKLLKTSMLKAHQVTTRNLSLAVSDCFWKMVRESVEQQADSFKATRFNLET EWKNNYPRLRELDRNELFEKAKNEILDEVISLSQVTPKHWEEILQQSLWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQ

[0290] | £66 WTDKQLPNKAVEVAWETLQEEFSRFMTEPKGKEHDDIFDKLKEAVKEESIKRHKWNDFAEDSLRVIQHNALEDRSISDKQQ WDAAIYFMEEALQARLKDTENAIENMVGPDWKKRWLYWKNRTQEQCVHNETKNELEKMLKCNEEHPAYLASDEITTVRK NLESRGVEVDPSLIKDTWHQVYRRHFLKTALNHCNLCRRGFYYYQRHFVDSELECNDVVLFWRIQRMLAITANTLRQQLTN TEVRRLEKNVKEVLEDFAEDGEKKIKLLTGKRVQLAEDLITDIFPSNLLLVVMLRDISWDCMVVAHRDTILSGWGIHSEFSYP VTMHHGSII MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSHHPTLKLQRPQLRTSFQQFSSLTNLPLRKLKFSPIKYGYQ PRRNFWPARLATRLLKLRYLILGSAVGGGYTAKKTFDQWKDMIPDLSEYKWIVPDIVWEIDEYIDFEKIRKALPSSEDLVKL APDFDKIVESLSLLKDFFTSGSPEETAFRATDRGSESDKHFRKVSDKEKIDQLQEELLHTQLKYQRILERLEKENKELRKLVLQ KDDKGIHHRKLKKSLIDMYSEVLDVLSDYDASYNTQDHLPRVVVVGDQSAGKTSVLEMIAQARIFPRGSGEMMTRSPVKVT LSEGPHHVALFKDSSREFDLTKEEDLAALRHEIELRMRKNVKEGCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSGMAP DTKETIFSISKAYMQNPNAIILCIQDGSVDAERSIVTDLVSQMDPHGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKLFPMKALG YFAVVTGKGNSSESIEAIREYEEEFFQNSKLLKTSMLKAHQVTTRNLSLAVSDCFWKMVRESVEQQADSFKATRFNLETEW KNNYPRLRELDRNELFEKAKNEILDEVISLSQVTPKHWEEILQQSLWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQWT DKQLPNKAVEVAWETLQEEFSRFMTEPKGKEHDDIFDKLKEAVKEESIKRHKWNDFAEDSLRVIQHNALEDRSISDKQQWD AAIYFMEEALQARLKDTENAIENMVGPDWKKRWLYWKNRTQEQCVHNETKNELEKMLKCNEEHPAYLASDEITTVRKNL ESRGVEVDPSLIKDTWHQVYRRHFLKTALNHCNLCRRGFYYYQRHFVDSELECNDVVLFWRIQRMLAITANTLRQQLTNTE VRRLEKNVKEVLEDFAEDGEKKIKLLTGKRVQLAEDLITDIFPSNLLLVVMLRDISWDCMVVAHRDTILSGWGIHSEFSYPV TMHHGSII MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSHHPTLKLQRPQLRTSFQQFSSLTNLPLRKLKFSPIKYGYQ PRRNFWPARLATRLLKLRYLILGSAVGGGYTAKKTFDQWKDMIPDLSEYKWIVPDIVWEIDEYIDFGSPEETAFRATDRGSE SDKHFRKVSDKEKIDQLQEELLHTQLKYQRILERLEKENKELRKLVLQKDDKGIHHRKLKKSLIDMYSEVLDVLSDYDASY NTQDHLPRVVVVGDQSAGKTSVLEMIAQARIFPRGSGEMMTRSPVKVTLSEGPHHVALFKDSSREFDLTKEEDLAALRHEIE LRMRKNVKEGCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSGMAPDTKETIFSISKAYMQNPNAIILCIQDGSVDAERSI VTDLVSQMDPHGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKLFPMKALGYFAVVTGKGNSSESIEAIREYEEEFFQNSKLLKT SMLKAHQVTTRNLSLAVSDCFWKMVRESVEQQADSFKATRFNLETEWKNNYPRLRELDRNELFEKAKNEILDEVISLSQVT PKHWEEILQQSLWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQWTDKQLPNKAVEVAWETLQEEFSRFMTEPKGKEH DDIFDKLKEAVKEESIKRHKWNDFAEDSLRVIQHNALEDRSISDKQQWDAAIYFMEEALQARLKDTENAIENMVGPDWKKR WLYWKNRTQEQCVHNETKNELEKMLKCNEEHPAYLASDEITTVRKNLESRGVEVDPSLIKDTWHQVYRRHFLKTALNHCN LCRRGFYYYQRHFVDSELECNDVVLFWRIQRMLAITANTLRQQLTNTEVRRLEKNVKEVLEDFAEDGEKKIKLLTGKRVQL

[0291]

[0292] AEDLITDIFPSNLLLVVMLRDISWDCMVVAHRDTILSGWGIHSEFSYP VTMHHGSIIAttorney Docket No. : UCH-42525

[0293] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0294] | | if if if X7 X8 X9soormsoormsoorm MIPDLSEYKWIVPDIVWEIDEYIDFEKIRKALPSSEDLVKLAPDFDKIVESLSLLKDFFTSGHKLVSEVIGASDLLLLLGSPEETA | | 11 923 729726 _ _ FRATDRGSESDKHFRKGLLGELILLQQQIQEHEEEARRAAGQYSTSYAQQKRKVSDKEKIDQLQEELLHTQLKYQRILERLE KENKELRKLVLQKDDKGIHHRKLKKSLIDMYSEVLDVLSDYDASYNTQDHLPRVVVVGDQSAGKTSVLEMIAQARIFPRGS GEMMTRSPVKVTLSEGPHHVALFKDSSREFDLTKEEDLAALRHEIELRMRKNVKEGCTVSPETISLNVKGPGLQRMVLVDLP GVINTVTSGMAPDTKETIFSISKAYMQNPNAIILCIQDGSVDAERSIVTDLVSQMDPHGRRTIFVLTKVDLAEKNVASPSRIQQI

[0295] o IEGKLFPMKALGYFAVVTGKGNSSESIEAIREYEEEFFQNSKLLKTSMLKAHQVTTRNLSLAVSDCFWKMVRESVEQQADSF KATRFNLETEWKNNYPRLRELDRNELFEKAKNEILDEVISLSQVTPKHWEEILQQSLWERVSTHVIENIYLPAAQTMNSGTFN TTVDIKLKQWTDKQLPNKAVEVAWETLQEEFSRFMTEPKGKEHDDIFDKLKEAVKEESIKRHKWNDFAEDSLRVIQHNALE DRSISDKQQWDAAIYFMEEALQARLKDTENAIENMVGPDWKKRWLYWKNRTQEQCVHNETKNELEKMLKCNEEHPAYL ASDEITTVRKNLESRGVEVDPSLIKDTWHQVYRRHFLKTALNHCNLCRRGFYYYQRHFVDSELECNDVVLFWRIQRMLAIT ANTLRQQLTNTEVRRLEKNVKEVLEDFAEDGEKKIKLLTGKRVQLAEDLITDIFPSNLLLVVMLRDISWDCMVVAHRDTILS GWGIHSEFSYPVTMHHGSII MWRLRRAAVACEVCQSLVKHSSGIKGSLPLQKLHLVSRSIYHSHHPTLKLQRPQLRTSFQQFSSLTNLPLRKLKFSPIKYGYQ PRRNFWPARLATRLLKLRYLILGSAVGGGYTAKKTFDQWKDMIPDLSEYKWIVPDIVWEIDEYIDFEKIRKALPSSEDLVKL APDFDKIVESLSLLKDFFTSGHKLVSEVIGASDLLLLLGSPEETAFRATDRGSESDKHFRKGLLGELILLQQQIQEHEEEARRA AGQYSTSYAQQKRKVSDKEKIDQLQEELLHTQLKYQRILERLEKENKELRKLVLQKDDKGIHHRKLKKSLIDMYSEVLDVL SDYDASYNTQDHLPRVVVVGDQSAGKTSVLEMIAQARIFPRGSGEMMTRSPVKVTLSEGPHHVALFKDSSREFDLTKEEDL AALRHEIELRMRKNVKEGCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSGMAPDTKETIFSISKAYMQNPNAIILCIQDGS VDAERSIVTDLVSQMDPHGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKLFPMKALGYFAVVTGKGNSSESIEAIREYEEEFFQ NSKLLKTSMLKAHQVTTRNLSLAVSDCFWKMVRESVEQQADSFKATRFNLETEWKNNYPRLRELDRNELFEKAKNEILDE VISLSQVTPKHWEEILQQSLWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQWTDKQLPNKAVEVRI MYSEVLDVLSDYDASYNTQDHLPRVVVVGDQSAGKTSVLEMIAQARIFPRGSGEMMTRSPVKVTLSEGPHHVALFKDSSRE FDLTKEEDLAALRHEIELRMRKNVKEGCTVSPETISLNVKGPGLQRMVLVDLPGVINTVTSGMAPDTKETIFSISKAYMQNP NAIILCIQDGSVDAERSIVTDLVSQMDPHGRRTIFVLTKVDLAEKNVASPSRIQQIIEGKLFPMKALGYFAVVTGKGNSSESIE AIREYEEEFFQNSKLLKTSMLKAHQVTTRNLSLAVSDCFWKMVRESVEQQADSFKATRFNLETEWKNNYPRLRELDRNELF EKAKNEILDEVISLSQVTPKHWEEILQQSLWERVSTHVIENIYLPAAQTMNSGTFNTTVDIKLKQWTDKQLPNKAVEVAWET LQEEFSRFMTEPKGKEHDDIFDKLKEAVKEESIKRHKWNDFAEDSLRVIQHNALEDRSISDKQQWDAAIYFMEEALQARLK DTENAIENMVGPDWKKRWLYWKNRTQEQCVHNETKNELEKMLKCNEEHPAYLASDEITTVRKNLESRGVEVDPSLIKDT WHQVYRRHFLKTALNHCNLCRRGFYYYQRHFVDSELECNDVVLFWRIQRMLAITANTLRQQLTNTEVRRLEKNVKEVLED

[0296]

[0297] FAEDGEKKIKLLTGKRVQLAEDLITDIFPSNLLLVVMLRDISWDCMVVAHRDTILSGWGIHSEFSYPVTMHHGSIIAttorney Docket No. : UCH-42525

[0298] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0299] EXAMPLES

[0300] The following examples, which are included herein for illustration purposes only, are not intended to be limiting.

[0301] Example 1: Mitochondrial Proteins as Predictors of Response to Anti-Cancer Agents The mitochondria exist in networks within cells and form both an outer and inner membrane. The inner mitochondrial membrane (IMM) is commonly referred to as the mitochondrial cristae. The cristae must remain structurally folded so that mitochondria can appropriately function. Critical to this function is the protein OPA1, which maintains mitochondrial cristae structure and function. When the cristae become disorganized, the mitochondria are prone to undergo programmed apoptosis.

[0302] The present disclosure shows that while hyper-fragmented mitochondrial networks are permissive to cytotoxic therapy induced apoptosis, some tumors have fused networks at baseline that are resistant resistance to cytotoxic therapy, such as ADCs. In addition, hyperfragmented mitochondrial networks that are permissive to cytotoxic therapy induced apoptosis often undergo remodeling into fused networks during acquired therapy resistance to cytotoxic therapy, such as ADCs, leading to a lack of further clinical benefit to previously effected therapies. This is demonstrated through the quantification of defined mitochondrial phenotypes (fused networks with organized cristae vs. hyper-fragmented networks with disorganized cristae). Accordingly, it is shown that a tumor’s expression of the protein OPA1 is predictive of cytotoxic therapy response, inclusive of ADCs with cytotoxic therapy payloads, such as topoisomerase I inhibitors, addressing this critical unmet clinical need, since the majority of patients do not respond to cytotoxic therapies, inclusive of ADCs.

[0303] Mitochondrial membrane potential (AT) and OPA1 mediated cristae structure dictate therapeutic response to cytotoxic therapy.

[0304] A screen of cancer cell lines in response to cisplatin, a well-established cytotoxic chemotherapy, was performed, and it was found that tumor cells with the highest mitochondrial membrane potential were the most resistant to cisplatin induced apoptosis (FIGs. 1A-B). In addition, a significant inverse correlation between mitochondrial membrane potential and cell death was identified (FIG. 1C), suggesting that mitochondrial membrane potential predicts for response to cytotoxic therapy. Next, super-resolution Airyscan microscopy was used to evaluate whether mitochondrial structure (fused vs. fragmented) andAttorney Docket No. : UCH-42525

[0305] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0306] cristae architecture predicted for response to cisplatin (FIGs. 1D-E). Tumor cells with hyperfragmented mitochondria, and open cristae with reduced mitochondrial membrane potential within their individual cristae, were most sensitive to cisplatin (FIG. ID). In contrast, tumor cells with fused mitochondrial networks and closed cristae, with significantly increased mitochondrial membrane potential, were resistant to cisplatin (FIG. IE). Quantification of mitochondrial fragmentation and cristae mitochondrial membrane potential is shown in FIGs.

[0307] 1F-G

[0308] OPA1 mediated organization of mitochondrial networks and cristae governs selective cytotoxic therapy response.

[0309] Mitochondrial network remodeling in the H1975 cancer line was evaluated following CRISPR / Cas9 knockdown of the mitochondrial protein OPA1, which is known to regulate mitochondrial fusion and cristae junction architecture. H1975 is a cell line isolated from the lungs of a patient with non-small cell lung cancer. Super-resolution STED microscopy and machine learning based software were used to segment and analyze mitochondrial networks. As predicted, OPA1 knockdown induced hyper-fragmentation of the outer mitochondrial membrane (OMM) and remodeling of the IMM from organized / closed Type I cristae to disorganized / open Type II / III cristae (FIGs. 2A-D) Immunoblots confirmed efficient CRISPR / Cas9 knockdown of OPA1 (FIG. 2E).

[0310] Next, apoptosis in isogenic H1975 sgOPAl knockout and sgNT (non-targeting) control cell lines was assessed following treatment with vehicle (veh), topoisomerase I inhibitors (Topi), TROP2 antibody (TROP2), or TROP2-TopI ADC (an antibody with Topi payload). As exemplified herein, the topoisomerase inhibitor is DXd (an exatecan derivative), the TROP2 antibody is a polyclonal TROP-2 anti-human antibody (Polyclonal, R&D Systems™, Cat# AF650), and the TROP2-TopI ADC is Datopotamab deruxtecan (Dato-DXd, purchased from Sellekchem, Cat#D4050). Dato-DXd is an antibody-drug conjugate comprising an anti-TROP2 antibody (datopotamab) and DXd.

[0311] Importantly, H1975 sgOPAl cells with hyper-fragmented mitochondria and Type II / III (open) cristae were significantly more sensitive to Topi and TROP2-TopI, as well as staurosporine (stauro), than control sgNT cell lines with fused mitochondria and Type I (closed) cristae, (FIG. 2F). This result strongly supports a mechanistic link between OPA1-L expression and ADC response via an OPA1-L direct effect on mitochondrial and cristae architecture.Attorney Docket No. : UCH-42525

[0312] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0313] To further probe this link, TROP2-TopI was combined with venetoclax, which is known to reduce OPA1-L, inhibit BCL-2, and prime tumors to apoptosis, to assess for additive anti-tumor efficacy of this combination. Encouragingly, venetoclax induced a clear reduction in protein expression of the OPA1-L isoform and hyper-fragmentation of TROP2-TopI resistant H1975 cells (FIG.2G-H), consistent with prior work. Next, it was tested whether venetoclax induced reduction of OPA1-L would sensitize H1975 cells to TROP2-Topl. Surprisingly, the combination of venetoclax plus a TROP2-TopI led to tumor cell apoptosis levels that were significantly higher than with Topi, TROP2 antibody, TROP2-TopI, or venetoclax monotherapy (FIG.21).

[0314] Lastly, whether genetic deletion of OPA1 would sensitize H1975 mouse tumor xenografts to anti-cancer therapies. The ADC Dato-DXd was used as the exemplary anticancer therapy. H1975 sgNT control and sgOPAl knockdown cell lines were implanted into the flanks of NSG mice. When tumors reached a size of approximately 100-200mm3, the mice were treated with vehicle or a single dose of Dato-DXd (5mg / kg / iv). Tumor volumes were measured from day 0 (time of treatment) to day 21. Table 3 shows the percent change in tumor volume, calculated as the difference between tumor volumes on day 21 and day 0 over the tumor volume on day 0. The results demonstrate that H1975 sgOPAl tumors with OPA1 knocked down were significantly more sensitive than the matched isogenic H1975 sgNT control tumors that retained full expression of OPA1 (FIG. 4A-B).

[0315] Therefore, OPA1 mediated regulation of mitochondrial fusion and cristae junction architecture are directly linked to ADC induced apoptosis, suggesting a causative relationship that can be exploited by leveraging a tumor’s OPA1 expression level to predict likelihood of cytotoxic therapy benefit in the clinic.

[0316] Table 3. Growth inhibition of H1975 tumor xenografts, as shown in FIG. 4A-B sgRNA Anti-Cancer Average % Change Standard Error of Treatment in Tumor growth the Mean

[0317] NT (non-targeted) Vehicle 528.07 93.24 NT (non-targeted) Dato-DXd 248.49 15.38 OP Al Vehicle 345.39 38.43 OPA1 Dato-DXd 73.15 15.30

[0318]

[0319] Attorney Docket No. : UCH-42525

[0320] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0321] OPA1 knockout and knockdown were performed as previously described in Sessions et al. “Opal and Drpl reciprocally regulate cristae morphology, ETC function, and NAD+ regeneration in KRas-mutant lung adenocarcinoma.” Cell Reports (2022). In the examples described herein, the nucleic acid encoding the sgRNA used to target human OPA1 (sgOPAl) was TCAGTGGAAAGATATGATAC (SEQ ID NO: 1). Another nucleic acid encoding sgRNA that can target human OPA1 is AAATGTAGCCAGTCCAAGCA (SEQ ID NO: 2). As used herein, “sgNT” describes non-targeted sgRNA used as a control. The backbones for sgRNAs exemplified herein is the lentiCRISPR v2, as described in Sajana et al. “Improved vectors and genome-wild libraries for CRISPR screening.” Nature Methods (2014) and is available at AddGene as Plasmid #52961.

[0322] OPA1 represents a predictive biomarkers of cytotoxic therapy sensitivity, inclusive of ADCs with cytotoxic therapy payloads.

[0323] OPA1 and ADC receptor target levels were analyzed in tumor lysates from PDXs (N=12) established from patients receiving TROP2-TopI ADC treatment. The PDXs were collected from solid tumors in patients with advanced and / or metastatic cancer. Importantly, expression of OPA1-L and total OPA1 protein levels were dramatically reduced in Sensitive (S) vs. Resistant (R) tumors (FIG. 3A, bolded box). The presence of the OMM protein TOM20, which confirms mitochondrial presence in all PDXs, suggests that tumors with low levels of OPA1 (OPAlLo tumors) have significant defects in cristae organization (FIG. 3A).

[0324] In addition, ADC receptor expression did not predict for TROP2-TopI sensitivity.

[0325] Of direct clinical relevance is the assessment of OPA1 protein levels in tumors at baseline, prior to treatment with cytotoxic therapy (e.g., ADCs with cytotoxic chemotherapy payloads). There was a profound difference in the median progression free survival (PFS) and overall survival (OS) when assessing OPAlLo, ADC Sensitive tumors (n=4) vs. OPAlHi, ADC Resistant tumors (n=8), as shown in Table 4. OPAlLo tumors have low levels of OPA1; OPAlHi tumors have higher levels of OPAL Specifically, OPA1-L protein expression in tumor tissue was measured by densitometry. OPA1-L expression values were normalized to mitochondrial TOM20. OPAlLo tumors were defined as tumors wherein the ratio of OPA1-L to TOM20 is less than 1. OPAlHi tumors were defined as tumors wherein the ratio of OPA1-L to TOM20 is greater than 1. The median PFS for OPAlLo, ADC Sensitive tumors was 418 days compared to only 103 days in OPAlHi, ADC Resistant tumors. Similarly, the median OS for OPAlLo, ADC Sensitive tumors was 619 daysAttorney Docket No. : UCH-42525

[0326] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0327] compared to only 143.5 days in OPAlHi, ADC Resistant tumors. These results have significant clinical implications as they show that a tumor’s OPA1 expression level can predict for both substantially longer PFS and OS, supporting the potential value of OPA1 tumor assessment prior to treatment administration as a way to precisely guide patient selection and enrich for likelihood of patients that are biomarker positive (i.e., OPAlLo).

[0328] Table 4. OPA1 protein levels in tumors before treatment with cytotoxic therapy and associated patient outcomes

[0329] OPAlLo tumors (ADC Sensitive) OPAlHi tumors (ADC Resistant) Progression free Overall survival Progression free Overall survival survival (PFS; (OS; days) survival (PFS; (OS; days) days) days)

[0330] 71 143 168 221

[0331] 196 Unknown 162 649

[0332] 532 660 77 160

[0333] 418 619 82 82

[0334] 161 294

[0335] 43 419

[0336] 79 175

[0337] 38 66

[0338]

[0339] Next, immunofluorescence (IF) staining was performed on formalin fixed paraffin embedded (FFPE) TROP2-TopI sensitive (76-S) vs. resistant patient tumors (38-R) (FIG.

[0340] 3B). These tumors were stained for the mitochondrial protein MTC02 / DAPI, imaged by Airyscan (FIG.3B panels i and iii), and then evaluated using machine learning Aivia software to trace networks and quantify mitochondrial morphologies, as shown in FIG.3B panels ii and iv. Importantly, quantification of mitochondrial length (pm) and area (pm2) showed a significant increase in resistant (38) vs. sensitive (76) patient tumors (FIG.3C-D).

[0341] Finally, IF staining and machine learning quantitative analyses (Aivia software) were performed on longitudinal tumor biopsies from patient 54-S, obtained prior to therapy (1BX) and after repeated TROP2-TopI administration (2BX). Strikingly, the results indicate that TROP2-TopI administration led to a significant increase in both mitochondrial length and area in 2BX vs. 1BX, consistent with the patient’s clinical course of initial TROP2-TopIAttorney Docket No. : UCH-42525

[0342] UCLA Ref. No.: [UCLA 2025-055-2] WO

[0343] response followed by subsequent resistance (FIGs. 3E-G). These results strongly link both OPA1 expression and its governance of mitochondrial structure as predictors of ADC response in human tumors.

[0344] INCORPORATION BY REFERENCE

[0345] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0346] EQUIVALENTS

[0347] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

Attorney Docket No. : UCH-42525UCLA Ref. No.: [UCLA 2025-055-2] WOCLAIMSWe claim:

1. A method of reducing levels of OPA1 in a subject comprising administering an anti-OPA1 agent.

2. The method of claim 1, wherein the method further comprises treating cancer in the subject by administering an anti-cancer agent.

3. A method of treating cancer in a subject comprising administering an anti-OPAl agent and an anti-cancer agent.

4. The method of any one of claims 1-3, wherein levels of OPA1 in the subject are reduced relative to a reference level.

5. The method of any one of claims 1-4, wherein the anti-OPAl agent is a small molecule, a polypeptide (e.g., an OPA1 -specific PROTAC), an inhibitory oligonucleotide, or a gene-editing agent.

6. The method of any one of claims 1-4, wherein the anti-OPAl agent is a BH3 mimetic (e.g., venetoclax or navitoclax), preferably wherein the BH3 mimetic is venetoclax.

7. The method of claim 5, wherein the anti-OPAl agent is an inhibitory oligonucleotide specific for OPAL8. The method of claim 7, wherein the inhibitory oligonucleotide is selected from siRNA, shRNA, and antisense RNA, or is a polynucleotide that encodes a molecule selected from siRNA, shRNA, and antisense RNA.

9. The method of claim 5, wherein the anti-OPAl agent is a gene editing agent that edits a gene encoding OPA1 or reduces the amount or activity of RNA encoding OPAL10. The method of claim 9, wherein the gene editing agent is a CRISPR-Cas system with a sgRNA targeting OP Al .

11. The method of claim 10, wherein the sgRNA targeting OPA1 is encoded by a nucleic acid that comprises a sequence that has at least about 80%, about 90%, about 95%, aboutAttorney Docket No. : UCH-42525UCLA Ref. No.: [UCLA 2025-055-2] WO96%, about 97%, about 98%, or about 99% sequence identity to SEQ ID NO: 1 or SEQ ID NO: 2.

12. The method of claim 10, wherein the sgRNA targeting OPA1 is encoded by a nucleic acid that comprises a sequence of SEQ ID NO: 1.

13. The method of claim 10, wherein the sgRNA targeting OPA1 is encoded by a nucleic acid that comprises a sequence of SEQ ID NO: 2.

14. A method of treating cancer comprising administering an anti-cancer agent to a subject, wherein the subject has reduced levels of OPA1 relative to a reference level.

15. The method of any one of claims 1-2 and 4-14, wherein the levels of OPA1 are measured in mitochondria.

16. The method of any one of claims 1-2 and 4-15, wherein the levels of OPA1 comprise the levels of the OPA1-L isoform.

17. The method of any one of claims 1-2 and 4-16, wherein the levels of OPA1 comprise the levels of the total OPA1 protein.

18. The method of any one of claims 2-17, wherein the subject has reduced levels of OPA1 in the cancer relative to a reference level.

19. The method of any one of claims 1-2 and 4-18, wherein the levels of OPA1 are measured in a subject sample.

20. A method of treating cancer comprising administering an anti-cancer agent to a subject, wherein the subject has reduced mitochondrial membrane potential relative to a reference level.

21. The method of claim 20, wherein the subject has reduced mitochondrial membrane potential in the cancer relative to a reference level.

22. The method of claim 20 or 21, wherein the mitochondrial membrane potential is measured in a subject sample.Attorney Docket No. : UCH-42525UCLA Ref. No.: [UCLA 2025-055-2] WO23. A method of treating cancer in a subject comprising administering an anti-cancer agent to the subject, wherein the subject has reduced mitochondrial length or mitochondrial area relative to a reference level.

24. The method of claim 23, wherein the subject has reduced mitochondrial length or mitochondrial area in the cancer relative to a reference level.

25. The method of claim 23 or 24, wherein the reduced mitochondrial length or mitochondrial area is measured in a subject sample.

26. A method of treating cancer in a subject comprising administering an anti-cancer agent to the subject, wherein the subject has increased mitochondrial fragmentation, reduced mitochondrial cristae organization, and / or reduced mitochondrial cristae density relative to a reference level.

27. The method of claim 26, wherein the subject has increased mitochondrial fragmentation, reduced mitochondrial cristae organization, and / or reduced mitochondrial cristae density in the cancer relative to a reference level.

28. The method of claim 26 or 27, wherein the increased mitochondrial fragmentation, reduced mitochondrial cristae organization, and / or reduced mitochondrial cristae density is measured in a subject sample.

29. The method of any one of claims 19, 22, 25, or 28, wherein the subject sample comprises at least one of peripheral blood, plasma, serum, or cancer tissue (e.g., a tumor xenograft or a tumor biopsy).

30. The method of any one of claims 4-29, wherein the reference level is a value obtained from a subject or a plurality of subjects that do not have cancer.

31. The method of any one of claims 4-30, wherein the reference level is measured from a reference sample.

32. The method of claim 31, wherein the reference sample comprises at least one of peripheral blood, plasma, serum, or cancer tissue (e.g., a tumor xenograft or a tumor biopsy).Attorney Docket No. : UCH-42525UCLA Ref. No.: [UCLA 2025-055-2] WO33. The method of claim 31 or 32, wherein the reference sample is of the same or comparable tissue type as the subject sample.

34. The method of any one of claims 31-33, wherein the reference sample is a plurality of cells or a tissue that does not exhibit the same phenotype as the subject sample.

35. The method of any one of claims 31-34, wherein the reference sample comprises non-cancerous tissue from the subject.

36. The method of any one of claims 31-35, wherein the reference sample is obtained from a subject or a plurality of subjects that do not have cancer.

37. The method of any one of claims 2-36, wherein the anti-cancer agent is a small molecule.

38. The method of claim 37, wherein the anti-cancer agent is a topoisomerase inhibitor.

39. The method of claim 37, wherein the anti-cancer agent is cisplatin, carboplatin, or DXd.

40. The method of any one of claims 2-36, wherein the anti-cancer agent is an antibody.

41. The method of claim 40, wherein the anti-cancer agent is an anti-TROP2 antibody.

42. The method of any one of claims 2-36, wherein the anti-cancer agent is an antibodydrug conjugate.

43. The method of claim 42, wherein the anti-cancer agent is a TROP2 antibody conjugated to a topoisomerase inhibitor.

44. The method of claim 42 or 43, wherein the anti-cancer agent is datopotamab deruxtecan (Dato-DXd).

45. The method of any one of claims 2-44, wherein the cancer is a tumor.

46. The method of any one of claims 2-45, wherein the cancer is non-small cell lung cancer (NSCLC).

47. The method of any one of claims 2-45, wherein the cancer is breast cancer.Attorney Docket No. : UCH-42525UCLA Ref. No.: [UCLA 2025-055-2] WO48. The method of any one of claims 2-44, wherein the cancer is breast cancer, urothelial cancer, kidney cancer, head & neck cancer, lung cancer, mesothelioma, ovarian cancer, cervical cancer, gastric cancer, colorectal cancer, pancreatic cancer, testicular cancer, endometrial cancer, esophageal cancer, brain cancer, bone cancer, leukemia, lymphoma, multiple myeloma, testicular cancer, oral cancer, gallbladder cancer, uterine cancer, vaginal cancer, vulvar cancer, cervical cancer, penile cancer, prostate cancer, anal or rectal cancer, endocrine tumors, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, retinoblastoma, or sarcoma.

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