Therapy for neurofibromatosis type 1

Abstract

This application describes a technology relating to treating neurofibromatosis type 1 and particularly, but not exclusively, to compositions and methods for gene replacement therapy treatments of patients having NF1-related tumors, for example, new recombinant adeno-associated virus vectors comprising a neurofibromatosis type 1 GAP-related domain fused to a Ras hypervariable region and use thereof to treat neurofibromatosis type 1.

Description

[0001]JHU-43764.601 Client Docket No: P18504-02 THERAPY FOR NEUROFIBROMATOSIS TYPE 1 CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to and the benefit of U.S. Provisional Patent Application No.63 / 697,752, filed September 23, 2024, which is incorporated by reference herein in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant CA230179 awarded by the National Institutes of Health and grant W81XWH-18-1-0236 awarded by the Department of Defense. The government has certain rights in the invention. SEQUENCE LISTING The text of the computer readable sequence listing filed herewith, titled “JHU-43764-601- SQL”, created September 18, 2025, having a file size of 72,786 bytes, is hereby incorporated by reference in its entirety. FIELD Provided herein is technology relating to treating neurofibromatosis type 1 (NF1) and particularly, but not exclusively, to compositions, methods, systems, and kits for gene replacement therapy treatments of patients having NF1-related tumors. BACKGROUND Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome caused by alterations in the NF1 gene. NF1 mutations produce tumor growth in the peripheral nervous system and often cause morbidity and mortality. NF1 gene replacement therapy, though promising, is hindered by the large size of the NF1 gene and delivery challenges. Accordingly, new gene therapy technologies are needed. SUMMARY Provided herein are embodiments of a gene replacement construct comprising a membrane- targeted truncated NF1 gene that effectively suppressed the Ras signaling pathway and restored Schwann cell differentiation in NF1 induced pluripotent stem cells (iPSC). In some JHU-43764.601 Client Docket No: P18504-02 embodiments, the gene replacement construct finds use in systemic application. During the development of embodiments of the technology described herein, an Adeno-Associated Virus (AAV) vector that was engineered using in vivo capsid evolution through sequential DNA shuffling and peptide library screening in an NF1 xenograft mouse model. The experiments produced a tailored vector that exhibited greatly reduced liver uptake, enhanced tumor targeting across various neurofibroma and glioma, and showed therapeutic efficacies in xenografts. Data collected during the experiments indicated that the AAV-NF gene replacement construct provides a viable AAV vector for NF1 treatment. Moreover, the technology is generally applicable to non-NF1 diseases and thus provides a replicable strategy for vector development to treat other tumor-related diseases. For instance, in some embodiments the technology relates to a recombinant adeno- associated virus (rAAV). In some embodiments, the rAAV comprises a nucleic acid comprising a nucleotide sequence encoding a polypeptide comprising a neurofibromatosis type 1 GAP-related domain (NF1-GRD) fused to a Ras hypervariable region (HVR); and a capsid polypeptide comprising an amino acid sequence that is optimized for tropism to NF1- related tumors. In some embodiments, the NF1-GRD is optimized for expression and anti- tumor effectiveness. In some embodiments, the NF1-GRD comprises amino acids 1200– 1532 of NF1 (SEQ ID NO: 18) (GRD333). In some embodiments, the NF1-GRD has an amino acid sequence provided by SEQ ID NO: 18 (GRD333). In some embodiments, the Ras HVR comprises a HVR amino acid sequence from a HRas HVR, NRas HVR, KRas4A HVR, or KRas4B HVR. In some embodiments, the Ras HVR comprises a HVR amino acid sequence from a KRas4B HVR. In some embodiments, the Ras HVR comprises a sequence provided by SEQ ID NO: 16 (C24). In some embodiments, the nucleic acid comprises a nucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 43 (GRD333-C24). In some embodiments, the capsid polypeptide comprises an amino acid sequence provided by SEQ ID NO: 31 to 42. In some embodiments, the capsid polypeptide comprises an amino acid sequence provided by SEQ ID NO: 32 (K57) or SEQ ID NO: 36 (K55). In some embodiments, the capsid polypeptide comprises an amino acid sequence provided by SEQ ID NO: 36 (K55). In some embodiments, the NF1-GRD has an amino acid sequence that has at least 75% identity to SEQ ID NO: 18 (GRD333). In some embodiments, the capsid polypeptide comprises an amino acid sequence that has at least 75% identity to SEQ ID NO: 32 (K57) or SEQ ID NO: 36 (K55). In some embodiments, the JHU-43764.601 Client Docket No: P18504-02 capsid polypeptide comprises an amino acid sequence that has at least 75% identity to SEQ ID NO: 36 (K55). Additional embodiments relate to a method of treating a patient having neurofibromatosis type 1 (NF1). For instance, in some embodiments, methods comprise administering a recombinant adeno-associated virus (rAAV) to the patient, wherein the rAAV comprises a nucleic acid comprising a nucleotide sequence encoding a polypeptide comprising a neurofibromin 1 GAP-related domain (NF1-GRD) fused to a Ras hypervariable region (HVR); and a capsid polypeptide comprising an amino acid sequence that is optimized for tropism to NF1-related tumors. In some embodiments, the patient is a human. In some embodiments, the patient has a mutation in a NF1 gene. In some embodiments, the patient has a tumor. In some embodiments, a nucleotide sequence encoding a polypeptide comprising SEQ ID NO: 43 is integrated into a chromosome (e.g., chromosome 19) of the patient after said administration. In some embodiments, the technology relates to kits for producing a recombinant adeno-associated virus (rAAV). In some embodiments, kits comprise a first AAV vector comprising a nucleic acid comprising a nucleotide sequence encoding a polypeptide comprising a neurofibromin 1 GAP-related domain (NF1-GRD) fused to a Ras hypervariable region (HVR); and a second AAV vector comprising a nucleic acid comprising a cap gene sequence encoding a capsid polypeptide comprising an amino acid sequence that is optimized for tropism to NF1-related tumors. In some embodiments, the first AAV vector comprises a nucleotide sequence encoding a GRD333 polypeptide (SEQ ID NO: 18). In some embodiments, the first AAV vector comprises a nucleotide sequence encoding a GRD333- C24 polypeptide (SEQ ID NO: 43). In some embodiments, the second AAV vector comprises a nucleotide sequence encoding a K55 cap gene sequence (SEQ ID NO: 9) or a K57 cap gene sequence (SEQ ID NO: 11). In some embodiments, the second AAV vector comprises a nucleotide sequence encoding a capsid polypeptide comprising a K55 peptide (SEQ ID NO: 36) or a K57 peptide (SEQ ID NO: 32). In some embodiments, the second AAV vector comprises a nucleotide sequence encoding a K55 capsid (SEQ ID NO: 10) or a K57 capsid (SEQ ID NO: 12). In some embodiments, kits further comprise a helper plasmid. In some embodiments, the compositions and kits find use in treating a patient having NF1. In some embodiments, the technology provides a rAAV as described herein for use in treating NF1. In some embodiments, the rAAV comprises a nucleic acid comprising a JHU-43764.601 Client Docket No: P18504-02 nucleotide sequence encoding a polypeptide comprising a neurofibromin 1 GAP-related domain (NF1-GRD) fused to a Ras hypervariable region (HVR); and a capsid polypeptide comprising an amino acid sequence that is optimized for tropism to NF1-related tumors. In some embodiments, the technology provides use of a rAAV for the manufacture of a medicament for treating NF1. Additional embodiments will be apparent to persons skilled in the relevant art based on the teachings contained herein. BRIEF DESCRIPTION OF THE DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. These and other features, aspects, and advantages of the present technology will become better understood with regard to the following drawings. FIG. 1A to 1H describe a transgene for NF1 gene replacement therapy. FIG. 1A. Different Ras HVR sequences were attached to NF1 GRD for optimization. FIG. 1B. NF1 cell lines, ST88-14 and ipNF9511bc, and immortalized normal human Schwann cell line, ipn02.3λ, were used for experiments described herein. Anti-NF1 western blotting showed the status of NF1 expression. FIG. 1C. Inhibition of NF1 cells by GRD fused with various Ras HVR sequences. ipNF9511bc cells were transfected with indicated GRD constructs packaged in AAV-DJ at different MOIs. After 3 days, viable cells were measured via WST-8 at Abs 450nm, with AAV-DJ-EGFP as control (100%). FIG. 1D. Low impact of GRD-C24 construct in normal human Schwann cells. GRD- C24 construct package in AAV was transfected in ipn02.3λ cells and compared with AAV- DJ-EGFP as control. FIG. 1E. Optimization of NF1 GRD domain. Different lengths of GRD sequences surrounding the 230 AA core GRD sequence were tested in ipNF9511bc cells and the expression as well as the inhibition of pERK1 / 2 were revealed by western blotting. The 333 AA version (NF1 AA 1200-1532) showed the highest expression and most potent inhibition of pERK1 / 2. JHU-43764.601 Client Docket No: P18504-02 FIG. 1F. Membrane localization of GRD-C24 in NF1 cells. ipNF9511bc cells were infected with AAV carrying 2HA-GRD or 2HA-GRD-C24 (KRas-4B) transgene and anti-HA immunofluorescent staining showed the localization of GRD-C24 in the plasma membrane, in comparison to the diffused expression pattern of GRD alone. FIG. 1G. Suppression of Erk pathway by GRD-C24 in NF1 cells. ipNF9511bc cells were transfected with AAV-GRD-C24 and harvested after 36 hr. GRD-C24 inhibited pErk1 / 2 more potently than GRD alone. FIG. 1H. GRD-C24 induced apoptosis in NF1 cells. ipNF9511bc cells were transfected with AAV-GRD-C24 and after 36 hr cells were stained with annexin V. FIG. 2A to 2E show that capsid DNA shuffling and selection in NF1 xenograft mice provided new AAV vectors for NF1 tumors. FIG. 2A. Example of an orthotopic xenograft ST88-14 tumor grown in the mouse sciatic nerve. ST88-14 cells were injected in the sciatic nerve of NSG mice and tumor was formed in the nerve. FIG. 2B. Capsid 557-2 is the top candidate selected from a capsid DNA shuffling library. A DNA shuffling library was created from 12 natural serotypes of AAV capsids and packaged in 293T cells. Selection in ST88-14 tumor-bearing mice resulted in 557-2, whose pattern of resemblance to the template capsids was shown in the graph generated by Xover 3.0. FIG. 2C. Improved transduction by 557-2-GFP in ST88-14 tumor compared to AAV9- GFP. AAVs were injected intravenously to the ST88-14 tumor-bearing mice at the dose of 5 × 1011per mouse and after 2 weeks tumors were harvested for anti-GFP IHC. FIG. 2D. AAV 557-2 showed a significantly reduced liver retention with more tumor distribution in a panel of three orthotopic NF1 xenografts. Three xenografts of NF1-related tumor cells, ST88-14, ipNF03.3 and RHT92, were injected in the sciatic nerve of NSG mice. AAV9-GFP or 557-2-GFP were injected intravenously to the mice at a dose of 5 × 1011vg. Tissues were harvested after two weeks, and quantitative PCR was used to determine titers of AAV genome in different tissues. FIG. 2E. AAV 557-2-GRDC24 significantly slowed down the ST8814 tumor growth in mice. ST8814 cells were implanted in the NSG mice and after 14 days, tumor sizes were assessed by IVIS imaging, and AAV 557-2-GRDC24 was injected intravenously at a dose of JHU-43764.601 Client Docket No: P18504-02 1 × 1012vg per mouse. Two weeks later, the tumor growth was imaged and compared to the control. FIG. 3A to 3I show improving capsid 557-2 via selection of random peptide library in ST88-14 NF1 xenograft tumor model. FIG. 3A. A predicted structure of 557-2 generated by AlphaFold 3.0. The position between residue N588 and T589 in the VR-VIII loop were identified as the insertion site of a 7mer random peptide library. FIG. 3B. A 7mer random peptide library was selected in xenograft mice carrying ST88-14 tumor with Cre recombinase expression. ST88-14-luc-cre cells were implanted in the sciatic nerve of NSG mice and AAV 557-2 library was injected intravenously. After 2 weeks, tumors were harvested, and the capsid sequences were recovered by a Cre- dependent PCR. The recovered capsid DNA was cloned into library vector, which was used for the next round of selection. After 2 rounds of selection, NGS was done to determine the enrichment of mutant capsids. FIG. 3C. A predicted structure of the top peptide candidate K55 generated by AlphaFold 3.0. The inserted 7mer peptide is displayed in the VR-VIII loop. FIG. 3D. TEM pictures of AAV vectors K55-GFP and K55-GRDC24. Scale bar: 100 nm. FIG. 3E. Markedly improved transduction of K55-GFP in ST8814 and RHT92 xenograft tumors. A dose of 1 × 1012vg AAV9-GFP or K55-GFP was injected intravenously in the mice bearing tumors in the sciatic nerve. After two weeks, tumors were harvested and the expression of GFP was evaluated by anti-GFP IHC. FIG. 3F. AAV K55-GFP showed significantly reduced liver retention and markedly improved tumor distribution compared to the benchmark AAV-GFP, with another candidate K57-GFP as comparison, in a panel of two ST8814, one ipNF03.3 and one RHT92 tumors. AAVs were injected intravenously at a 1012vg dose, and the viral genome was quantified in tissues using qPCR. FIG. 3G. Distribution of AAV-K55 in NF1 xenografts and PDXs, including LN229 NF1 (– / –) glioma, and a panel of solid human xenograft tumors. AAV-K55-GFP was injected intravenously at a dose of 1012vg and tumors were harvested and GFP-positive tumor cells were quantified by flow cytometry. Data are presented as mean values with standard JHU-43764.601 Client Docket No: P18504-02 deviation. S462 and JH-0-031: n=6 xenograft tumors; RHT92, JH-2-002, and LN229: n=4 xenograft tumors; all others: n=3 xenograft tumors, as biological replicates. FIG. 3H. Comparison of GFP transduction by different AAV mutants. The top capsid candidates (not including K55) from the selection of random peptide library (FIG.3B) were used to package GFP and intravenously injected in ST88-14-bearing NSG mice. Anti-GFP IHC of the tumors was performed. FIG. 3I. IHC of xenograft tumors transduced by AAV-K55-GFP. Distribution of AAV-K55 in NF1 xenografts and PDXs, including the subcutaneous LN229 NF1 (– / –) glioma, and a panel of solid human xenograft tumors. AAV-K55-GFP was injected IV at the dose of 1012vg and tumors were harvested and anti-GFP IHC was performed using DAB as visualization and hematoxylin as counterstain. Scale bar = 50 µm. FIG. 4A to 4J show that AAV-K55 transduced S100B+ pNF xenograft tissues and showed a seroprevalence profile similar to that of AAV9. FIG. 4A. Circulation of AAV K55-GFP in mouse plasma. 1012vg of AAV were injected intravenously in NSG mice and viral genome in the plasma was quantified via serial blood draw and qPCR. FIG. 4B. A direct comparison of the AAV9-binding antibody profile and K55-binding antibody profile in a panel of heathy human serum samples. FIG. 4C. Profiles of K55-binding antibody and neutralizing antibody in healthy human serum samples. AAV K55-luc was used for the assays. FIG. 4D. A pNF iPSC-derived tumor (3MM, 3PNF_SiPSsv_MM_11, NF1 (– / –)) implanted together with pNF patient fibroblasts (FB, NF (+ / –)), was shown to be substantially transduced by AAV-K55-GFP via IV administration. Xenograft was harvested two weeks after the AAV treatment. Top image: H&E staining. Bottom image: anti-GFP IHC. Scale bar = 50 µm. FIG. 4E. AAV-K55-GFP transduced mostly the S100B-positive population (tumor) in 3MM-FB neurofibroma xenograft. A section was stained with anti-GFP (green) and anti- S100B (red) antibodies. Scale bar = 50 µm. FIG. 4F. Higher magnification of the GFP-stained and S100B-stained sections in FIG. 4E. AAV-K55-GFP transduced mostly the S100B-positive population (tumor) in 3MM- FB neurofibroma xenograft. A section was stained with anti-GFP (green) and anti-S100B JHU-43764.601 Client Docket No: P18504-02 (red) antibodies. Yellow color in the merged picture indicates the co-localization of anti-GFP (green) and anti-S100B (red) staining. Scale bar = 25 µm. FIG. 4G to FIG. 4J. Limited distribution of AAV-K55 in the brain and nerves. AAV- K55-GFP was injected intravenously in NSG mice and the brain, sciatic nerve and optic nerve were harvested after 14 days. Anti-GFP immunohistochemistry indicated limited GFP expression in the brain (FIG. 4G and FIG.4H, scale bar = 100 µm) and no detectable expression in the sciatic and optic nerve (FIG.4I and FIG. 4J, scale bar = 20 µm). FIG. 5A to 5K indicate that AAV K55-GRDC24 showed anti-tumor efficacies in 2 NF1 xenograft models and a comparison to AAV9-GRDC24. FIG. 5A. Transient efficacies of AAV K55-GRDC24 in ST88-14 xenograft tumor. NSG mice were implanted with ST8814 tumor cells in the sciatic nerve and after 2 weeks, one dose of 1012vg AAV were injected intravenously. Tumor growth was monitored via IVIS imaging and showed significant inhibition by K55-GRDC24 compared to the control. FIG. 5B. Two doses of AAV K55-GRDC24 enabled a more sustained response. In a procedure similar to FIG.5A, a second dose of 1012vg AAV was injected intravenously one week after the first dose. FIG. 5C. Efficacies of AAV K55-GRDC24 in RHT92 xenograft tumor. One dose of 1012vg AAV was injected intravenously one month after the tumor implantation in the sciatic nerve. FIG. 5D. In RHT92 xenograft tumor model, two doses of AAV K55-GRDC24 resulted in a substantial response. In a procedure similar to the experiment shown in FIG. 5C, a second dose of 1012 AAV was injected intravenously 5 days after the first dose (n=4). FIG. 5E. Comparing the payload expression of one dose versus two doses of AAV- K55-GFP. AAV-K55-GFP was injected intravenously in the ST88-14 tumor-bearing mice at the dose of 1012vg. Another dose was given in the double dose cohort 5 days later. All tumors were harvested 14 days after the initial dose and Western blotting indicated the enhanced expression of GFP in the tumors treated with two doses. FIG. 5F. ST88-14 xenograft tumor-bearing mice were treated with AAV-K55- GRDC24 IV at 1012vg, and tumor sections of untreated control, day 14, and day 42 after the treatment were stained by H&E (scale bar = 50 µm). FIG. 5G. Treatment with AAV9-GRDC24. AAV9-GRDC24 show no treatment efficacy in ST88-14 xenograft tumors. NSG mice were implanted with ST88-14-luc cells and JHU-43764.601 Client Docket No: P18504-02 after 14 days, were injected intravenously with AAV9-GRDC24 at 1012vg (n = 8 mice). Controls were untreated animals (n = 7 mice). Tumor sizes were evaluated before and 14 days after the treatment and animals were also treated with 5 mg / ml dexamethasone IP shortly before the AAV injection and 3 times a week after. All treated mice died between day 15 and 21. Data are presented as mean values with SD and analyzed by one-tailed t- test. FIG. 5H. Survival of ST88-14-luc xenograft-bearing mice treated with AAV-K55- GRDC24 at 1012vg as shown in FIG. 5A. No animal died during the treatment course (n=5 mice). FIG. 5I. Treatment with 2 × 1012vg of AAV-K55-GRDC24 significantly suppressed the growth of ST88-14 xenograft tumors. NSG mice were implanted with ST88-14-luc cells in the sciatic nerve and after 14 days, were injected intravenously with AAV-K55-GRDC24 at 2 × 1012vg (n = 4 mice). Controls were untreated animals (n = 5 mice). Tumor sizes were evaluated before and after the treatment using IVIS imaging. Animals were treated with 5 mg / ml dexamethasone IP shortly before the AAV injection and 3 times a week after. Data are presented as mean values with SD and analyzed by one-tailed t-test. FIG. 5J and FIG. 5K. Treating ST88-14 xenograft tumors with selumetinib (SEL) in combination of AAV-K55-GRDC24. FIG. 5J. IC50 of ST88-14 cells with selumetinib was determined at 3.8 µM. ST88-14 cells were incubated with a series of selumetinib dilutions for 72 hours and the viable cells were measured by Cell Counting Kit-8 (CCK-8). Three biological replicates were performed. FIG. 5K. ST88-14-luc cells were implanted in the sciatic nerve of NSG mice and after 14 days, the animals were treated with selumetinib at 100 mg / kg twice daily via oral gavage with or without intravenous injection of 1012vg AAV-K55-GRDC24 (n=4 mice). Data are analyzed by two-tailed t-test. FIG. 6A and 6B. Inhibition of NF1 GRD attached to different HVR C-terminal sequences of Ras. FIG. 6A. Inhibition of ipNF9511bc cells by GRD fused with various Ras HVR sequences. ipNF9511bc cells were transfected with indicated GRD constructs packaged in AAV-DJ at different MOIs. After 3 days, viable cells were measured via WST-8 at Abs 450nm, with AAV-DJ-EGFP as control (100%). JHU-43764.601 Client Docket No: P18504-02 FIG. 6B. Inhibition of ST88-14 cells by GRD fused with various Ras HVR sequences. ST88-14 cells were transfected with indicated GRD constructs packaged in AAV-DJ at different MOIs. After 3 days, viable cells were measured via WST-8 at Abs 450nm, with AAV-DJ-EGFP as control (100%). FIG. 7A and 7B. Optimization of NF1 GRD sequences attached to 24 AA at the C- terminus of KRas4B. Inhibition of ipNF9511bc cells (FIG. 7A) and ST88-14 cells (FIG. 7B) by various length of GRD sequences fused with KRas-C24 sequence. Cells were transfected with indicated GRD constructs (GRD367: AA 1172-1538, GRD333: AA 1200-1532, GRD230: AA 1248-1477, GRD282: AA 1222-1503) packaged in AAV-DJ at different MOIs. After 3 days, viable cells were measured via WST-8 at Abs 450nm, with AAV-DJ-EGFP as control (100%). FIG. 8A to 8E. Expression of GRDC24 in NF1 iPSC-derived neural crest cells. FIG. 8A. Western blotting of NF1 protein in iPSC derived from normal human fibroblast (Fips) and the Fips cells with NF1 knockout (NF1 (– / –)). FIG. 8B. Fips and NF1 (– / –) iPSC cells were differentiated to neural crest cells (NC). Flow cytometry of NC marker NGFR confirmed the NC differentiation (blue) of Fips and NF1 (– / –) cells. FIG. 8C. NF1 (– / –) NC cells were transfected with AAV GRD-C24, which led to suppression of pErk1 / 2. FIG. 8D. Suppression of NF1 (– / –) NC cells by AAV-GRD-C24. NCs derived from Fips or NF1 (– / –) iPSC were transfected with AAV-DJ-GRD-C24 or AAV-DJ-GFP as control at different MOI and cell growth was measured after 3 days. FIG. 8E. Morphology of Fips and NF1 (– / –) cells after Schwann cell (SC) differentiation. Fips or NF1 (– / –) NCs were incubated in the SC media for 7 days (left panel) or 20 days (right panel) and the cell morphology showed far less organized in NF1 (– / –) population that in Fips (left panels). FIG. 9A and B. Expression of GRDC24 rescued the NF1 (– / –) NC’s differentiation to Schwann cells FIG. 9A. Fips and NF1 (– / –) NCs transfected by AAV-DJ-GRD-C24 at indicated time and were differentiated to SC in SC media for 20 days. The cell morphology showed similar features as Fips cells in contrast to that of NF1 (– / –) cells. JHU-43764.601 Client Docket No: P18504-02 FIG. 9B. GRD-C24 restored the myelination of NF1 (– / –) SC. Fips and NF1 (– / –) NCs were transfected by AAV-DJ-GRD-C24 at indicated time before or shortly after SC differentiation and co-cultured with rat dorsal root ganglia (DRG) neuron with differentiated SC for 20 days. Immunofluorescence staining of neuron marker βIII-tubulin and myelination marker MPZ showed myelinated SC along the neuron. It is to be understood that the figures are not necessarily drawn to scale, nor are the objects in the figures necessarily drawn to scale in relationship to one another. The figures are depictions that are intended to bring clarity and understanding to various embodiments of apparatuses, systems, and methods disclosed herein. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts. Moreover, it should be appreciated that the drawings are not intended to limit the scope of the present teachings in any way. DETAILED DESCRIPTION Provided herein is technology relating to treating neurofibromatosis type 1 (NF1) and particularly, but not exclusively, to compositions, methods, systems, and kits for gene replacement therapy treatments of patients having NF1-related tumors. Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder affecting approximately 1 in 2,500 individuals, characterized by the loss of the 320 kDa tumor suppressor protein neurofibromin 1 (NF1). Thousands of pathogenic mutations have been identified. Manifestations of NF1 can affect almost all organ systems and patients have a wide phenotypic variability. In general, NF1 is associated with higher rates of benign and malignant tumors and the life expectancy is 10 years to 15 years shorter than that of the general population. The hallmark is the development of plexiform neurofibromas (pNF), which are benign tumors of the peripheral nerves that may cause disfigurement or neurologic dysfunction and occur in about 50% of the patients. In a recent study, 41% of patients with NF1 developed neoplasms other than neurofibromas. The most common neoplasms observed included low-grade gliomas (LGGs, 16.6%), malignant peripheral nerve sheath tumors (MPNST, 15.1%), which originate from pre-existing pNF due to the accumulation of additional genetic alterations, breast cancer (2.9%), high-grade glioma (HGG, 1.7%), pheochromocytoma (1.2%), GIST (1.2%), and melanoma (0.9%). These tumor manifestations result from altered Ras due to reduced functional levels of NF1 gene JHU-43764.601 Client Docket No: P18504-02 product, neurofibromin, which encodes the GTPase-activating protein (GAP)-related domain (GRD) and catalyzes the inactivation of Ras by accelerating GTP hydrolysis, thereby influencing several signaling pathways across multiple organ systems. In NF1 patients, loss of NF1 results in excessive Ras activation that drives the RAF-MEK-ERK cascade, leading to cell hyperproliferation and tumor formation. The clinical treatment for these benign and malignant tumors poses unique challenges and often account not only for the chronic nature of this disorder, but also for the complex intracellular pathways in the target cells, leaving many antineoplastics that target rapidly dividing, metabolically active cells ineffective. Selumetinib, a MEK inhibitor, is currently the only FDA-approved treatment for pNF, achieving disease control in a fraction of patients and tumor reductions of 20-30%, though it does not eradicate tumors. It is also effective in the treatment of LGG but has shown no efficacy in the treatment of MPNSTs or other NF1-related cancers. Regardless, all available therapies fail to adequately treat the underlying genetic cause, thereby failing to minimize the risk of future morbidities. Thus, gene therapy may offer the potential to bridge this gap and provide a more efficacious treatment than are currently available. As a gene delivery vector, recombinant adeno-associated virus (rAAV) offers the advantage of low pathogenicity, rare genomic integration and long-term transgene expression, and has shown successes in a number of monogenic diseases, such as Retinal Dystrophy (AAV2), Spinal Muscular Atrophy (SMA, AAV9), Haemophilia A and B (AAV8) and Duchenne Muscular Dystrophy (DMD, AAVRh74). From a clinical perspective, an useful AAV vector should specifically and efficiently express high levels of the therapeutic transgene product in the desired target tissue, following a single peripheral delivery of low particle doses to improve patient safety. However, the small packaging capacity and limited tropism in tumor tissues have made the use of AAV in treating cancers challenging. Most importantly, in contrast to the non-tumoral diseases, where partial transduction of target tissues can achieve spectacular therapeutic efficacies, a much higher transduction rate is required when treating tumors, benign or malignant, in which constant cell division depletes the transduced cells and minimizes therapeutic responses. Furthermore, unlike non-tumoral tissue in which differentiated cell populations are usually well established, intratumoral heterogeneity is a hallmark of neoplasm characterized by under-differentiated cells that makes development of targeted vectors especially difficult. See, e.g., Wang (2024) JHU-43764.601 Client Docket No: P18504-02 “Adeno-associated virus as a delivery vector for gene therapy of human diseases” Signal Transduction and Targeted Therapy volume 9, Article number: 78 (2024), incorporated herein by reference. In NF1 tumors, where the NF1 gene alterations function as the initiating and key driver mutation, gene therapy holds enormous promise. However, NF1 gene therapy faces two main challenges: 1) the NF1 gene is very large (i.e., 8400 bp) and thus exceeds the packaging limit of AAV vectors; 2) naturally occurring AAV serotypes have weak tropism with NF1 tumors. To address needs for NF1 gene therapy, some previous approaches have included use of a construct comprising a neurofibromin 1 GTPase-activating protein-related domain (NF1-GRD) and a membrane-targeting amino acid sequence. See, e.g., U.S. Pat. App. Pub. No.20210395736, which is incorporated herein by reference. In the present disclosure, technologies are described relating to a construct comprising a “miniNF1” gene, a GRD domain, and a membrane-targeting domain. In addition, technologies described herein relate to engineered recombinant (rAAV) vectors produced using directed evolution, e.g., using a combination of capsid DNA shuffling and subsequent biopanning of a random peptide library, to improve the tropism of rAAV for NF1 tumors. In particular, experiments were conducted to test a rAAV named “AAV-NF (K55)”. Data collected during the experiments indicate that the AAV-NF (K55) had improved tropism to NF1-related neurofibroma and glioma in xenograft mouse models, had greatly reduced liver transduction, and achieved significant therapeutic efficacies in treating NF1 xenograft tumors. In this detailed description of the various embodiments, for purposes of explanation, numerous specific details are set forth to provide a thorough understanding of the embodiments disclosed. One skilled in the art will appreciate, however, that these various embodiments may be practiced with or without these specific details. In other instances, structures and devices are shown in block diagram form. Furthermore, one skilled in the art can readily appreciate that the specific sequences in which methods are presented and performed are illustrative and it is contemplated that the sequences can be varied and still remain within the spirit and scope of the various embodiments disclosed herein. All literature and similar materials cited in this application, including but not limited to, patents, patent applications, articles, books, treatises, and internet web pages are expressly incorporated by reference in their entirety for any purpose. Unless defined JHU-43764.601 Client Docket No: P18504-02 otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which the various embodiments described herein belongs. When definitions of terms in incorporated references appear to differ from the definitions provided in the present teachings, the definition provided in the present teachings shall control. The section headings used herein are for organizational purposes only and are not to be construed as limiting the described subject matter in any way. Definitions To facilitate an understanding of the present technology, a number of terms and phrases are defined below. Additional definitions are set forth throughout the detailed description. Throughout the specification and claims, the following terms take the meanings explicitly associated herein, unless the context clearly dictates otherwise. The phrase “in one embodiment” as used herein does not necessarily refer to the same embodiment, though it may. Furthermore, the phrase “in another embodiment” as used herein does not necessarily refer to a different embodiment, although it may. Thus, as described below, various embodiments of the invention may be readily combined, without departing from the scope or spirit of the invention. In addition, as used herein, the term “or” is an inclusive “or” operator and is equivalent to the term “and / or” unless the context clearly dictates otherwise. The term “based on” is not exclusive and allows for being based on additional factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meaning of “a”, “an”, and “the” include plural references. The meaning of “in” includes “in” and “on.” As used herein, the terms “about”, “approximately”, “substantially”, and “significantly” are understood by persons of ordinary skill in the art and will vary to some extent on the context in which they are used. If there are uses of these terms that are not clear to persons of ordinary skill in the art given the context in which they are used, “about” and “approximately” mean plus or minus less than or equal to 10% of the particular term and “substantially” and “significantly” mean plus or minus greater than 10% of the particular term. JHU-43764.601 Client Docket No: P18504-02 As used herein, disclosure of ranges includes disclosure of all values and further divided ranges within the entire range, including endpoints and sub-ranges given for the ranges. As used herein, the disclosure of numeric ranges includes the endpoints and each intervening number therebetween with the same degree of precision. For example, for the range of 6–9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0–7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. As used herein, the suffix “-free” refers to an embodiment of the technology that omits the feature of the base root of the word to which “-free” is appended. That is, the term “X-free” as used herein means “without X”, where X is a feature of the technology omitted in the “X-free” technology. For example, a “calcium-free” composition does not comprise calcium, a “mixing-free” method does not comprise a mixing step, etc. Although the terms “first”, “second”, “third”, etc. may be used herein to describe various steps, elements, compositions, components, regions, layers, and / or sections, these steps, elements, compositions, components, regions, layers, and / or sections should not be limited by these terms, unless otherwise indicated. These terms are used to distinguish one step, element, composition, component, region, layer, and / or section from another step, element, composition, component, region, layer, and / or section. Terms such as “first”, “second”, and other numerical terms when used herein do not imply a sequence or order unless clearly indicated by the context. Thus, a first step, element, composition, component, region, layer, or section discussed herein could be termed a second step, element, composition, component, region, layer, or section without departing from technology. As used herein, the word “presence” or “absence” (or, alternatively, “present” or “absent”) is used in a relative sense to describe the amount or level of a particular entity (e.g., component, action, element). For example, when an entity is said to be “present”, it means the level or amount of this entity is above a pre-determined threshold; conversely, when an entity is said to be “absent”, it means the level or amount of this entity is below a pre-determined threshold. The pre-determined threshold may be the threshold for detectability associated with the particular test used to detect the entity or any other threshold. When an entity is “detected” it is “present”; when an entity is “not detected” it is “absent”. JHU-43764.601 Client Docket No: P18504-02 As used herein, an “increase” or a “decrease” refers to a detectable (e.g., measured) positive or negative change, respectively, in the value of a variable relative to a previously measured value of the variable, relative to a pre-established value, and / or relative to a value of a standard control. An increase is a positive change preferably at least 10%, more preferably 50%, still more preferably 2-fold, even more preferably at least 5-fold, and most preferably at least 10-fold relative to the previously measured value of the variable, the pre- established value, and / or the value of a standard control. Similarly, a decrease is a negative change preferably at least 10%, more preferably 50%, still more preferably at least 80%, and most preferably at least 90% of the previously measured value of the variable, the pre- established value, and / or the value of a standard control. Other terms indicating quantitative changes or differences, such as “more” or “less,” are used herein in the same fashion as described above. As used herein, a “system” refers to a plurality of real and / or abstract components operating together for a common purpose. In some embodiments, a “system” is an integrated assemblage of hardware and / or software components. In some embodiments, each component of the system interacts with one or more other components and / or is related to one or more other components. In some embodiments, a system refers to a combination of components and software for controlling and directing methods. For example, a “system” or “subsystem” may comprise one or more of, or any combination of, the following: mechanical devices, hardware, components of hardware, circuits, circuitry, logic design, logical components, software, software modules, components of software or software modules, software procedures, software instructions, software routines, software objects, software functions, software classes, software programs, files containing software, etc., to perform a function of the system or subsystem. Thus, the methods and apparatus of the embodiments, or certain aspects or portions thereof, may take the form of program code (e.g., instructions) embodied in tangible media, such as floppy diskettes, CD-ROMs, hard drives, flash memory, or any other machine-readable storage medium wherein, when the program code is loaded into and executed by a machine, such as a computer, the machine becomes an apparatus for practicing the embodiments. In the case of program code execution on programmable computers, the computing device generally includes a processor, a storage medium readable by the processor (e.g., volatile and non-volatile memory and / or storage elements), at least one input device, and at least one output device. JHU-43764.601 Client Docket No: P18504-02 One or more programs may implement or utilize the processes described in connection with the embodiments, e.g., through the use of an application programming interface (API), reusable controls, or the like. Such programs are preferably implemented in a high-level procedural or object-oriented programming language to communicate with a computer system. However, the program(s) can be implemented in assembly or machine language, if desired. In any case, the language may be a compiled or interpreted language, and combined with hardware implementations. As used herein, the term “sample” or “biological sample” refers to anything that may contain cells of interest (e.g., cancer or tumor cells thereof) for which a screening method or treatment is desired. The sample may be a biological sample, such as a biological fluid or a biological tissue. Such a sample may include diverse cells, proteins, and genetic material. Examples of biological tissues also include organs, tumors, lymph nodes, arteries, and individual cell(s). Examples of biological fluids include urine, blood, plasma, serum, saliva, semen, stool, sputum, cerebral spinal fluid, tears, mucus, amniotic fluid, or the like. As used herein, the term “subject” or “patient” refers to a human or non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline, and murine mammals. In some embodiments, the subject is human. As used herein, the terms “treatment,” “treating,” and the like, refer to obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. “Treatment,” as used herein, covers any treatment of a disease in a biological organism, e.g., a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject predisposed to the disease or at risk of acquiring the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, e.g., arresting its development; and (c) relieving the disease, e.g., causing regression of the disease. As used herein, the term “prevent” means to stop or hinder something from happening, especially by advance planning or action, or prophylactic treatment. Prevention implies anticipatory counteraction, such as by administering a therapeutic or a composition containing a therapeutic to a patient at risk of developing a disease that is preventable via the therapeutic. JHU-43764.601 Client Docket No: P18504-02 As used herein, the phrase “prior to treatment” can refer to a time prior to the commencement of treatment and can also refer to a time prior to the current treatment. That is, “prior to treatment” can refer to a prior treatment. As used herein, the terms “pharmaceutically acceptable” and “physiologically acceptable” mean a biologically acceptable formulation, gaseous, liquid or solid, or mixture thereof, suitable for one or more routes of administration, in vivo delivery or contact. A “pharmaceutically acceptable” or “physiologically acceptable” composition is a material that is not biologically or otherwise undesirable, e.g., the material may be administered to a subject without causing substantial undesirable biological effects. Thus, such a pharmaceutical composition may be used, for example in administering an AAV vector or AAV virion as disclosed herein or transformed cell to a subject. As used herein, the term “unit dosage form” refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity optionally in association with a pharmaceutical carrier (excipient, diluent, vehicle or filling agent) which, when administered in one or more doses, produces a desired effect (e.g., prophylactic or therapeutic effect). In some embodiments, unit dosage forms may be within, for example, ampules and vials, including a liquid composition, or a composition in a freeze-dried or lyophilized state; a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo. Individual unit dosage forms can be included in multi- dose kits or containers. AAV vectors or AAV virions, and pharmaceutical compositions thereof, can be packaged in single or multiple unit dosage form for ease of administration and uniformity of dosage. As used herein, the term “therapeutically effective amount” will fall in a relatively broad range determinable through experimentation and / or clinical trials. For example, in some embodiments, a therapeutically effective dose is on the order of from approximately 106to approximately 1015AAV virions, e.g., from approximately 108to 1012AAV virions. For example, in some embodiments, a therapeutically effective dose is on the order of from approximately 106to approximately 1015infectious units, e.g., from approximately 108to approximately 1012infectious units. Other effective dosages can be readily established by one of ordinary skill in the art through routine trials establishing dose response curves. As used herein, the term an “effective amount” or “sufficient amount” refers to an amount providing, in single or multiple doses, alone or in combination, with one or more JHU-43764.601 Client Docket No: P18504-02 other compositions (therapeutic agents such as a drug), treatments, protocols, or therapeutic regimens agents, a detectable response of any duration of time (long or short term), an expected or desired outcome in or a benefit to a subject of any measurable or detectable degree or for any duration of time (e.g., for minutes, hours, days, months, years, or cured). As used herein, the term “effective amount” or “sufficient amount” refer to doses for treatment (e.g., to ameliorate or to provide a therapeutic benefit or improvement) typically effective to provide a response to one, multiple, or all adverse symptoms, consequences or complications of the disease, one or more adverse symptoms, disorders, illnesses, pathologies, or complications, for example, caused by or associated with the disease, to a measurable extent, although decreasing, reducing, inhibiting, suppressing, limiting or controlling progression or worsening of the disease is a satisfactory outcome. As used herein, the term “prophylaxis” and grammatical variations thereof mean a method in which contact, administration, or in vivo delivery to a subject is prior to disease. Administration or in vivo delivery to a subject can be performed prior to development of an adverse symptom, condition, complication, etc. caused by or associated with the disease. For example, a screen (e.g., a genetic screen) can be used to identify such subjects as candidates for the described methods and uses, but the subject may not manifest the disease. Such subjects therefore include those screened positive for an insufficient amount or a deficiency in a functional gene product (e.g., a protein (e.g., NF1)), or producing an aberrant (e.g., hyperactive), partially functional, or non-functional gene product leading to disease; and subjects screening positive for an aberrant, or defective (mutant) gene product (protein) leading to disease, even though such subjects do not manifest symptoms of the disease. As used herein, “multiplicity of infection” (MOI) generally refers to the number of virions that are added per cell during infection. As used herein, “operably linked” means incorporated into a genetic construct so that expression control sequences effectively control expression of a coding sequence of interest. The term “operatively linked to” refers to the functional relationship of a nucleic acid with another nucleic acid sequence. Promoters, enhancers, transcriptional and translational stop sites, and other signal sequences are examples of nucleic acid sequences operatively linked to other sequences. For example, operative linkage of gene to a transcriptional control element refers to the physical and functional relationship between JHU-43764.601 Client Docket No: P18504-02 the gene and promoter such that the transcription of the gene is initiated from the promoter by an RNA polymerase that specifically recognizes, binds to and transcribes the DNA. As used herein, the term “vector” or “construct” refers to a polynucleotide capable of transporting into a cell another polynucleotide to which the vector sequence has been linked. For example, in some embodiments, a “vector” is a replicon, such as a plasmid, phage, virus, or cosmid into which another DNA segment may be inserted to bring about the replication of the inserted segment. “Plasmid” and “vector” are used interchangeably, as a plasmid is a commonly used form of vector. Vectors can be expression vectors. An “expression vector” is a vector that includes one or more expression control sequences, and an “expression control sequence” is a DNA sequence that controls and regulates the transcription and / or translation of another DNA sequence. The term “expression vector” includes any vector, (e.g., a plasmid, cosmid, or phage chromosome) containing a gene construct in a form suitable for expression by a cell (e.g., linked to a transcriptional control element). As used herein, the term “AAV” is an abbreviation for “adeno-associated virus” and may be used to refer to the virus itself or derivatives thereof. The term covers all subtypes and both naturally occurring and recombinant forms, except where required otherwise. The abbreviation “rAAV” refers to recombinant adeno-associated virus, also referred to as a recombinant AAV vector (or “rAAV vector”). The term “AAV” or “adeno-associated virus” includes AAV type 1 (AAV1), AAV type 2 (AAV2), AAV type 3 (AAV3), AAV type 4 (AAV4), AAV type 5 (AAV5), AAV type 6 (AAV6), AAV type 7 (AAV7), AAV type 8 (AAV8), AAV type 9 (AAV9), avian AAV, bovine AAV, canine AAV, equine AAV, primate AAV, non-primate AAV, and ovine AAV. “Primate AAV” refers to AAV capable of infecting primates, “non- primate AAV” refers to AAV capable of infecting non-primate mammals, “bovine AAV” refers to AAV capable of infecting bovine mammals, etc. As used herein, the term “AAV vector” refers to an AAV vector nucleic acid sequence encoding for a capsid polypeptide (e.g., the AAV vector comprises a nucleic acid sequence encoding for a capsid polypeptide). In some embodiments, the vector capsid polypeptide is a variant capsid polypeptide and the vector is capable of comprising a longer nucleic acid insert as compared to a vector comprising a non-variant parent capsid polypeptide and / or another variant capsid polypeptide. The AAV vectors can further comprise a heterologous JHU-43764.601 Client Docket No: P18504-02 nucleic acid sequence not of AAV origin (i.e., a nucleic acid heterologous to AAV) as part of the longer nucleic acid insert. This heterologous nucleic acid sequence typically comprises a sequence of interest for the genetic transformation of a cell. In general, the heterologous nucleic acid sequence is flanked by at least one AAV inverted terminal repeat sequence and generally by two AAV inverted terminal repeat sequences (ITRs). As used herein, the term “AAV virion” or “AAV virus” or “AAV viral particle” or “AAV vector particle” refers to a viral particle comprising at least one AAV capsid polypeptide (including both variant capsid polypeptides and non-variant parent capsid polypeptides) and an encapsidated polynucleotide AAV vector. If the particle comprises a heterologous nucleic acid (e.g., a polynucleotide other than a wild-type AAV genome, such as a transgene to be delivered to a mammalian cell), it can be referred to as an “AAV vector particle” or simply an “AAV vector”. Thus, production of AAV virion or AAV particle necessarily includes production of AAV vector as such a vector is contained within an AAV virion or AAV particle. As used herein, the term “packaging” refers to a series of intracellular events resulting in the assembly and encapsidation of an AAV virion or AAV particle. As used herein, the terms “rep” and “cap” genes refer to polynucleotide sequences encoding replication and encapsidation proteins of adeno-associated virus. AAV rep (replication) and capsid (capsid) are referred to herein as AAV “packaging genes.” As used herein, the term “helper virus” for AAV refers to a virus allowing AAV (e.g., wild-type AAV) to be replicated and packaged by a mammalian cell. A variety of such helper viruses for AAV are known in the art, including adenoviruses, herpesviruses, and poxviruses such as vaccinia. The adenoviruses comprise a number of different subgroups, although Adenovirus type 5 of subgroup C is most commonly used as a helper virus. Numerous adenoviruses of human, non-human mammalian, and avian origin are known and available from depositories such as the ATCC. Viruses of the herpes family include, for example, herpes simplex viruses (HSV) and Epstein-Barr viruses (EBV), as well as cytomegaloviruses (CMV) and pseudorabies viruses (PRV), which are also available from depositories such as ATCC. As used herein, the term “helper virus function(s)” refers to function(s) encoded in a helper virus genome allowing AAV replication and packaging (in conjunction with other requirements for replication and packaging described herein). As described herein, “helper JHU-43764.601 Client Docket No: P18504-02 virus function” may be provided in a number of ways, including by providing helper virus or providing, for example, polynucleotide sequences encoding the requisite function(s) to a producer cell in trans. The terms “transformation” and “transfection” refer to the introduction of a polynucleotide, e.g., an expression vector, into a recipient cell including introduction of a polynucleotide to the chromosomal DNA of the cell. As used herein, the terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The “polypeptides”, “proteins”, and “peptides” encoded by the “polynucleotide sequences” include full-length native sequences, as with naturally occurring proteins, as well as functional subsequences, modified forms or sequence variants so long as the subsequence, modified form, or variant retains some degree of functionality of the native full-length protein. In methods and uses of polypeptides and polynucleotides encoding polypeptides as described herein, such polypeptides, proteins, and peptides encoded by the polynucleotide sequences can be, but are not required to be, identical to a defective endogenous protein, or whose expression is insufficient, or deficient in a treated mammal. The terms also encompass a modified amino acid polymer, e.g., disulfide bond formation, glycosylation, lipidation, prenylation, palmitoylation, phosphorylation, or conjugation with a labeling component. Polypeptides such as NF1 polypeptides and GRD polypeptides, when discussed in the context of delivering a gene product to a mammalian subject, and compositions therefor, refer to the respective intact polypeptide, or any fragment or genetically engineered derivative thereof, retaining the desired biochemical function of the intact protein. As used herein, the term “residue” refers to an amino acid that is incorporated into a protein. The amino acid may be a naturally occurring amino acid and, unless otherwise limited, may encompass known analogs of natural amino acids that can function in a similar manner as naturally occurring amino acids. Conventional one and three-letter amino acid codes are used herein as follows – Alanine: Ala, A; Arginine: Arg, R; Asparagine: Asn, N; Aspartate: Asp, D; Cysteine: Cys, C; Glutamate: Glu, E; Glutamine: Gln, Q; Glycine: Gly, G; Histidine: His, H; Isoleucine: Ile, I; Leucine: Leu, L; Lysine: Lys, K; Methionine: Met, M; Phenylalanine: Phe, F; Proline: Pro, P; Serine: Ser, S; Threonine: Thr, T; Tryptophan: Trp, W; Tyrosine: Tyr, Y; Valine: Val, V. As used herein, the codes Xaa and X refer to any amino acid. JHU-43764.601 Client Docket No: P18504-02 As used herein, the term “HVR” (hypervariable region) refers to an amino acid sequence that is located at the C-terminal membrane targeting region of a Ras protein. The HVR is outside of the G domain of a Ras protein and is commonly referred to as the “hypervariable region”. The term HVR refers to an HVR from any species and / or any polypeptide sequence having activity of an HVR, whether obtained from a Ras homolog and / or comprising one or more substitutions relative to a Ras homolog. As used herein, the term “tag” refers to an amino acid sequence that is, in some embodiments, fused to or included in the amino acid sequence of a polypeptide, e.g: a) improving expression of the polypeptide; b) facilitating purification of the polypeptide; c) facilitating immobilization of the polypeptide; and / or d) facilitating detection of the polypeptide. Examples for tags are His tags (e.g., 5× His-tags, 6× His-tags, 7× His-tags, 8× His- tags, 9× His-tags, 10× His-tags, 11× His-tags, 12× His-tags, 16× His-tags, 20× His- tags), Strep-tags, Avi-tags, Myc-tags, GST-tags, JS-tags, cystein-tags, FLAG-tags, HA-tags, thioredoxin, or maltose binding proteins (MBP), CAT, GFP, YFP, etc. The person skilled in the art knows a vast number of tags suitable for different technical applications. The tag may, for example, make a tagged polypeptide suitable for, e.g., antibody binding in different ELISA assay formats or other technical applications. The technology described herein is not limited to polypeptides comprising a tag. For example, therapeutic embodiments may not comprise a tag and embodiments used for experimentation and research may comprise a tag. As used herein, the term “variant” refers to an amino acid sequence or nucleic acid sequence having conservative substitutions, non-conservative substitutions (that is, a degenerate variant), substitutions within the wobble position of a codon encoding an amino acid, amino acids added to the C-terminus of a peptide, or a peptide having 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence. As used herein, the term “conservative variant” refers to a particular nucleic acid sequence that encodes identical or essentially identical amino acid sequences. Conservative substitution tables providing functionally similar amino acids are well known in the art. The following sets forth exemplary groups which contain natural amino acids that are “conservative substitutions” for one another: Alanine (A), Serine (S), and Threonine (T); Aspartic acid (D) and Glutamic acid (E); Asparagine (N) and Glutamine (Q); Arginine (R) JHU-43764.601 Client Docket No: P18504-02 and Lysine (K); Isoleucine (I), Leucine (L), Methionine (M), and Valine (V); and Phenylalanine (F), Tyrosine (Y), and Tryptophan (W). As used herein, the term “percent (%) sequence identity” or “homology” refers to the percentage of nucleotides or amino acids in a candidate sequence that are identical with the nucleotides or amino acids in a reference nucleic acid or amino 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, ALIGN-2, or Megalign (DNASTAR) software. Appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared, can be determined by known methods. As used herein, the terms “polynucleotide” and “nucleic acid” are used interchangeably to refer to all forms of nucleic acid, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Polynucleotides include genomic DNA, cDNA, and antisense DNA, and spliced or unspliced mRNA, rRNA, tRNA, lncRNA, RNA antagomirs, and inhibitory DNA or RNA (RNAi, e.g., small or short hairpin (sh)RNA, microRNA (miRNA), aptamers, small or short interfering (si)RNA, trans-splicing RNA, or antisense RNA). Polynucleotides also include non-coding RNA, which include for example, but are not limited to, RNAi, miRNAs, lncRNAs, RNA antagomirs, aptamers, and any other non-coding RNAs known to those of skill in the art. Polynucleotides include naturally occurring, synthetic, and intentionally altered or modified polynucleotides as well as analogues and derivatives. The term “polynucleotide” also refers to a polymeric form of nucleotides of any length, including deoxyribonucleotides or ribonucleotides, or analogs thereof, and is synonymous with nucleic acid sequence. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs, and may be interrupted by non-nucleotide components. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The term polynucleotide, as used herein, refers interchangeably to double-stranded and single- stranded molecules. Unless otherwise specified or required, any embodiment as described herein encompassing a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double- JHU-43764.601 Client Docket No: P18504-02 stranded form. Polynucleotides can be single, double, or triplex, linear or circular, and can be of any length. In discussing polynucleotides, a sequence or structure of a particular polynucleotide may be described herein according to the convention of providing the sequence in the 5′ to 3′ direction. As used herein, the term “oligonucleotide,” refers to a short length of single-stranded polynucleotide chain. Oligonucleotides are typically less than 200 residues long (e.g., between 15 and 100), however, as used herein, the term is also intended to encompass longer polynucleotide chains. Oligonucleotides are often referred to by their length. For example, a 24-residue oligonucleotide is referred to as a “24-mer”. Oligonucleotides can form secondary and tertiary structures by self-hybridizing or by hybridizing to other polynucleotides. Such structures can include, but are not limited to, duplexes, hairpins, cruciforms, bends, and triplexes. It is well known that DNA (deoxyribonucleic acid) is a chain of nucleotides consisting of 4 types of nucleotides; A (adenine), T (thymine), C (cytosine), and G (guanine), and that RNA (ribonucleic acid) is comprised of 4 types of nucleotides; A, U (uracil), G, and C. It is also known that all of these 5 types of nucleotides specifically bind to one another in combinations called complementary base pairing. That is, adenine (A) pairs with thymine (T) (in the case of RNA, however, adenine (A) pairs with uracil (U)), and cytosine (C) pairs with guanine (G), so that each of these base pairs forms a double strand. Conventional codes are used herein as follows – R (G or A), Y (T / U or C), M (A or C), K (G or T / U), S (G or C), W (A or T / U), B (G or C or T / U), D (A or G or T / U), H (A or C or T / U), V (A or G or C), or N (A or G or C or T / U), gap (-). As used herein, the term “recombinant”, as applied to a polynucleotide, means the polynucleotide is the product of various combinations of cloning, restriction, or ligation steps, and other procedures resulting in a construct distinct and / or different from a polynucleotide found in nature. A recombinant virus is a viral particle comprising a recombinant polynucleotide. The terms respectively include replicates of the original polynucleotide construct and progeny of the original virus construct. As used herein, the term “gene” refers to a polynucleotide that encodes a protein or functional RNA molecule. For instance, the term “gene” refers to a nucleic acid (e.g., DNA) sequence that comprises coding sequences necessary for the production of a polypeptide, precursor, or RNA (e.g., rRNA, tRNA). The polypeptide can be encoded by a full length coding sequence or by any portion of the coding sequence so long as the desired activity or JHU-43764.601 Client Docket No: P18504-02 functional properties (e.g., enzymatic activity, ligand binding, signal transduction, immunogenicity, etc.) of the full-length or fragment are retained. The term also encompasses the coding region of a structural gene and the sequences located adjacent to the coding region on both the 5' and 3' ends for a distance of about 1 kb or more on either end such that the gene corresponds to the length of the full-length mRNA. Sequences located 5' of the coding region and present on the mRNA are referred to as 5' non-translated sequences. Sequences located 3' or downstream of the coding region and present on the mRNA are referred to as 3' non-translated sequences. The term “gene” encompasses both cDNA and genomic forms of a gene. A genomic form or clone of a gene contains the coding region interrupted with non-coding sequences termed “introns” or “intervening regions” or “intervening sequences.” Introns are segments of a gene that are transcribed into nuclear RNA (hnRNA); introns may contain regulatory elements such as enhancers. Introns are removed or “spliced out” from the nuclear or primary transcript; introns therefore are absent in the messenger RNA (mRNA) transcript. The mRNA functions during translation to specify the sequence or order of amino acids in a nascent polypeptide. As used herein, the terms “modulate” or “modulates” with respect to Ras activity includes any measurable alteration, either a decrease (e.g., inhibition) or increase (e.g., enhancement), of Ras activity. As used herein, the terms “inhibit” or “inhibits” with respect to Ras activity includes any measurable decrease of Ras activity. As used herein, the terms “detect”, “detecting” or “detection” may describe either the general act of discovering or discerning or the specific observation of a detectably labeled composition. As used herein, the term “stage of cancer” refers to a qualitative or quantitative assessment of the level of advancement of a cancer. Criteria used to determine the stage of a cancer include, but are not limited to, the size of the tumor and the extent of metastases (e.g., localized or distant). As used herein, the term “vector genome”, which is abbreviated “vg”, may refer to one or more polynucleotides comprising a set of the polynucleotide sequences of a vector, e.g., a viral vector. A vector genome may be encapsidated in a viral particle. Depending on the particular viral vector, a vector genome may comprise single-stranded DNA, double- stranded DNA, single-stranded RNA, or double-stranded RNA. A vector genome may JHU-43764.601 Client Docket No: P18504-02 include endogenous sequences associated with a particular viral vector and / or any heterologous sequences inserted into a particular viral vector through recombinant techniques. For example, a recombinant AAV vector genome may include at least one ITR sequence flanking a promoter, a stuffer, a sequence of interest, and a polyadenylation sequence. A complete vector genome may include a complete set of the polynucleotide sequences of a vector. In some embodiments, the nucleic acid titer of a viral vector may be measured in terms of vg / ml. Methods suitable for measuring this titer are known in the art (e.g., quantitative PCR). As used herein, the term “Ras pathway” or “Ras / Raf / MEK / ERK pathway” refers to the intracellular kinase cascade comprising RAS, RAF, mitogen-activated protein kinase kinase (MEK), and extracellular signal regulated kinase (ERK). The Ras / Raf / MEK / ERK signaling pathway is known in the art and described in McCormick (1993) Nature 363 (6424): 15-6, incorporated herein by reference. As used herein, an “activated Ras / Raf / MEK / ERK pathway” refers to a detectable increase in levels of phosphorylated MAPK, and / or increased expression and / or activation of its primary targets (Favres (2006) Bulletin du Cancer 93(4): 25-30; Kolch (2000) Biochem J 351(2): 289-305; Peysonnaux and Eychece (2001) Biol Cell 93 :53-62; Satyamoorthy et al. (2003) Cancer Res 63: 756-759; Houben et al. (2004) J Carcinog 3: 6, each of which is incorporated herein by reference). An “activated Ras / Raf / MEK / ERK pathway is also defined as an increase in kinase activity of members of the pathway. Methods for measuring kinase activity of Ras / Raf / MEK / ERK pathway members are taught, for example, in Davies et al. (2002), Nature 417: 949, incorporated herein by reference. The “mitogen-activated protein kinase” / “extracellular signal-regulated kinase” (MAPK / ERK, or just MAPK) pathways are signal transduction pathways that couple intracellular responses to the binding of growth factors (such as EGF) to cell surface receptors (such as EGFR). The MAPK pathways are one of the major downstream pathways controlling cellular processes associated with fibrosis, including cell growth, proliferation, differentiation, migration, protection from apoptosis, and transformation. There are several distinct MAPK pathways, important in the regulation of cell proliferation, differentiation, development, inflammation, survival, and migration. In transformed cells, the Ras-Raf-MEK-ERK pathway has been implicated in cell proliferation and survival. The Ras-Raf-MEK-ERK pathway is activated by a range of JHU-43764.601 Client Docket No: P18504-02 growth factor receptors (including EGFR, platelet-derived growth factor receptor, type-1 insulin-like growth factor receptor, and fibroblast growth factor receptor). The pathway can also be activated by cytokines, steroid hormones, and several agonists that act via G- protein-coupled receptors. Growth-factor stimulation of the MAPK pathways, such as by EGF or TGF-α, leads to sequential activation of Ras and Raf, which in turn activate MAPK kinases 1 and 2 (MEK1 and MEK2, or together, MEK1 / 2). MEK1 / 2 is a dual-specificity kinase that phosphorylates mitogen-activated protein kinases (MAPKs) and extracellular signal-related kinases (ERKs). MEK1 / 2 is essential to the propagation of growth factor signaling and is known to amplify signals to extracellular signal-regulated kinases 1 and 2 (ERK1 / 2, also known as MAPK1 / 2). MAPKs are part of a major signal transduction route that, upon activation, can phosphorylate a variety of intracellular targets including transcription factors, transcriptional adaptor proteins, membrane and cytoplasmic substrates, and other protein kinases. MAPKs transfer and amplify messages from the cell surface to the nucleus, producing a range of cellular effects, including cell proliferation. Description NF1 is one of the largest human proteins and has potentially numerous functionalities in addition to the well-studied GRD and SEC-PH domains. Bergoug “Neurofibromin Structure, Functions and Regulation” Cells 9 (2020). Recent high-resolution structures of the full-length NF1 protein have increased understanding of some of the major functions of NF1, e.g., maintaining the homodimer interface and integrity, regulating its attachment to the plasma membrane, and transitioning between the active and inactive conformations of Ras-binding for GTPase activity. Naschberger “The structure of neurofibromin isoform 2 reveals different functional states” Nature 599, 315-319 (2021); Lupton “The cryo-EM structure of the human neurofibromin dimer reveals the molecular basis for neurofibromatosis type 1” Nat Struct Mol Biol 28, 982-988 (2021); and Chaker-Margot “Structural basis of activation of the tumor suppressor protein neurofibromin” Mol Cell 82, 1288-1296 e1285 (2022). Accordingly, it was contemplated that a construct comprising the NF1 GRD domain and a membrane-targeting motif of Ras could provide a truncated NF1 substitute for the full length NF1 gene product in gene replacement therapy. In fact, full length NF1 may be JHU-43764.601 Client Docket No: P18504-02 less efficacious in gene therapy because its large size provides many targets for interactions (e.g., with substituted NF1) that could modulate its assembly (e.g., dimerization) and function. Young “Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization” Proc Natl Acad Sci U S A 120, e2208960120 (2023). In contrast, the truncated GRDC24 is devoid of dimerization interface and most likely free from the interference of substituted NF1. By optimizing the GAP-related domain (GRD), it was discovered that altering its length significantly impacts expression levels and, consequently, the anti-tumor effectiveness when delivered via an AAV vector in NF1 cell lines. The optimized GRD, spanning 333 amino acids (amino acids 1200-1532 of NF1), incorporates both N-terminal and C-terminal Spred1-binding sequences at its N-terminus and C-terminus (Hirata “Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1” J Biol Chem 291, 3124-3134 (2016)), potentially enhancing the stability of the GRD protein. Previous research has shown that appending different types or lengths of Ras hypervariable region (HVR) sequences to GRD can improve its membrane-targeting capabilities and Ras activity suppression Huang “Plasma membrane-targeted Ras GTPase-activating protein is a potent suppressor of p21ras function” Mol Cell Biol 13, 2420-2431 (1993); Bai “Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors” Gene Ther 26, 277-286 (2019); U.S. Pat. App. Pub. No. 20210395736, which is incorporated herein by reference. During the development of embodiments of the technology provided herein, experiments were conducted to systematically evaluate the HVRs from four Ras isoforms. The data collected indicated that the HVR from KRas4B provided the most effective suppression of NF1 cells when attached to GRD. While there is no direct study comparing the pathological impact of different Ras isoforms in NF1 tumors, KRas mutations are the most common in human cancers (Prior “The Frequency of Ras Mutations in Cancer” Cancer Res 80, 2969-2974 (2020)), underscoring its significant role in tumorigenesis. Utilizing the KRas4B HVR in the GRD-C24 construct described herein, which uses a poly-lysine sequence for membrane attachment unlike other Ras HVRs, is contemplated to result in JHU-43764.601 Client Docket No: P18504-02 superior membrane targeting and / or better co-localization with the most disease-relevant KRas, thus enhancing therapeutic outcomes. Cancer gene therapies often struggle with delivery methods. Viral vectors like lentivirus and herpes simplex virus 1 (HSV1) are effective at transducing cancer cells, but they are generally restricted to ex vivo use or intratumoral injections due to risks like genomic integration or strong immune reactions. Recombinant AAV vectors, while successful in systemic treatments for non-tumoral diseases, show limited effectiveness in continuously dividing tumor cells, which hampers their use in systemic cancer therapy. To alter AAV tropism, directed evolution of the capsid is commonly employed due to its ability to generate unbiased mutations without prior mechanistic knowledge and through iterative in vivo selections. Wang “Adeno-associated virus as a delivery vector for gene therapy of human diseases” Signal Transduct Target Ther 9, 78 (2024); Shih “Utilizing adeno-associated virus as a vector in treating genetic disorders or human cancers” IUBMB Life (2024). For NF1 tumors and Schwann cells, standard AAVs, including AAV9, demonstrated poor in vivo transduction when administered intravenously. During the development of embodiments of the technology described herein, experiments were conducted using directed evolution with capsid DNA shuffling in an NF1 xenograft mouse model to avoid creating a species-specific capsid not suitable for human translation. Hordeaux “The Neurotropic Properties of AAV-PHP.B Are Limited to C57BL / 6J Mice” Mol Ther 26, 664-668 (2018); Hordeaux “The GPI-Linked Protein LY6A Drives AAV-PHP.B Transport across the Blood-Brain Barrier” Mol Ther 27, 912-921 (2019). In addition, considering the complex origin of NF1 tumors from Schwann cell development, evolving the capsids in non-human primate nerve sheaths might not optimize tropism for NF1 tumors. The ST88-14 human MPNST cell line, with known NF1, CDKN2A, and SUZ12 alterations (DeClue “Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis” Cell 69, 265-273 (1992); Magallon-Lorenz “Deep genomic analysis of malignant peripheral nerve sheath tumor cell lines challenges current malignant peripheral nerve sheath tumor diagnosis” iScience 26, 106096 (2023)), was chosen for its sensitivity to GRD-C24 and its reliable tumor formation in the sciatic nerve, making it an suitable orthotopic model for vector selection and validation. JHU-43764.601 Client Docket No: P18504-02 The leading candidate of capsid DNA shuffling, AAV-557-2, exhibited reduced liver transduction and increased affinity for NF1 tumors compared to AAV9. Further refinement by integrating a random 7mer peptide into the VR-VIII loop enhanced NF1 tumor targeting, resulting in the vector K55-GRDC24, which demonstrated therapeutic efficacies in NF1 models. Notably, K55 showed significant transduction in various NF1 cell lines and a PDX model but not in other NF1 models or non-NF1-related human tumor xenografts, suggesting selectivity of K55 tropism in NF1. Importantly, AAV-K55 tropism is not limited to neurofibromas and can be extended to gliomas, such as the NF1-deficient LN229, which could thus provide a treatment for gliomas. Moreover, identifying the cell-surface binding partner of capsid K55 would be important for advancing its clinical application, potentially offering a key biomarker for patient selection and predicting clinical responses. NF1 tumors are suggested to originate from the precursors of Schwann cells, particularly from the HoxB7+ population. Mo “Humanized neurofibroma model from induced pluripotent stem cells delineates tumor pathogenesis and developmental origins” J Clin Invest 131 (2021). During the development of embodiments of the technology described herein, experiments were conducted that demonstrated that GRDC24 not only suppressed growth and induced apoptosis in NF1 cells but also restored Schwann cell differentiation when expressed during the neural crest or early Schwann cell stage of NF1 (– / –) iPSC differentiation. This indicated that systemic administration of AAV-GRDC24 rescues the differentiating Schwann cell precursors where NF1 loss of heterozygosity (LOH) occurs in NF1 haploinsufficient patients, and it could prevent future tumor formation in addition to treating existing tumors. Considering the moderate seroprevalence of existing binding and neutralizing antibodies against AAV-K55, this vector could be applicable to a wide range of patients for tumor prevention and treatment, an important clinical consideration. In summary, experiments conducted during the development of embodiments of the technology described herein demonstrated that an approach involving sequential selections through capsid DNA shuffling and peptide display libraries in a human xenograft mouse model can significantly enhance tropism towards target tumors while minimizing transduction in non-target organs (e.g., the liver) in developing AAV gene therapy for tumoral diseases. Due to the proliferative nature of tumors, multiple administrations of AAV vectors within a short timeframe, before eliciting an adaptive immune response, might be necessary to achieve a better clinical outcome. This strategy could raise safety concerns JHU-43764.601 Client Docket No: P18504-02 given the reported adverse effects associated with high-dose AAV therapies using natural serotypes. Duan “Lethal immunotoxicity in high-dose systemic AAV therapy” Mol Ther 31, 3123-3126 (2023). However, tailored AAV vectors (e.g., AAV-K55, named “AAV-NF” herein) having significantly reduced tropism to other tissues could provide a therapy with minimized and / or eliminated systemic toxicities, thereby enabling a multiple dosing regimen. Compositions In some embodiments, the technology provides compositions. For example, some embodiments provide a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding a GRD domain of NF1 (“NF1-GRD”) fused in frame to a nucleotide sequence encoding a Ras HVR. Some embodiments provide a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding an AAV cap gene that is optimized to provide improved tropism for NF1-related tumors. Some embodiments provide a nucleic acid (e.g., an AAV vector) comprising: 1) a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR; and 2) a nucleotide sequence encoding an AAV cap gene that is optimized to provide improved tropism for NF1-related tumors. Some embodiments provide a composition comprising a plurality of nucleic acids (e.g., a plurality of AAV vectors), e.g., a composition comprising: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR; and 2) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding an AAV cap gene that is optimized to provide improved tropism for NF1-related tumors. Some embodiments provide a recombinant AAV particle comprising a nucleic acid comprising: 1) a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR; and 2) a nucleotide sequence encoding an AAV cap gene that is optimized to provide improved tropism for NF1-related tumors. Some embodiments provide a recombinant AAV particle comprising: 1) a nucleic acid comprising a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR; and 2) an AAV capsid protein that comprises an amino acid sequence insertion that is optimized to provide improved tropism to NF1-related tumors for the recombinant AAV particle. JHU-43764.601 Client Docket No: P18504-02 In some embodiments, the nucleotide sequence encoding NF1-GRD fused to a nucleotide sequence encoding a Ras HVR has improved expression in cells after delivery by an AAV vector and the expression product (e.g., a polypeptide comprising NF1-GRD fused to a Ras HVR) has improved RAS suppression and / or anti-tumor effectiveness when delivered in an AAV vector. In some embodiments, the nucleotide sequence encoding the AAV cap gene expresses a capsid polypeptide that has improved tropism for NF1 tumors. In some embodiments, the NF1-GRD is a truncated NF1-GRD comprising 333 amino acids (i.e., amino acids 1200-1532 of NF1), referred to herein by the term “GRD” or “GRD333” (SEQ ID NO: 18). GRD333 amino acid sequence (SEQ ID NO: 18) VLADRFERLVELVTMMGDQGELPIAMALANVVPCSQWDELARVLVTLFDSRHLLYQLLWNMFSKEVELAD SMQTLFRGNSLASKIMTFCFKVYGATYLQKLLDPLLRIVITSSDWQHVSFEVDPTRLEPSESLEENQRNL LQMTEKFFHAIISSSSEFPPQLRSVCHCLYQVVSQRFPQNSIGAVGSAMFLRFINPAIVSPYEAGILDKK PPPRIERGLKLMSKILQSIANHVLFTKEEHMRPFNDFVKSNFDAARRFFLDIASDCPTSDAVNHSLSFIS DGNVLALHRLLWNNQEKIGQYLSSNRDHKAVGRRPFDKMATLLAYLGPPEHKP In some embodiments, the Ras HVR is an HVR from H-RAS, N-Ras, K-Ras4A, K- Ras4B. In some embodiments, the Ras HVR is an HVR from K-Ras4B. In some embodiments, GRD333 is fused to the C-terminal 24 amino acids of KRas4B (KHKEKMSKDGKKKKKKSKTKCVIM (SEQ ID NO: 16), referred to herein by the term “C24”) to provide a nucleic acid comprising a nucleotide sequence encoding GRD333 fused in frame to a nucleotide sequence encoding the C24 polypeptide amino acid sequence (referred to herein by the term “GRD-C24” or “GRD333-C24”). In some embodiments, the nucleic acid comprising a nucleotide sequence encoding GRD333-C24 expresses a polypeptide comprising GRD333 fused in frame to C24. GRD333-C24 (SEQ ID NO: 43) VLADRFERLVELVTMMGDQGELPIAMALANVVPCSQWDELARVLVTLFDSRHLLYQLLWNMFSKEVELAD SMQTLFRGNSLASKIMTFCFKVYGATYLQKLLDPLLRIVITSSDWQHVSFEVDPTRLEPSESLEENQRNL LQMTEKFFHAIISSSSEFPPQLRSVCHCLYQVVSQRFPQNSIGAVGSAMFLRFINPAIVSPYEAGILDKK PPPRIERGLKLMSKILQSIANHVLFTKEEHMRPFNDFVKSNFDAARRFFLDIASDCPTSDAVNHSLSFIS JHU-43764.601 Client Docket No: P18504-02 DGNVLALHRLLWNNQEKIGQYLSSNRDHKAVGRRPFDKMATLLAYLGPPEHKPKHKEKMSKDGKKKKKKS KTKCVIM In some embodiments, the optimized AAV cap gene encodes a capsid protein comprising a K55 polypeptide amino acid sequence SKVPLPN (SEQ ID NO: 36) or a K57 polypeptide amino acid sequence KQLPLVT (SEQ ID NO: 32). As described in the examples, several optimized capsid proteins demonstrated improved tropism for NF1- related tumors. Data indicated that capsid proteins comprising K55 or K57 were the two best performers in assays to test tropism of AAV vectors for NF1-related tumors. In some embodiments, the K55 or K57 polypeptide sequence is inserted in the VR-VIII loop of the AAV capsid protein (e.g., between the asparagine at amino acid 588 (N588) and the threonine at amino acid 589 (T589)). In some embodiments, the amino acid sequence of the capsid protein comprising the K55 polypeptide amino acid sequence is SEQ ID NO: 10. In some embodiments, the amino acid sequence of the capsid protein comprising the K57 polypeptide amino acid sequence is SEQ ID NO: 12. In some embodiments, the nucleotide sequence encoding the capsid protein comprising the K55 polypeptide amino acid sequence is SEQ ID NO: 9. In some embodiments, the nucleotide sequence encoding the capsid protein comprising the K57 polypeptide amino acid sequence is SEQ ID NO: 11. Accordingly, in some embodiments, the technology provides a nucleic acid (e.g., an AAV vector) comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a cap gene nucleotide sequence encoding a K55 capsid protein comprising the amino acid sequence SKVPLPN (SEQ ID NO: 36). In some embodiments, the technology provides a nucleic acid (e.g., an AAV vector) comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a cap gene nucleotide sequence encoding a K57 capsid protein comprising the amino acid sequence KQLPLVT (SEQ ID NO: 32). In some embodiments, the technology provides a nucleic acid (e.g., an AAV vector) comprising: 1) a nucleotide sequence encoding GRD333- C24; and 2) a K55 cap gene nucleotide sequence that is SEQ ID NO: 9. In some embodiments, the technology provides a nucleic acid (e.g., an AAV vector) comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a K57 cap gene nucleotide sequence that is SEQ ID NO: 11. Some embodiments provide a composition comprising a plurality of nucleic acids (e.g., a plurality of AAV vectors). For example, in some embodiments, the technology JHU-43764.601 Client Docket No: P18504-02 provides a composition comprising: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding GRD333-C24; and 2) a nucleic acid (e.g., an AAV vector) comprising a cap gene nucleotide sequence encoding a K55 capsid protein comprising the amino acid sequence SKVPLPN (SEQ ID NO: 36). In some embodiments, the technology provides a composition comprising: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding GRD333-C24; and 2) a nucleic acid (e.g., an AAV vector) comprising a cap gene nucleotide sequence encoding a K57 capsid protein comprising the amino acid sequence KQLPLVT (SEQ ID NO: 32). In some embodiments, the technology provides a composition comprising: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding GRD333-C24; and 2) a nucleic acid (e.g., an AAV vector) comprising a K55 cap gene nucleotide sequence that is SEQ ID NO: 9. In some embodiments, the technology provides a composition comprising: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding GRD333-C24; and 2) a nucleic acid (e.g., an AAV vector) comprising a K57 cap gene nucleotide sequence that is SEQ ID NO: 11. In some embodiments, the technology provides a composition comprising: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding GRD333-C24; 2) a nucleic acid (e.g., an AAV vector) comprising a cap gene nucleotide sequence encoding a K55 capsid protein comprising the amino acid sequence SKVPLPN (SEQ ID NO: 36); and 3) a helper vector. In some embodiments, the technology provides a composition comprising: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding GRD333- C24; 2) a nucleic acid (e.g., an AAV vector) comprising a cap gene nucleotide sequence encoding a K57 capsid protein comprising the amino acid sequence KQLPLVT (SEQ ID NO: 32); and 3) a helper vector. In some embodiments, the technology provides a composition comprising: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding GRD333-C24; 2) a nucleic acid (e.g., an AAV vector) comprising a K55 cap gene nucleotide sequence that is SEQ ID NO: 9; and 3) a helper vector. In some embodiments, the technology provides a composition comprising: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding GRD333-C24; 2) a nucleic acid (e.g., an AAV vector) comprising a K57 cap gene nucleotide sequence that is SEQ ID NO: 11; and 3) a helper vector. JHU-43764.601 Client Docket No: P18504-02 Some embodiments provide a recombinant AAV particle comprising a nucleic acid comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a cap gene nucleotide sequence encoding a K55 capsid protein comprising the amino acid sequence SKVPLPN (SEQ ID NO: 36). Some embodiments provide a recombinant AAV particle comprising a nucleic acid comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a cap gene nucleotide sequence encoding a K57 capsid protein comprising the amino acid sequence KQLPLVT (SEQ ID NO: 32). Some embodiments provide a recombinant AAV particle comprising a nucleic acid comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a K55 cap gene nucleotide sequence that is SEQ ID NO: 9. Some embodiments provide a recombinant AAV particle comprising a nucleic acid comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a K57 cap gene nucleotide sequence that is SEQ ID NO: 11. Some embodiments provide a recombinant AAV particle comprising: 1) a nucleic acid comprising a nucleotide sequence encoding GRD333-C24; and 2) a K55 capsid protein comprising the amino acid sequence SKVPLPN (SEQ ID NO: 36). Some embodiments provide a recombinant AAV particle comprising: 1) a nucleic acid comprising a nucleotide sequence encoding GRD333-C24; and 2) a K57 capsid protein comprising the amino acid sequence KQLPLVT (SEQ ID NO: 32). Some embodiments provide a recombinant AAV particle comprising: 1) a nucleic acid comprising a nucleotide sequence encoding GRD333- C24; and 2) a K55 capsid protein that is encoded by a cap gene nucleotide sequence that is SEQ ID NO: 9. Some embodiments provide a recombinant AAV particle comprising: 1) a nucleic acid comprising a nucleotide sequence encoding GRD333-C24; and 2) a K57 capsid protein that is encoded by a cap gene nucleotide sequence that is SEQ ID NO: 11. The technology comprises variants of the nucleic acids and polypeptides above, e.g., comprising one or more nucleotide or amino acid substitutions. Embodiments provide nucleic acids having at least 75% (e.g., at least 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) identity to the nucleic acids described herein. Embodiments provide polypeptides having at least 75% (e.g., at least 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) identity to the polypeptides described herein. Embodiments provide nucleic acids having at least 75% identity (e.g., at least 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) to the nucleic acids and / or polypeptides described herein provided that the variant nucleic acid or polypeptide functions as described herein. JHU-43764.601 Client Docket No: P18504-02 Additionally, in some embodiments, the technology provides vectors comprising nucleic acids as described above. For example, in some embodiments, the technology provides an AAV vector comprising a nucleic acid comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a cap gene nucleotide sequence encoding a K55 capsid protein comprising the amino acid sequence SKVPLPN (SEQ ID NO: 36) or a nucleotide sequence encoding a K57 capsid protein comprising the amino acid sequence KQLPLVT (SEQ ID NO: 32)). In some embodiments, the technology provides: 1) an AAV vector comprising a nucleic acid comprising a nucleotide sequence encoding GRD333-C24; and 2) an AAV vector comprising a cap gene nucleotide sequence encoding a K55 capsid protein comprising the amino acid sequence SKVPLPN (SEQ ID NO: 36) or encoding a K57 capsid protein comprising the amino acid sequence KQLPLVT (SEQ ID NO: 32)). Embodiments provide that any of the AAV vectors described herein may be, e.g., AAV1 (e.g., pAAV2 / 1), AAV2 (e.g., pAAV2-RC), AAV3B (e.g., pAAV-RC3B), AAV4 (e.g., pAAV-RC4), AAV5 (e.g., pAAV2 / 5 JC), AAV6 (e.g., pAAV-RC6), AAV7 (e.g., pAAV2 / 7), AAV8 (e.g., pAAV2 / 8), AAV9 (e.g., pAAV9n), AAV10 (e.g., pAAV2 / rh10), AAV11 (e.g., pAAV2 / hu11), AAV32 / 33 (e.g., pAAV2 / rh32.33), or AAV-DJ (e.g., pAAVDJ). In some embodiments, the AAV vector is AAV2, AAV3B, AAV6, or AAV-DJ. Further embodiments provide a cell, a tissue, an organ, and / or an organism comprising one or more nucleic acids as described herein. For example, some embodiments provide a cell, a tissue, an organ, and / or an organism comprising a nucleic acid (e.g., an AAV vector) comprising: 1) a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43); and 2) a nucleic acid comprising an AAV cap gene nucleotide sequence that encodes a capsid protein that is optimized to provide improved tropism for NF1-related tumors (e.g., an AAV cap gene comprising a nucleotide sequence encoding a K55 polypeptide amino acid sequence comprising SKVPLPN (SEQ ID NO: 36) or an AAV cap gene comprising a nucleotide sequence encoding a K57 polypeptide amino acid sequence comprising KQLPLVT (SEQ ID NO: 32). Some embodiments provide a cell, a tissue, an organ, and / or an organism comprising a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43). In some embodiments, the technology provides a cell comprising a nucleic acid comprising a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide JHU-43764.601 Client Docket No: P18504-02 sequence encoding a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43) and that is integrated into a chromosome (e.g., at the AAVS1 site of human chromosome 19). See, e.g., Kotin et al. (1990) “Site-specific integration by adeno-associated virus” Proceedings of the National Academy of Sciences of the United States of America. 87 (6): 2211–5; Surosky et al. (1997) “Adeno-associated virus Rep proteins target DNA sequences to a unique locus in the human genome” Journal of Virology. 71 (10): 7951–9, each of which is incorporated herein by reference. In some embodiments, the technology provides a tissue, organ, and / or organism comprising a cell comprising a nucleic acid comprising a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43) and that is integrated into a chromosome (e.g., at the AAVS1 site of human chromosome 19). In some embodiments, the technology provides a cell expressing a polypeptide comprising a NF1-GRD domain. In some embodiments, the technology provides a cell expressing a polypeptide comprising a NF1-GRD fused in frame to a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43). In some embodiments, the technology provides a tissue, organ, or organism comprising a cell expressing a polypeptide comprising a NF1-GRD domain. In some embodiments, the technology provides a tissue, organ, or organism comprising a cell expressing a polypeptide comprising a NF1-GRD fused in frame to a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43). In some embodiments, the technology provides a cell expressing a polypeptide comprising a K55 polypeptide amino acid sequence SKVPLPN (SEQ ID NO: 36) or a polypeptide comprising a K57 polypeptide amino acid sequence KQLPLVT (SEQ ID NO: 32). In some embodiments, the cell is deficient in expressing NF1 (e.g., a cell having a NF1 – / – or NF1 + / – genotype and / or a cell having a decreased level of NF1 expression and / or a cell having a decreased level of NF1 activity (e.g., decreased GTPase activity)) and / or a cell having aberrant (e.g., increased (e.g., tumor-forming)) Ras activity. In some embodiments, the cell is a tumor cell. In some embodiments, the cell is a plexiform neurofibroma. In some embodiments, the cell is a low-grade glioma, breast cancer cell, high-grade glioma, pheochromocytoma, GIST, or melanoma. In some embodiments, the cell is a MPNST cell. In some embodiments, the cell is a Schwann cell. In some embodiments, the cell has a mutation in the NF1 gene that encodes NF1 (e.g., a point mutation, inversion, deletion, insertion). In some embodiments, the cell has a mutation in a JHU-43764.601 Client Docket No: P18504-02 nucleotide sequence that controls expression of NF1. In some embodiments, the cell has a mutation in the gene that encodes Ras (e.g., a point mutation, inversion, deletion, insertion). In some embodiments, the cell has a mutation in a nucleotide sequence that controls expression of Ras. In some embodiments, a patient comprising having a cancer or comprising a tumor comprises the cell. In some embodiments, a patient having a Rasopathy comprises the cell. In some embodiments, a patient having neurofibromatosis type 1 comprises the cell. In some embodiments, a patient having a MPNST comprises the cell. The technology is not limited in the cells comprising the NF1-GRD nucleic acids or proteins or into which a NF1-GRD construct is introduced. For example, cells encompassed by the technology provided herein include any cell into which foreign nucleic acids can be introduced and expressed as described herein. It is to be understood that the basic concepts of the present technology described herein are not limited by cell type. Cells according to the present disclosure include eukaryotic cells, mammalian cells, animal cells, human cells, and the like. Further, cells include any cells in which it would be beneficial or desirable to provide the NF1-GRD construct (e.g., nucleic acid and / or polypeptide). Such cells may include those that are deficient in expression of NF1 or having aberrant Ras activity (e.g., leading to a disease or detrimental condition). Such diseases or detrimental conditions are readily known to those of skill in the art, e.g., cancers (e.g., Rasopathies, neurofibroma, neurofibromatosis, malignant peripheral nerve sheath tumors). Providing the nucleic acid and polypeptide constructs described herein into such cells provide a therapeutic treatment in some embodiments. Pharmaceutical compositions and treatment In some embodiments, a gene delivery vector (e.g., a rAAV comprising: 1) a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43); and 2) an AAV capsid polypeptide that is optimized to provide improved tropism for NF1-related tumors (e.g., a capsid polypeptide comprising a K55 polypeptide amino acid sequence SKVPLPN (SEQ ID NO: 36) or a capsid polypeptide comprising a K57 polypeptide amino acid sequence KQLPLVT (SEQ ID NO: 32)) is provided in the form of a medicament or a pharmaceutical composition and is used in some embodiments in the manufacture of a medicament or a pharmaceutical composition. The pharmaceutical composition may comprise a pharmaceutically acceptable carrier. JHU-43764.601 Client Docket No: P18504-02 Preferably, the carrier is suitable for parenteral administration. In some embodiments, the carrier is suitable for intravenous, intraperitoneal, or intramuscular administration. Pharmaceutically acceptable carrier or excipients are described in, for example, Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro (Editor) Publishing Company (1997). Exemplary pharmaceutical composition embodiments comprise, e.g., sterile saline, dextrose solution, or buffered solution, or other pharmaceutically acceptable sterile fluids. Alternatively, a solid carrier may be used such as, for example, microcarrier beads. Pharmaceutical compositions are typically sterile and stable under the conditions of manufacture and storage. Pharmaceutical compositions may be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to delivery of the gene therapy vectors. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. In many cases, embodiments comprise isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin. The vectors of the present disclosure may be administered in a time or controlled release formulation, for example in a composition that includes a slow release polymer or other carriers that protect the compound against rapid release, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers may, for example, be used, such as ethylene vinyl acetate, polyanhydrics, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polyglycolic copolymers (PLG). In some embodiments, the technology provides a gene therapy vectors (e.g., a rAAV comprising: 1) a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43); and 2) an AAV capsid polypeptide that is optimized to provide improved tropism to NF1-related tumors (e.g., an AAV capsid polypeptide comprising a K55 amino acid sequence SKVPLPN (SEQ ID NO: 36) or an AAV capsid polypeptide comprising a K57 amino acid sequence KQLPLVT (SEQ ID NO: 32)) that are formulated with acceptable carriers, are administered parenterally, such JHU-43764.601 Client Docket No: P18504-02 as by intravenous, intraperitoneal, subcutaneous, intramuscular administration, limb perfusion, or combinations thereof. In some embodiments, the administration is systemic, such that the gene delivery vectors are delivered through the body of the subject. When delivered systemically, the improved tropism for NF1-related tumors provided by the optimized capsid protein delivers the NF1-GRD (e.g., GRD333-C24) to the site where therapy is most beneficial for the patient. In some embodiments, the gene delivery vectors are administered directly into the targeted tissue, e.g., neural tissues. In some embodiments, the gene delivery vectors are administered locally, such as by a catheter. The route of administration can be determined by the person of skill in the art, taking into consideration, for example, the nature of target tissue, gene delivery vectors, intended therapeutic effect, and maximum load that can be administered and absorbed by the targeted tissue(s). Generally, an effective amount, particularly a therapeutically effective amount, of the gene delivery vectors are administered to a subject in need thereof. An effective or therapeutically effective amount of vector may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the viral vector to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. In some embodiments, a range for therapeutically or prophylactically effective amounts of a nucleic acid, nucleic acid construct, AAV vector, or pharmaceutical composition may be from 1 × 1011and 1 × 1014genome copy (gc) / kg or 1 × 1012and 1 × 1013genome copy (gc) / kg. It is to be noted that dosage values may vary with the severity of the condition to be alleviated. The dosage may also vary based on the efficacy of the virion employed. For example, AAV8 is better at infecting liver as compared to AAV2 and AAV9 is better at infecting brain than AAV8, in these two cases one would need less AAV8 or AAV9 for the case of liver or brain respectively. For any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgement of the person administering or supervising the administration of the compositions. Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that may be selected by medical practitioners. In some embodiments, the effective dose range for small animals (mice), following intramuscular injection, may be between 1 × 1012and 1 × 1013genome copy (gc) / kg, and for JHU-43764.601 Client Docket No: P18504-02 larger animals (cats or dogs) and for human subjects, between 1 × 1011and 1 × 1012gc / kg, or between 1 × 1011and 1 × 1014genome copy (gc) / kg. In various embodiments, the gene delivery vectors are administered as a bolus or by continuous infusion over time. In some embodiments, several divided doses are administered over time or the dose is proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. In some embodiments, the gene delivery vectors can be administered daily, weekly, biweekly, or monthly. The duration of treatment can be for at least one week, one month, 2 months, 3 months, 6 months, or 8 months or more. In some embodiments, the duration of treatment can be for up to 1 year or more, 2 years or more, 3 years or more, or indefinitely. Methods In some embodiments, a therapeutically effective amount of a gene delivery vector (e.g., a rAAV comprising: 1) a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43); and 2) an AAV capsid polypeptide that is optimized to provide improved tropism to NF1-related tumors (e.g., an AAV capsid polypeptide comprising a K55 amino acid sequence SKVPLPN (SEQ ID NO: 36) or an AAV capsid polypeptide comprising a K57 amino acid sequence KQLPLVT (SEQ ID NO: 32)) is administered to a subject to treat a condition or disease. In some embodiments, the technology comprises administration for a period of time until an individual is generally healthy and free of disease and / or the methods ameliorate a disorder associated with a condition or disease. Thise, in some embodiments, methods involve treating a disease. In some embodiments, the disease is neurofibromatosis type 1 (NF1). In some embodiments, the disease involves formation of a tumor (e.g., benign tumor, malignant tumor). In some embodiments, the disease reduces life expectancy by 10 years to 15 years shorter than that of the general population. In some embodiments, the disease involves the formation of plexiform neurofibromas (pNF). In some embodiments, the disease involves formation of neoplasms other than neurofibromas. In some embodiments, the disease involves formation of a neoplasm that is, e.g., a low-grade glioma, a malignant peripheral nerve sheath tumor, breast cancer, a high-grade glioma, pheochromocytoma, GIST, or a melanoma. In some embodiments, the disease is caused by altered Ras activity (e.g., excessive Ras activation). JHU-43764.601 Client Docket No: P18504-02 In some embodiments, the disease is caused by reduced functional levels of NF1 gene product. In some embodiments, a gene therapy technology as described herein finds use in treating a subject having, suspected of having, predisposed to have, and / or in need of a treatment for, a cancer or benign tumor disease (e.g., a neurofibromatosis type 1 and / or a MPNST). For instance, in some embodiments, the technology reduces the incidence of disease and / or delays or ameliorates a disease. In some embodiments, the amelioration of disease provided by the gene therapy methods herein is a result of reducing symptoms in an affected subject or reducing the incidence of the disease or disorder in a population as compared to an untreated population. In some embodiments, the gene therapy has the effect of treating and / or preventing various benign tumor and / or cancer conditions and diseases as assessed by particular markers and disorders of said benign tumor and / or cancer conditions and diseases (e.g., genetic tests indicating NF1 mutations or Ras mutations; tests indicating aberrant NF1 and / or aberrant Ras activity). In some embodiments, therefore, the technology provides a gene therapy method or the use of an rAAV vector comprising: 1) a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43); and 2) an AAV capsid polypeptide that is optimized to provide improved tropism to NF1- related tumors (e.g., an AAV capsid polypeptide comprising a K55 amino acid sequence SKVPLPN (SEQ ID NO: 36) or an AAV capsid polypeptide comprising a K57 amino acid sequence KQLPLVT (SEQ ID NO: 32) as described above for use in the treatment or prevention in a subject, e.g., of at least a disorder or marker of a cancer or benign tumor disease (e.g., a neurofibromatosis type 1 and / or a MPNST). In some embodiments, the gene therapy described herein is used to extend the lifespan of a subject. Extended lifespan can be an increase in the average lifespan of an individual of that species who reaches adulthood and / or an extension of the maximum lifespan of that species. In some embodiments, extended lifespan can be a 5%, 10%, 15%, 20%, or more increase in maximum lifespan and / or a 5%, 10%, 15%, 20%, or more increase in average lifespan. Foreign nucleic acids, alternatively referred to as heterologous nucleic acids (e.g., a recombinant nucleic acid comprising a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43) JHU-43764.601 Client Docket No: P18504-02 may be introduced into a cell using any method known to those skilled in the art for such introduction. Such methods include transfection, transduction, viral transduction, microinjection, lipofection, nucleofection, nanoparticle bombardment, transformation, conjugation and the like. One of ordinary skill in the art will readily understand and adapt such methods using readily identifiable literature sources. Foreign nucleic acids may be delivered to a subject by administering to the subject, such as systemically administering to the subject, such as by intravenous administration or injection, intraperitoneal administration or injection, intramuscular administration or injection, intracranial administration or injection, intraocular administration or injection, subcutaneous administration or injection, a nucleic acid or vector including a nucleic acid as described herein. In some embodiments, a recombinant nucleic acid comprising a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43) is packaged in a viral particle comprising an AAV capsid polypeptide that is optimized to provide improved tropism to NF1-related tumors (e.g., an AAV capsid polypeptide comprising a K55 amino acid sequence SKVPLPN (SEQ ID NO: 36) or an AAV capsid polypeptide comprising a K57 amino acid sequence KQLPLVT (SEQ ID NO: 32)); and the viral particle is administered to a patient. Gene therapy methods and methods of delivering genes to subjects, for example, using adeno-associated viruses (AAV) and AAV vectors, are described in U.S. Pat. No. 6,967,018; Int’l Pat. Pub. No. WO 2014 / 093622; U.S. Pat. App. Pub. No. 2008 / 0175845; U.S. Pat. App. Pub. No. 2014 / 0100265; EP 2432490; EP 2352823; EP 2384200; Int’l Pat. App. Pub. No. WO 2014 / 127198, Int’l Pat. App. Pub. No. WO 2005 / 122723; Int’l Pat. App. Pub. No. WO 2008 / 137490; Int’l Pat. App. Pub. No. WO 2013 / 142114; Int’l Pat. App. Pub. No. WO 2006 / 128190; Int’l Pat. App. Pub. No. WO 2009 / 134681; EP 2341068; Int’l Pat. App. Pub. No. WO 2008 / 027084; Int’l Pat. App. Pub. No. WO 2009 / 054994; Int’l Pat. App. Pub. No. WO 2014059031; U.S. Pat. No. 7,977,049; and Int’l Pat. App. Pub. No. WO 2014 / 059029, each of which is incorporated herein by reference in its entirety. Subjects Embodiments provide methods for treating a subject. In some embodiments, subject has a disease caused by altered Ras activity (e.g., excessive Ras activation). In some embodiments, the subject has a disease caused by reduced functional levels of NF1 gene JHU-43764.601 Client Docket No: P18504-02 product. In some embodiments, the subject is a human. In some embodiments, the subject is a human having or in need of a treatment for a Rasopathy (see, e.g., Rauen “The RASopathies” Annu Rev Genomics Hum Genet. 2013; 14: 355–369, incorporated herein by reference). In some embodiments, the subject is a human having or in need of a treatment for neurofibromatosis type 1. In some embodiments, the subject is a human having or in need of a treatment for a MPNST. In some embodiments, the subject is a human having or in need of a treatment for neurofibromatosis type 1 (NF1). In some embodiments, the subject is a human having or in need of a treatment for a tumor (e.g., benign tumor, malignant tumor). In some embodiments, the subject is a human having a disease that reduces life expectancy by 10 years to 15 years relative to the life expectancy of the general population. In some embodiments, the subject is a human having or in need of a treatment for a disease involving the formation of plexiform neurofibromas (pNF). In some embodiments, the subject is a human having or in need of a treatment for a disease involving formation of neoplasms other than neurofibromas. In some embodiments, the subject is a human having or in need of a treatment for a disease involving formation of a neoplasm that is, e.g., a low-grade glioma, a malignant peripheral nerve sheath tumor, a breast cancer, a high-grade glioma, a pheochromocytoma, a GIST, or a melanoma. In some embodiments, the technology provides a method for treating a neurofibromatosis in a subject. In some embodiments, methods comprise administering to the subject an effective amount of a NF1-GRD gene therapy construct (e.g., a rAAV comprising: 1) a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43); and 2) an AAV capsid polypeptide that is optimized to provide improved tropism to NF1-related tumors (e.g., an AAV capsid polypeptide comprising a K55 amino acid sequence SKVPLPN (SEQ ID NO: 36) or an AAV capsid polypeptide comprising a K57 amino acid sequence KQLPLVT (SEQ ID NO: 32)). In some embodiments, the subject has a neurofibromatosis that is neurofibromatosis type 1, Schwannomatosis, a sporadic schwannoma, and / or a disease otherwise characterized by the presence of a tumor of Schwann cell origin. In some embodiments, the tumor of Schwann cell origin is a schwannoma or a malignant peripheral nerve sheath tumor (MPNST). JHU-43764.601 Client Docket No: P18504-02 In some embodiments, the subject exhibits no detectable symptoms and / or phenotypes of disease and in some embodiments the subject exhibits detectable symptoms and / or phenotypes of disease. One serious symptom that affects a person with neurofibromatosis type 1 is a malignant peripheral nerve sheath tumor (MPNST). MPNST typically forms from unexpected growth of a preexisting neurofibroma, particularly a plexiform neurofibroma. The first symptom is typically unexplained or sudden pain in the area in or around existing tumors. Other symptoms may include, e.g., swelling (often painless) in the extremities (arms or legs), difficulty moving the extremity that has the tumor, and / or soreness localized to the area of the tumor or in the extremity. In some instances, neurofibromatosis type 1 is associated with learning disabilities in individuals affected by the disease. In some instances, the disease is associated with a partial absence seizure disorder. In some instances, neurofibromatosis type 1 is associated with poor language, visual-spatial skills, learning disability (e.g., attention deficit hyperactivity disorder), headache, epilepsy, or the like. In some embodiments, the subject is diagnosed as having a disease based on a genetic test, e.g., a genetic test indicating a genetic defect producing aberrant NF1 activity and / or aberrant Ras activity. In some embodiments, a subject has a point mutation, deletion, insertion, microdeletion, and / or splicing mutations of the neurofibromin 1 (NF1) tumor suppressor gene, e.g., at 17q11.2. Detection of such genetic markers, in various embodiments, is provided by techniques known in the art, e.g., a nucleic acid amplification- based test (e.g., PCR), a probe-based method (e.g., FISH), and / or nucleic acid sequencing. In some embodiments, a biomarker is used for detecting disease or to classify disease (e.g., a diagnostic biomarker). In some embodiments, a biomarker is used to predict a response to a therapy or to predict an adverse event (e.g., a predictive biomarker). In some embodiments, a biomarker is used to indicate an effective drug dose (e.g., a metabolic and / or a pharmacodynamic biomarker). In some embodiments, a biomarker is used to estimate the chances of progression or recurrence (e.g., an outcome biomarker). In some embodiments, a biomarker indicates the presence of a disease (e.g., neurofibromatosis), the presence of a specific tumor type (e.g., a MPNST), the presence of a nontumor phenotype (e.g., pain), indicates a cumulative disease burden (e.g., systemic tumor burden), indicates disease progression (e.g., growth of plexiform neurofibroma), or indicates malignant transformation (e.g., MPNST formation from a neurofibroma). Several neurofibromatosis- JHU-43764.601 Client Docket No: P18504-02 associated biomarkers are known in the art. See, e.g., Hanemann at al. (2016) “Current status and recommendations for biomarkers and biobanking in neurofibromatosis” Neurology 87 (Supplement 1): S40-S48, incorporated herein by reference. In some embodiments, a method is provided for treating a subject in need of such treatment with an effective amount of a nucleic acid construct as described herein (e.g., one or more doses of a therapeutically or prophylactically effective amount of a nucleic acid, nucleic acid construct, AAV vector, or pharmaceutical composition as described herein (e.g., a rAAV comprising: 1) a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43); and 2) an AAV capsid polypeptide that is optimized to provide improved tropism to NF1-related tumors (e.g., an AAV capsid polypeptide comprising a K55 amino acid sequence SKVPLPN (SEQ ID NO: 36) or an AAV capsid polypeptide comprising a K57 amino acid sequence KQLPLVT (SEQ ID NO: 32). In some embodiments, the method comprises administering to the subject an effective amount of a nucleic acid construct as described herein (e.g., one or more doses of a therapeutically or prophylactically effective amount of a nucleic acid, nucleic acid construct, AAV vector, or pharmaceutical composition as described herein (e.g., a rAAV comprising: 1) a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43); and 2) an AAV capsid polypeptide that is optimized to provide improved tropism to NF1-related tumors (e.g., an AAV capsid polypeptide comprising a K55 amino acid sequence SKVPLPN (SEQ ID NO: 36) or an AAV capsid polypeptide comprising a K57 amino acid sequence KQLPLVT (SEQ ID NO: 32)) in any one of the pharmaceutical preparations described herein. The subject can be any subject in need of such treatment. In some embodiments, a subject is tested to assess the presence, the absence, or the level of a disease (e.g., a Rasopathy, a neurofibromatosis (e.g., neurofibromatosis type 1), a cancer (e.g., a MPNST)), e.g., by assaying or measuring a biomarker, a metabolite, a physical symptom, an indication, etc., to determine the risk of or assess the presence, the absence, or the level of a disease (e.g., a Rasopathy, a neurofibromatosis (e.g., neurofibromatosis type 1), a cancer (e.g., a MPNST)), and thereafter the subject is treated with a nucleic acid, nucleic acid construct, AAV vector, or pharmaceutical composition as described herein) based on the outcome of the test. In some embodiments, a patient is tested, treated, and then tested again to monitor the response to therapy. In some JHU-43764.601 Client Docket No: P18504-02 embodiments, cycles of testing and treatment may occur without limitation to the pattern of testing and treating (e.g., test / treat, test / treat / test, test / treat / test / treat, test / treat / test / treat / test, test / treat / treat / test / treat / treat, etc), the periodicity, or the duration of the interval between each testing and treatment phase. Kits Some embodiments relate to kits. In some embodiments, kits comprise a nucleic acid construct as described herein (e.g., one or more doses of a therapeutically or prophylactically effective amount of a nucleic acid, nucleic acid construct, AAV vector, or pharmaceutical composition as described herein). In some embodiments, kits comprise a nucleic acid construct as described herein (e.g., one or more doses of a therapeutically or prophylactically effective amount of a nucleic acid, nucleic acid construct, AAV vector, or pharmaceutical composition as described herein) and a means for intravenous, intraperitoneal, subcutaneous, and / or intramuscular administration of the nucleic acid construct. In some embodiments, kits comprise a nucleic acid construct as described herein (e.g., one or more doses of a therapeutically or prophylactically effective amount of a nucleic acid, nucleic acid construct, AAV vector, or pharmaceutical composition as described herein) and a means for intravenous administration or injection, intraperitoneal administration or injection, intramuscular administration or injection, and / or subcutaneous administration or injection. In some embodiments, kits comprise a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding a GRD domain of NF1 (“NF1-GRD”) fused in frame to a nucleotide sequence encoding a Ras HVR. Some embodiments provide a nucleic acid (e.g., an AAV vector) comprising a cap gene nucleotide sequence encoding a capsid polypeptide that is optimized to provide improved tropism for NF1-related tumors. Some embodiments provide a nucleic acid (e.g., an AAV vector) comprising: 1) a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR; and 2) a cap gene nucleotide sequence encoding a capsid protein that is optimized to provide improved tropism for NF1-related tumors. Some embodiments of kits comprise a plurality of nucleic acids (e.g., a plurality of AAV vectors), e.g., one or more vials or vessels comprising: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR; and 2) a nucleic acid (e.g., an JHU-43764.601 Client Docket No: P18504-02 AAV vector) comprising a cap gene nucleotide sequence encoding a capsid polypeptide that is optimized to provide improved tropism for NF1-related tumors. Some embodiments comprise a recombinant AAV particle comprising: 1) a nucleic acid comprising a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR; and 2) a capsid polypeptide that is optimized to provide improved tropism for NF1- related tumors. In some embodiments, kits comprise a nucleic acid (e.g., an AAV vector) comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a cap gene nucleotide sequence encoding a K55 capsid protein comprising the amino acid sequence SKVPLPN (SEQ ID NO: 36). In some embodiments, kits comprise a nucleic acid (e.g., an AAV vector) comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a cap gene nucleotide sequence encoding a K57 capsid protein comprising the amino acid sequence KQLPLVT (SEQ ID NO: 32). In some embodiments, kits comprise a nucleic acid (e.g., an AAV vector) comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a K55 cap gene nucleotide sequence that is SEQ ID NO: 9. In some embodiments, kits comprise a nucleic acid (e.g., an AAV vector) comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a K57 cap gene nucleotide sequence that is SEQ ID NO: 11. Some embodiments provide kits comprising a plurality of nucleic acids (e.g., a plurality of AAV vectors), e.g., one or more vials or vessels comprising: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding a nucleotide sequence encoding GRD333-C24; and 2) a nucleic acid (e.g., an AAV vector) comprising a cap gene nucleotide sequence encoding a K55 capsid protein comprising the amino acid sequence SKVPLPN (SEQ ID NO: 36). In some embodiments, kits comprise one or more vials or vessels comprising: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding GRD333-C24; and 2) a nucleic acid (e.g., an AAV vector) comprising a cap gene nucleotide sequence encoding a K57 capsid protein comprising the amino acid sequence KQLPLVT (SEQ ID NO: 32). In some embodiments, kits comprise one or more vials or vessels comprising: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding GRD333-C24; and 2) a nucleic acid (e.g., an AAV vector) comprising a K55 cap gene nucleotide sequence that is SEQ ID NO: 9. In some embodiments, kits comprise one or more vials or vessels comprising: 1) a nucleic acid (e.g., an AAV vector) comprising a JHU-43764.601 Client Docket No: P18504-02 nucleotide sequence encoding GRD333-C24; and 2) a nucleic acid (e.g., an AAV vector) comprising a K57 cap gene nucleotide sequence that is SEQ ID NO: 11. Some embodiments provide kits comprising a plurality of nucleic acids (e.g., a plurality of AAV vectors), e.g., kits comprising: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding GRD333-C24; 2) a nucleic acid (e.g., an AAV vector) comprising a cap gene nucleotide sequence encoding a K55 capsid protein comprising the amino acid sequence SKVPLPN (SEQ ID NO: 36); and 3) a helper vector. In some embodiments, kits comprise: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding GRD333-C24; 2) a nucleic acid (e.g., an AAV vector) comprising a cap gene nucleotide sequence encoding a K57 capsid protein comprising the amino acid sequence KQLPLVT (SEQ ID NO: 32); and 3) a helper vector. In some embodiments, kits comprise: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding GRD333-C24; 2) a nucleic acid (e.g., an AAV vector) comprising a K55 cap gene nucleotide sequence that is SEQ ID NO: 9; and 3) a helper vector. In some embodiments, kits comprise: 1) a nucleic acid (e.g., an AAV vector) comprising a nucleotide sequence encoding GRD333-C24; 2) a nucleic acid (e.g., an AAV vector) comprising a K57 cap gene nucleotide sequence that is SEQ ID NO: 11; and 3) a helper vector. Some embodiments provide kits comprising a recombinant AAV particle comprising a nucleic acid comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a cap gene nucleotide sequence encoding a K55 capsid protein comprising the amino acid sequence SKVPLPN (SEQ ID NO: 36). Some embodiments provide kits comprising a recombinant AAV particle comprising a nucleic acid comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a cap gene nucleotide sequence encoding a K57 capsid protein comprising the amino acid sequence KQLPLVT (SEQ ID NO: 32). Some embodiments provide kits comprising a recombinant AAV particle comprising a nucleic acid comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a K55 cap gene nucleotide sequence that is SEQ ID NO: 9. Some embodiments provide kits comprising a recombinant AAV particle comprising a nucleic acid comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a K57 cap gene nucleotide sequence that is SEQ ID NO: 11. Some embodiments provide kits comprising a recombinant AAV particle comprising: 1) a nucleic acid comprising a nucleotide sequence encoding GRD333-C24; and 2) a K55 capsid protein comprising the amino acid sequence SKVPLPN (SEQ ID NO: 36). Some JHU-43764.601 Client Docket No: P18504-02 embodiments provide kits comprising a recombinant AAV particle comprising: 1) a nucleic acid comprising a nucleotide sequence encoding GRD333-C24; and 2) a K57 capsid protein comprising the amino acid sequence KQLPLVT (SEQ ID NO: 32). Some embodiments provide kits comprising a recombinant AAV particle comprising: 1) a nucleic acid comprising a nucleotide sequence encoding GRD333-C24; and 2) a K55 capsid protein comprising an amino acid sequence encoded by a cap gene nucleotide sequence that is SEQ ID NO: 9. Some embodiments provide kits comprising a recombinant AAV particle comprising: 1) a nucleic acid comprising a nucleotide sequence encoding GRD333-C24; and 2) a K57 capsid protein comprising an amino acid sequence encoded by a cap gene nucleotide sequence that is SEQ ID NO: 11. Additionally, in some embodiments, the technology provides kits comprising vectors comprising nucleic acids as described above. For example, in some embodiments, the technology provides a kit comprising an AAV vector comprising a nucleic acid comprising: 1) a nucleotide sequence encoding GRD333-C24; and 2) a cap gene nucleotide sequence encoding a K55 capsid protein comprising the amino acid sequence SKVPLPN (SEQ ID NO: 36) or a nucleotide sequence encoding a K57 capsid protein comprising the amino acid sequence KQLPLVT (SEQ ID NO: 32)). In some embodiments, the technology provides a kit comprising: 1) an AAV vector comprising a nucleic acid comprising a nucleotide sequence encoding GRD333-C24; and 2) an AAV vector comprising a cap gene nucleotide sequence encoding a K55 capsid protein comprising the amino acid sequence SKVPLPN (SEQ ID NO: 36) or encoding a K57 capsid protein comprising the amino acid sequence KQLPLVT (SEQ ID NO: 32)). In some embodiments, the kits provide an AAV vector that is AAV1 (e.g., pAAV2 / 1), AAV2 (e.g., pAAV2-RC), AAV3B (e.g., pAAV-RC3B), AAV4 (e.g., pAAV-RC4), AAV5 (e.g., pAAV2 / 5 JC), AAV6 (e.g., pAAV-RC6), AAV7 (e.g., pAAV2 / 7), AAV8 (e.g., pAAV2 / 8), AAV9 (e.g., pAAV9n), AAV10 (e.g., pAAV2 / rh10), AAV11 (e.g., pAAV2 / hu11), AAV32 / 33 (e.g., pAAV2 / rh32.33), or AAV-DJ (e.g., pAAVDJ). In some embodiments, the AAV vector is AAV2, AAV3B, AAV6, or AAV-DJ. Kits provided herein find use in the instant methods. Kits of the technology comprise one or more containers comprising a nucleic acid construct as described herein (e.g., one or more doses of a therapeutically or prophylactically effective amount of a nucleic acid, nucleic acid construct, AAV vector, or pharmaceutical composition as described herein JHU-43764.601 Client Docket No: P18504-02 (e.g., a rAAV comprising: 1) a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43); and 2) an AAV capsid polypeptide that is optimized to provide improved tropism to NF1-related tumors (e.g., an AAV capsid polypeptide comprising a K55 amino acid sequence SKVPLPN (SEQ ID NO: 36) or an AAV capsid polypeptide comprising a K57 amino acid sequence KQLPLVT (SEQ ID NO: 32))). In some embodiments, kits comprise a second agent. In some embodiments, kits further comprise instructions for use in accordance with any of the methods provided herein. The kit may further comprise a description of selecting an individual for suitable treatment. Instructions supplied in the kits of the technology are typically written instructions on a label or package insert (e.g., a paper insert included with the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also contemplated. In some embodiments, the kit is a package containing a sealed container comprising any one of the preparations described above, together with instructions for use. The kit can also include a diluent container containing a pharmaceutically acceptable diluent. The kit can further comprise instructions for mixing the preparation and the diluent. The diluent can be any pharmaceutically acceptable diluent. Well-known diluents include 5% dextrose solution and physiological saline solution. The container can be an infusion bag, a sealed bottle, a vial, a vial with a septum, an ampule, an ampule with a septum, or a syringe. The containers can optionally include indicia indicating that the containers have been autoclaved or otherwise subjected to sterilization techniques. The kit can include instructions for administering the various solutions contained in the containers to subjects. Combination therapies Some embodiments provide a combination therapy, e.g., administration of a nucleic acid construct as described herein (e.g., one or more doses of a therapeutically or prophylactically effective amount of a nucleic acid, nucleic acid construct, AAV vector, or pharmaceutical composition as described herein (e.g., a rAAV comprising: 1) a nucleotide sequence encoding a NF1-GRD fused in frame to a nucleotide sequence encoding a Ras HVR (e.g., GRD333-C24, SEQ ID NO: 43); and 2) an AAV capsid polypeptide that is optimized to provide improved tropism to NF1-related tumors (e.g., an AAV capsid JHU-43764.601 Client Docket No: P18504-02 polypeptide comprising a K55 amino acid sequence SKVPLPN (SEQ ID NO: 36) or an AAV capsid polypeptide comprising a K57 amino acid sequence KQLPLVT (SEQ ID NO: 32))) in combination with another (e.g., second) medical intervention (e.g., drug, surgery, radiation, etc.). In some embodiments, combination therapies comprise administration of a nucleic acid construct as described herein before a second medical intervention. In some embodiments, combination therapies comprise administration of a nucleic acid construct as described herein after a second medical intervention. In some embodiments, combination therapies comprise administration of a nucleic acid construct as described herein substantially concurrently with a second medical intervention. In some embodiments, a combination therapy comprises administering a nucleic acid construct as described herein and a farnesyltransferase inhibitor (e.g., tipifarnib) or a geranylgeranyltransferase inhibitor. In some embodiments, a combination therapy comprises administering a nucleic acid construct as described herein and an agent targeting the RAF / MAPK / ERK pathway and / or the PI3K / AKT / mTOR pathway. In some embodiments, a combination therapy comprises administering a nucleic acid construct as described herein and a BRAF inhibitor, a MEK inhibitor, an mTOR inhibitor, a c-Kit inhibitor, an EGFR inhibitor, an anti- angiogenic agent, a proteasome inhibitor, chemokine receptor inhibitor, a tyrosine kinase inhibitor, and / or a vascular endothelial growth factor (VEGF) inhibitor. In some embodiments, a combination therapy comprises administering a nucleic acid construct as described herein and one or more of sorafenib (NEXAVAR), sirolimus, everolimus (AFINITOR), imatinib mesylate (GLEEVEC), nilotinib (TASIGNA), sunitinib (SUTENT), erlotinib (TARCEVA), rapamycin, ranibizumab, selumetinib (AZD6244), PD-0325901, pirfenidone, cabozantinib (XL184), bortezomib, or bevacizumab (AVASTIN). In some embodiments, a combination therapy comprises administering a nucleic acid construct as described herein and a chemotherapeutic agent (e.g., vincristine, carboplatin, pegylated interferon-alfa-2b). In some embodiments, a combination therapy comprises administering a nucleic acid construct as described herein and a microRNA, siRNA, or antisense nucleic acid. Uses In various embodiments, the technology finds use in genetic therapy. In additional embodiments, the technology finds use in research (e.g., in vitro, ex vivo, and / or in vivo) to JHU-43764.601 Client Docket No: P18504-02 study a Rasopapthy, neurofibromatosis type 1, and / or MPNST diseases. In some embodiments, the technology provides a nucleic acid for use in studying disease in a model system (e.g., a mammal (e.g., a mouse, rat, dog) and / or a cell culture system). In some embodiments, the technology provides a nucleic acid for use in the preparation of a medicament. In some embodiments, the technology provides a nucleic acid for use in the preparation of a medicament for treating a subject. In some embodiments, the technology provides a nucleic acid for use in the preparation of a medicament to treat a subject having a Rasopathy, neurofibromatosis type 1, and / or a MPNST disease. In some embodiments, the technology finds use in constructing a genetic delivery vector, e.g., an AAV vector as described herein comprising a nucleic acid encoding a NF1-GRD construct and / or a nucleic acid encoding a NF1-GRD construct further comprising a a Ras HVR sequence. Although the disclosure herein refers to certain illustrated embodiments, it is to be understood that these embodiments are presented by way of example and not by way of limitation. Examples Methods Cell culture – Immortalized human pNF cell line pNF9511.bc and ipNF03.3, immortalized human normal Schwann cell line ipn023.λ, were generated as described in Li (Immortalization of human normal and NF1 neurofibroma Schwann cells, Lab Invest 96, 1105-1115 (2016)), and obtained from American Type Culture Collection (ATCC). Human MPNST cell line ST88-14, S462 and a patient-derived xenoline RHT92 were provided by Melissa L. Fishel at the Indiana University (see, e.g., Gampala “Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours” Br J Cancer 124, 1566-1580 (2021)). NF1-deficient LN229 glioma cell line was provided by Karisa Schreck of the Johns Hopkins University (see, e.g., McGillicuddy “Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis” Cancer Cell 16, 44-54 (2009)). A549, HCC4006, SKMEL2, SW480, HCT116, MCF7 and 143B cell lines were obtained from ATCC. All the above mentioned cells were maintained in DMEM (ATCC) media supplemented with 10% FBS (Sigma) and penicillin / streptomycin (Gibco). Fips, a normal human iPSC line derived from fibroblast, and its isogenic NF1 (– / –) JHU-43764.601 Client Docket No: P18504-02 iPSC generated by Crispr, were provided by Meritxell Carrió and Eduard Serra at the Germans Trias i Pujol Research Institute in Spain, and were cultured and differentiated to NC and SC as reported by Carrio (Reprogramming Captures the Genetic and Tumorigenic Properties of Neurofibromatosis Type 1 Plexiform Neurofibromas, Stem Cell Reports 12, 411-426 (2019)). Reagents and antibodies – Rabbit anti-NF1 antibody (A300-140A) was purchased from Bethyl laboratories. The rabbit anti-phospho-Erk1 / 2 (p44 / 42 MAPK) (Thr202 / Tyr204) antibody (#9101), anti-Erk1 / 2 (p44 / 42 MAPK) antibody (#9102), and rabbit anti-GFP antibody (#2555) were purchased from Cell Signaling Technologies. The mouse anti-βIII- tubulin antibody Tuj1 was obtained from R&D Systems; mouse anti-NGFR (p75) antibody (AB-N07) was purchased from Advanced Targeting System; and rabbit anti-S100B antibody (Z0311) was purchased from DAKO. The anti-βActin (C-11, SC-1615HRP) HRP antibody was purchased from Santa Cruz Biotech and mouse anti-HA antibody (26183) was purchased from Invitrogen. Xenograft mouse models, AAV treatment and biodistribution studies – ST88-14, S462, and RHT92 cells were transfected with luciferase using lentivirus, and 150,000 cells in 3 µl were implanted in the sciatic nerve of NSG mice (female, 6-10 weeks old). IVIS Imaging was used to monitor the tumor growth. Two or three weeks after the ST88-14 or RHT92 implantation, respectively, 1012vg AAV-GRDC24 were injected via tail vein. JH2-002 and JH2-031 patient-derived xenografts (PDXs) were passaged as subcutaneous tumors in NSG mice. The LN229 glioma, A549 lung cancer, HCC4006 NSCLC, SKMEL2 melanoma, SW480 and HCT116 colon cancer, and MCF7 breast cancer cells were implanted subcutaneously in the NSG mice.143B osteosarcoma cells were implanted intratibially in NSG mice. For biodistribution studies, 5 × 1011vg of AAV-GFP were injected intravenously in the tumor-bearing NSG mice. After two weeks, tissues and tumors were harvested and vector genome was quantified by q-PCR using primers targeting CMV promoter. AAV plasmids – All the recombinant AAV vectors included the AAV2 Rep. The pscAAV plasmid was purchased from Cell Biolabs, Inc. pscAAV-GFP and pscAAV-GRDC24 were used to generate AAV-GFP and AAV-GRDC24. 13 hybrid pAAV-Rep-Cap (pAAV-RC) vectors, which encode the rep of AAV2 and variable cap genes of different serotypes, were obtained and used. pAAV-RC3B, pAAV-RC4, pAAV-RC6, and pAAV-DJ were purchased from Cell Biolabs; pAAV2-RC was purchased from Stratagene; and pAAV2 / 1, pAAV2 / 5 JC, JHU-43764.601 Client Docket No: P18504-02 pAAV2 / 7, pAAV2 / 8, pAAV9n, pAAV2 / rh10, pAAV2 / hu11, and pAAV2 / rh32.33 were obtained from Penn Vector Core of the University of Pennsylvania. The pHelper plasmid (Stratagene) and AAVpro-293T cells (Clontech) were used for AAV packaging. AAV production and purification –AAV production and purification followed the published protocol as described in Challis (Systemic AAV vectors for widespread and targeted gene delivery in rodents. Nat Protoc 14, 379-414 (2019)). The plasmid with transgene, pAAV- Rep-Cap, and pHelper were transfected in AAVpro-293T cells by Lipofectamine 2000 in DMEM media supplemented with 10% FBS. Supernatant was collected on day 3 and day 4 post-transfection, cells were harvested on day 4, and AAV was purified by iodixanol density gradients in an Optima XE-90 ultracentrifuge. Titers were determined by q-PCR with primers targeted on Rep2, GRD, or the promoters, with the linearized ITR-containing plasmid used as a standard. AAV capsid DNA shuffling and in vivo selection – The DNA shuffling procedure followed the previously published method with modifications. See, e.g., Grimm “In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno- associated viruses. J Virol 82, 5887-5911 (2008)” and Pekrun “Using a barcoded AAV capsid library to select for clinically relevant gene therapy vectors. JCI Insight 4 (2019). Twelve capsid DNA AAV 1-11 and 32 / 33 were cloned into the pBluescript II SK plasmid between the SpeI and XbaI sites and amplified by PCR. A mass of 1 µg of the 12 capsid DNA was digested by 0.1 µl DNAse I (Roche, #04716728001) at 25ºC for 75, 90, or 115 sec, after which the reaction was stopped by adding 10 mM EDTA and heating at 75ºC for 10 minutes. Digested samples were electrophoresed on a 1% agarose gel, and the best digestion time was assessed by evaluating the best separation of fragments of approximately 200-300 bp. The fragments between 100-500bp were harvested and subjected to primerless first PCR using Phusion polymerase (NEB). After a second PCR using flanking primers, the product was cloned into pITR-Rep2 vector containing AAV ITR and AAV2 Rep (Rep2) sequences between PacI and AscI sites using Rapid DNA Ligation Kit (Roche). The ligation product was then transformed into MegaX DH10B Competent E.coli (Thermo Fisher) using electroporation, and DNA was isolated with a QIAGEN Maxiprep kit. Colonies were counted on a dilution plate and the diversity of the shuffling library was estimated. AAV libraries were produced with AAVpro-293T production cells and purified with iodixanol density gradients. Two ST88-14-luc tumor-bearing NSG mice were injected intravenously JHU-43764.601 Client Docket No: P18504-02 with 5 × 1011vg of AAV library; after two weeks, animals were perfused, tumors were harvested, and capsid DNA from both mice was recovered by PCR and pooled together to create the next round library. In vivo biopanning of random peptide library – The creation of the 7mer random peptide followed the previously established procedure with modifications. See, e.g., Ravindra Kumar “Multiplexed Cre-dependent selection yields systemic AAVs for targeting distinct brain cell types” Nat Methods 17, 541-550 (2020). The REP_AAP plasmid containing AAV2 Rep (Rep2) and AAP from AAV9, and the Acceptor plasmid containing ITRs, a modified AAV9 construct for library creation, and the SV40-polyA sequence flanked by lox71 and lox66 (LXSV) were kindly provided by Viviana Gradinaru at California Institute of Technology. The plasmid pITR-Rep2-LXSV was constructed to include ITRs, Rep2 and LXSV. The 557-2 capsid sequence was cloned in the pITR-Rep2-LXSV plasmid with PacI and AscI, and an AgeI site was introduced to amino acids 588-589 with site-directed mutagenesis. The 7mer random peptide library DNA was constructed by PCR using a primer with randomized 21mer nucleotides and by NEBuilder HiFi DNA Assembly (NEB). In the AAV library production, 100 ng of library DNA, 15 µg REP_AAP, and 25 µg pHelper were used in each 15 cm plate of AAVpro-293T cells. AAV library was purified by iodixanol density gradients. Two ST88-14-luc-cre tumor-bearing NSG mice were injected intravenously with 2.5 × 1011vg of AAV library; after two weeks, animals were perfused, tumors were harvested, and capsid DNA from both mice was recovered by PCR and pooled together to create the next round library. The AAV libraries before selection and after first round and second round selection were subject to NGS sequencing. The frequencies of unique 7mer peptide inserts were compared and an enrichment score of (second round / first round) * (first round / before) was calculated. The top 10 candidates were further validated by testing in ST88-14-luc tumor-bearing mice with AAVs packaged with GFP. Transmission electron microscopy – Recombinant AAVs were stained by uranyl formate and analyzed with a Thermo-Fisher Talos L120C G2 transmission electron microscope by Barbara Smith at the Johns Hopkins University School of Medicine Microscope Facility. Immunohistochemistry and Immunofluorescence Staining – The immunofluorescence staining followed the procedure described previously. See, e.g., Bai “Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme” Neuro Oncol 13, 974-982 (2011). Cells were grown in medium on chamber slides (Nunc) and JHU-43764.601 Client Docket No: P18504-02 washed with PBS and fixed for 10 minutes with 4% paraformaldehyde solution and permeated with methanol for 2 minutes with 3 washes in PBS. The slides were first blocked by 10% goat serum in PBS for 30 minutes at room temperature and incubated with the first antibody and subsequently with AlexaFluor 488 (Green) or AlexaFluor 594 (Red) secondary antibody (Invitrogen) in 10% goat serum in PBS at room temperature. They were then washed 3 times in PBS, and the nuclei were stained with DAPI. After staining, the slides were covered with mounting medium (Vector Laboratories) and examined on a fluorescence microscope. For immunohistochemistry (IHC) staining, tumors were preserved in 10% formalin, and paraffin sections were obtained. Paraffin section of tumors were deparaffinized, rehydrated, and antigen-retrieved using the Citra buffer (Biogenex) as described in Staedtke “Neutrophil depletion enhanced the Clostridium novyi-NT therapy in mouse and rabbit tumor models” Neurooncol Adv 4, vdab184 (2022). GFP-positive cells were stained using rabbit anti-GFP antibody (Cell Signaling, #2555), biotin-conjugated goat F(ab')2 anti-rabbit IgG, (JacksonImmunoResearch, 111-066-144), streptavidin peroxidase (Biogenex HK330-9KT), and 3, 3'-diaminobenzidine (DAB, BioGenex). Sections were counterstained by hematoxylin. Cell Growth Assay – The viable cells were measured with Cell Counting Kit-8 (Dojindo Laboratories, Japan) containing WST-8 tetrazolium salt at 450 nm on a PerkinElmer NIVO plate reader. Three biological samples were measured in each experiment. Flow cytometry – For apoptosis assay, ST88-14 cells were treated with AAVDJ-EGFP or AAVDJ-GRDC24 for 24 hours at MOI 2000 in a 6-well plate. Supernatant was collected and cells were washed by 1 ml PBS and treated by 200 µl accutase at 37ºC for 3 to 5 minutes. Cells were stained by Annexin V (FITC) following the procedure of the FITC Annexin Vi Apoptosis Detection Kit I (BD Pharmingen, #556547) and analyzed with a Beckman Coulter CytoFLEX flow cytometer. For quantifying AAV-GFP transduced xenograft tumor cells, the procedure below was used. A dose of 1012vg of AAV-GFP was injected intravenously in a tumor-bearing mouse; after 2 weeks, the animal was euthanized and perfused. The tumor was cut into small pieces and processed by vortexing and then shaking in a mixture of collagenase (Sigma, C7657, 10mg / ml in PBS) and hyaluronidase (Sigma, H3506, 1.25mg / ml in PBS) at 1:2 ratio at 37ºC / 200-300 rpm for 8 to 12 minutes. The sample was then passed through a 70-µm cell strainer and rinsed with 3 to 5 ml PBS. If trace amount of blood was discernable, the sample was further treated with ACK Lysing Buffer (Thermo Fisher). JHU-43764.601 Client Docket No: P18504-02 Tumor cells were then centrifuged and resuspended in 300 to 400 µl of 2% PFA and analyzed for GFP-positive cells with a Beckman Coulter CytoFLEX flow cytometer. An untreated xenograft tumor was used as negative control. Ten thousand cells were analyzed in one sample. Statistical Analysis – The results are presented as a mean value plus or minus the standard deviation. Data were analyzed by GraphPad Prism 8.0. The p-values were determined by a Student’s t-test. A p-value under 0.05 was accepted as statistically significant. Sample sizes were chosen to achieve statistical significance. Sequences – Table 1 provides nucleotide and amino acid sequences for AAV caps (e.g., sequences named “557-1”, “557-2”, “561-4”, “561-6”, “K55”, and “K57”) provided herein. Table 1 – AAV cap sequences AAV cap DNA sequence Protein sequence (SEQ ID NO:) (SEQ ID NO:) Table 2 – Nucleotide and amino acid sequences of AAV cap gene insertions Peptide name Nucleotide sequence Amino acid sequence (SEQ ID NO:) (SEQ ID NO:) JHU-43764.601 Client Docket No: P18504-02 Example 1 – Optimization of NF1 GRD as payload for rAAV vectors During the development of embodiments of the technology described herein, experiments were conducted in which the human NF1 cDNA version of 8457 bp (NCBI accession NM_000267.3 (SEQ ID NO: 17)), which encodes an NF1 protein of 2818 amino acids (NCBI accession NP_000258.1 (SEQ ID NO: 44)), was used as a template to produce “miniNF1” as a payload for AAV vectors. Due to the large size and packaging limit for AAV of approximately 4.8 kb, a truncated NF1 version was produced so that a single AAV vector could be used. In the NF1 gene, the GRD of approximately 300 amino acids is the only defined domain with enzymatic activity and is responsible for inactivating GTP-bound Ras and suppressing Ras-mediated mitogenic pathways. Gutmann “Neurofibromatosis type 1” Nat Rev Dis Primers 3, 17004 (2017). It has been demonstrated previously that adding a 10-amino acid H-Ras C-terminal sequence significantly increased the targeting of GRD to plasma membrane and suppression of RAS-MEK-ERK pathway in NF1 cells. Bai “Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors” Gene Ther 26, 277-286 (2019). Experiments were conducted to optimize the GRD construct for AAV delivery to restore RAS suppression and anti-tumor efficacies. From the 4 common forms of Ras, H-RAS, N-Ras, K-Ras4A and K-Ras4B, the C-terminal hypervariable regions (HVRs) were selected and attached to the GRD. See Simanshu “RAS Proteins and Their Regulators in Human Disease” Cell 170, 17-33 (2017) (FIG.1A). Human MPNST cell line ST88-14 and immortalized pNF cell line ipNF9511bc, in which bi-allelic NF1 was lost, and an immortalized normal human Schwann cell line ipn02.3λ with normal NF1 expression were used as testing platforms. Li “Immortalization of human normal and NF1 neurofibroma Schwann cells” Lab Invest 96, 1105-1115 (2016). (FIG. 1B). GRD fusion proteins with different Ras HVRs in different lengths transduced by an AAV vector were compared and the data indicated that the fusion with the C-terminal 24 amino acids of KRas4B (C24) produced the most growth inhibition in NF1 cells (FIG.1C; FIG. 6A and 6B). By comparison, GRDC24 displayed far less cytotoxicity in non-NF1 cells, such as ipn02.3λ, especially at lower multiplicity of infection (MOI) of 500 and 100 (FIG.1D). NF1 GRD contains a minimal domain of 230 amino acids (amino acids 1248-1477) with GTPase-activating protein (GAP) function. Dunzendorfer-Matt “The neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation” Proc Natl Acad Sci U S A 113, 7497-7502 (2016). Other functional sequences JHU-43764.601 Client Docket No: P18504-02 exist surrounding the minimal domain, including the Spred1-binding sequences of amino acids 1202-1217 and 1511-1530. Hirata “Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein- related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1” J Biol Chem 291, 3124-3134 (2016). Four GRD versions of different lengths were tested (i.e., 367 amino acids (amino acids 1172-1538 of NF1), 333 amino acids (amino acids 1200-1532 of NF1), 282 amino acids (amino acids 1222-1503 of NF1), and 230 amino acids (amino acids 1248-1477 of NF1)) in fusion with KRas4B-C24 and packaged in a self- complementary AAV vector. In ipNF9511bc cells, the GRD of 333 amino acids demonstrated the highest expression level and most potent suppression of Erk phosphorylation and cell growth, which was confirmed in ST88-14 cells (FIG.1E; FIG. 7A and FIG. 7B). The 333 amino acid version was subsequently used in the following experiments and is referred to below as “GRD”. When expressed in NF1 cells via AAV, GRD-C24 showed subcellular localization in the plasma membrane and significantly enhanced inhibition of pErk1 / 2, in contrast to unmodified GRD, with markedly induced apoptosis (FIG.1F through FIG.1H). This agrees with previous studies showing the reduction of proliferative and increase of apoptotic cell populations in NF1 cells treated by AAV GRD fused with the HRas C-terminal 10 amino acids. Bai “Feasibility of using NF1- GRD and AAV for gene replacement therapy in NF1-associated tumors” Gene Ther 26, 277- 286 (2019). Example 2 – Expression of GRDC24 in NF1 – / – cells rescues Schwann Cell differentiation NF1 tumor cells have been suggested to originate from Schwann cell precursors. Mo “Humanized neurofibroma model from induced pluripotent stem cells delineates tumor pathogenesis and developmental origins” J Clin Invest 131 (2021). Carrio (Reprogramming Captures the Genetic and Tumorigenic Properties of Neurofibromatosis Type 1 Plexiform Neurofibromas. Stem Cell Reports 12, 411-426 (2019)) demonstrated induced pluripotent stem cells (iPSCs) of normal human fibroblasts (Fips) could differentiate to neural crest (NC) cells and then to Schwann cells (SCs) with myelinating function when co-cultured with neurons, while the isogenic NF1 (– / –) iPSCs lost the ability to differentiate from NC to functional SCs. In this study, NF1 (– / –) iPSCs were used to examine whether expression of GRDC24 restored the SC differentiation in those cells. The loss of NF1 protein in the JHU-43764.601 Client Docket No: P18504-02 isogenic NF1 (– / –) iPSCs and the successful differentiation to NC cells were confirmed by western blotting and NGFR (p75) flow cytometry (FIG. 8A and 8B). Expression of GRDC24 via AAV inhibited pErk1 / 2 and significantly suppressed the proliferation in NF1 (– / –) NC cells, while the growth of Fips NC cells was less affected especially at lower MOIs (FIG.8C and 8D). When differentiated to SCs, NF1 (– / –) cells displayed a disorganized morphology compared to Fips (FIG. 8E), which agreed with previous observation. Carrio, supra. GRDC24 packaged in AAV-DJ was applied to NF1 (– / –) cells 3 days prior or 2 days after the start of SC differentiation and in both cases, NF1 (– / –) cells were able to acquire the SC morphology with S100b-positive staining (FIG.9A and FIG. 9B). In the co-culture assay with the rat dorsal root ganglion neuron, NF1 (– / –) cells transduced with GRDC24 at both time points were capable of developing myelination around the neurons, similar to the normal Fips cells (FIG.8B). These results indicated that expression of GRDC24 may rescue the SC differentiation of NF1 (– / –) cells during the NC or early stage of SC differentiation. Example 3 – Creating a new rAAV vector specific for NF1 tumors Shuffling of capsid DNA of various AAV serotypes and subsequent selection may create novel AAV vectors with enhanced tropism for the target cell populations. Grimm “In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses” J Virol 82, 5887-5911 (2008); and Pekrun “Using a barcoded AAV capsid library to select for clinically relevant gene therapy vectors” JCI Insight 4 (2019). Experiments were performed during the development of embodiments of the technology described herein in which a panel of natural AAV capsids (AAV 1-11 and 32.33) were used as templates to create a shuffling library for selection in human MPNST ST88-14 xenograft tumor implanted in the mouse sciatic nerve (FIG. 2A). The diversity of the library was about 3.3 × 106based on the number ofE.colicolonies formed during library DNA preparation. AAV library was produced, purified, and injected intravenously in two ST88- 14 xenograft tumor-bearing mice. Tumors were harvested after 14 days and capsid DNA samples from two mice were recovered by PCR, which were pooled together and cloned in the pITR-Rep2 vector for packaging the library of the second round selection. Twenty E. coli clones from the first and second rounds of selection were sequenced using the Sanger method as a library quality control before proceeding with the initially planned deep sequencing. The results surprisingly indicated a 60% enrichment of clone 557-2 in the JHU-43764.601 Client Docket No: P18504-02 second round (10% in the first round), 15% of 557-1 (35% in the second round), 10% of 561-4 (none in the first round), and one clone (564-6) was a hybrid of 557-1 and 557-2 (see Table 1). Analysis of capsid G557-2 using Xover 3.0 revealed that 557-2 shared the most resemblance with AAV 11. Huang “ReX: A suite of computational tools for the design, visualization, and analysis of chimeric protein libraries” Biotechniques 60, 91-94 (2016) (FIG. 2B). Next, clones 557-2, 557-1, 561-4, and 564-6 were validated by testing GFP- packaged vectors in the ST88-14-bearing xenograft model. Intravenous injection of AAV- 557-2-GFP demonstrated improved tumor transduction compared to AAV9-GFP (FIG.2C), while the other candidates showed negative results. AAV-557-2 also showed drastically lower liver transduction in comparison to AAV9, with a higher delivery to three different xenograft NF1 tumors (FIG. 2D). When packaged with GRD-C24 as payload and injected intravenously in the ST88-14 tumor-bearing mice, 557-2 significantly slowed the tumor growth, measured at 14 days after the treatment (FIG. 2E). However, the treatment effect was transient and disappeared at the 21-day imaging, indicating ongoing tumor growth of the cells not transfected by AAV-557-2-GRDC24. Facing the expected challenge of treating a rapidly growing tumor, experiments were conducted to improve the transduction of the AAV vector 557-2 in NF1 tumors. Screening the library of random peptides inserted in the VR-VIII loop of AAV9 has shown considerable success in various animal models. Deverman “Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain” Nat Biotechnol 34, 204-209 (2016); Gonzalez “Cross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing” Nat Commun 13, 5947 (2022); and Wang “Adeno- associated virus as a delivery vector for gene therapy of human diseases” Signal Transduct Target Ther 9, 78 (2024). The N588-T589 of VR-VIII loop was chosen as the insertion site of randomized heptamers, as illustrated in a 3D model of 557-2 VP1 created by AlphaFold 3 (FIG. 3A). A heptamer library was produced largely following the cre-dependent CREATE method, with modifications (Ravindra Kumar “Multiplexed Cre-dependent selection yields systemic AAVs for targeting distinct brain cell types” Nat Methods 17, 541-550 (2020)) and was selected in mice bearing ST88-14-Cre-luc tumor over 2 rounds (FIG.3B). The AAV DNA from the initial R0 library, first round R1 and second round R2 selections were analyzed by NGS sequencing and clones were sorted according the factors of enrichment. Twelve clones were chosen for further validation in ST88-14 xenograft tumors and anti- JHU-43764.601 Client Docket No: P18504-02 GFP IHC (FIG. 3E and FIG. 3H). Table 2 provides the nucleotide sequences encoding the mutated peptides and the amino acid sequences of the mutated peptides inserted at amino acids 558 to 589 of capsid 557-2. Data collected from the testing indicated that that K55 and K57 were the best and second best performing candidates, respectively. A 3-D model produced by AlphaFold 3 showed the additional heptamer “SKVPLPN” in the K55 VR-VIII loop and transmission electron microscopy (TEM) revealed the images of the AAV-K55-GFP and AAV-K55- GRDC24 (FIG. 3C and FIG. 3D). Staining of tumor sections from mice injected intravenously with AAV-K55-GFP demonstrated a strong transduction of GFP, in comparison to the AAV9-GFP as a benchmark (FIG.3E). Example 4 – Validation of K55 and K57 in other NF1-related cell lines and xenografts Both K55 and K57 retained the very low liver transduction from AAV-557-2, and in a panel of two ST88-14, one ipNF03.3 and one RHT92 tumor, AAV-K55-GFP showed remarkably higher transduction in those NF1 tumors, compared to AAV9-GFP (FIG. 3F). In addition to IHC, flow cytometry was used to evaluate transduction in tumor cells because it offers unbiased quantification. In a panel of NF1-related human xenograft tumors grown in mice, it was found that AAV-K55-GFP achieved a 30-40% transduction in ST88-14, 50-60% in RHT92, and over 20% in JH2-002 (a patient-derived xenograft (PDX) MPSNT), while S462 MPNST and JH-2-031 PDX MPNST were resistant to this vector (FIG. 3G). Interestingly, NF1-deficient glioma xenograft, LN229, also was transduced by one dose of AAV-K55-GFP at approximately 30% (FIG. 3G). As tumors were harvested 14 days after AAV injection, the dilution effect resulting from tumor cell division may underestimate the transduction rates of AAV vectors. Among several NF1-unrelated human xenograft tumors, which were implanted in mice subcutaneously except for the intra-tibially implanted 143B, AAV-K55- GFP did not show significant levels of transduction (FIG.3H and FIG. 3I). Example 5 – Blood clearance and seroprevalence of AAV-K55 antibodies in human Following injection in the tail vein, the clearance of AAV-K55-GRDC24 in mouse plasma over a time course of 7 days displayed a pattern similar to the blood clearance of other known rAAVs, with a plasma half-life of 1.22 days (FIG. 4A). See, e.g., Kotchey “A potential role of distinctively delayed blood clearance of recombinant adeno-associated virus serotype JHU-43764.601 Client Docket No: P18504-02 9 in robust cardiac transduction” Mol Ther 19: 1079–89 (2011). In the assay of AAV-binding antibody (B-ab), AAV-K55 loaded with luciferase (luc) was compared directly with AAV9-luc in 40 serum samples of healthy adults, showing 17.5% equal or above the cut-off of dilution factor 400 versus 12.5% found with AAV9 (FIG. 4B). In a panel of 50 serum samples of healthy adults, 20% showed AAV-K55 binding antibody titers equal of above dilution factor 400 and 26% contained neutralizing antibody (N-Ab) titer equal of above the dilution factor 31.6 (FIG. 4C). The AAV-K55-GFP vector demonstrated substantial transduction in an NF1 (– / –) iPSC-derived neurofibroma xenograft (3MM) as shown by anti-GFP immunohistochemistry (IHC) (FIG. 4D). In this model, pNF-derived iPSCs were 3D co-cultured with pNF patient NF (+ / –) fibroblasts during Schwann cell (SC) differentiation before being implanted into the mouse sciatic nerve. The data demonstrated that AAV-K55-GFP primarily transduced the S100B-positive population, indicating the delivery targeted the neurofibroma Schwann cells, not the NF (+ / –) fibroblasts (FIG. 4E and FIG. 4F). It is worth noting that in healthy mice, AAV-K55 showed only limited brain penetration and no detectable transduction in cells in sciatic nerve and optic nerve (FIG. 4G to FIG. 4J). Example 6 – AAV K55-GRDC24 showed significant therapeutic efficacies in NF1 xenograft tumor models Due to continuous tumor growth, treating oncologic diseases has been a daunting challenge for AAV vectors because untransduced tumor cells are expected to quickly rebound and diminish any therapeutic effects. ST8814 cells were implanted orthotopically in the mouse sciatic nerve and allowed to grow 2 weeks before the treatment. Through tail vein injection, one dose of AAV K55-GRDC24 significantly suppressed the growth of ST8814 tumor initially, but a quick rebound was observed after 4 weeks (FIG. 5A). Although multiple doses of AAV via systemic delivery have not been used clinically to avoid adaptive immunity, the unique challenge of treating tumors may call for repeated doses in a short treatment window before the development of an adaptive immunity. Two doses of AAV K55-GRDC24 administered 7 days apart substantially enhanced the therapeutic effect over an extended period in ST8814 xenografts (FIG.5B). In RHT92 xenograft model, AAV-K55-GRDC24 also markedly slowed down the tumor growth (FIG. 5C), and adding a second dose produced a more substantial response (FIG. 5D). The two- JHU-43764.601 Client Docket No: P18504-02 dose method caused higher expression of the payload in the tumor as demonstrated with AAV-K55-GFP (FIG. 5E). FIG. 5F shows a comparison of the morphology of the ST88-14 xenograft tumor after 14 days of treatment and after 42 days of treatment with the untreated control. AAV9- GRDC24 showed no significant therapeutic effects when administered intravenously at the same 1012vg dose and resulted in mortalities in mice between days 15 and 21 of treatment, which was not observed with AAV-K55-GRDC24 treatment at this dose, presumably due to the higher levels of vector distribution in other organs such as the liver (FIG. 5G and FIG. 5H; see also, FIG. 3F). Similarly, the one-time 2 × 1012vg dose achieved extended inhibition in ST88-14 xenograft tumors (FIG.5I). NF1 treatment has been transformed since the FDA approval of selumetinib for pNF patients. However, clinically, selumetinib and other MEKi have not been efficacious for MPNST. Selumetinib is efficacious in ST88-14 cells with an IC50 of 3.8 µM (FIG. 5J). At a dose of 100 mg / kg, selumetinib was tested either alone or in combination with an intravenous injection of AAV-K55-GRDC24 at 1012vg / mouse (FIG. 5K). The combination of selumetinib with AAV-K55-GRDC24 demonstrated enhanced tumor suppression compared to selumetinib alone. REFERENCES 1. Ratner, N. & Miller, S.J. A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer 15, 290-301 (2015). 2. Landry, J.P. et al. Comparison of Cancer Prevalence in Patients With Neurofibromatosis Type 1 at an Academic Cancer Center vs in the General Population From 1985 to 2020. JAMA Netw Open 4, e210945 (2021). 3. Fisher, M.J. et al. Management of neurofibromatosis type 1-associated plexiform neurofibromas. Neuro Oncol 24, 1827-1844 (2022). 4. Fangusaro, J. et al. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol 20, 1011-1022 (2019). 5. Shih, F.H., Chang, H.H. & Wang, Y.C. Utilizing adeno-associated virus as a vector in treating genetic disorders or human cancers. IUBMB Life (2024). JHU-43764.601 Client Docket No: P18504-02 6. Wang, J.H., Gessler, D.J., Zhan, W., Gallagher, T.L. & Gao, G. Adeno-associated virus as a delivery vector for gene therapy of human diseases. Signal Transduct Target Ther 9, 78 (2024). 7. Marusyk, A., Janiszewska, M. & Polyak, K. Intratumor Heterogeneity: The Rosetta Stone of Therapy Resistance. Cancer Cell 37, 471-484 (2020). 8. Gutmann, D.H. et al. Neurofibromatosis type 1. Nat Rev Dis Primers 3, 17004 (2017). 9. Bai, R.Y. et al. Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors. Gene Ther 26, 277-286 (2019). 10. Simanshu, D.K., Nissley, D.V. & McCormick, F. RAS Proteins and Their Regulators in Human Disease. Cell 170, 17-33 (2017). 11. Li, H., Chang, L.J., Neubauer, D.R., Muir, D.F. & Wallace, M.R. Immortalization of human normal and NF1 neurofibroma Schwann cells. Lab Invest 96, 1105-1115 (2016). 12. Dunzendorfer-Matt, T., Mercado, E.L., Maly, K., McCormick, F. & Scheffzek, K. The neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation. Proc Natl Acad Sci U S A 113, 7497-7502 (2016). 13. Hirata, Y. et al. Interaction between a Domain of the Negative Regulator of the Ras- ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1. J Biol Chem 291, 3124-3134 (2016). 14. Mo, J. et al. Humanized neurofibroma model from induced pluripotent stem cells delineates tumor pathogenesis and developmental origins. J Clin Invest 131 (2021). 15. Carrio, M. et al. Reprogramming Captures the Genetic and Tumorigenic Properties of Neurofibromatosis Type 1 Plexiform Neurofibromas. Stem Cell Reports 12, 411- 426 (2019). 16. Grimm, D. et al. In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J Virol 82, 5887-5911 (2008). 17. Pekrun, K. et al. Using a barcoded AAV capsid library to select for clinically relevant gene therapy vectors. JCI Insight 4 (2019). JHU-43764.601 Client Docket No: P18504-02 18. Huang, W., Johnston, W.A., Boden, M. & Gillam, E.M. ReX: A suite of computational tools for the design, visualization, and analysis of chimeric protein libraries. Biotechniques 60, 91-94 (2016). 19. Deverman, B.E. et al. Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat Biotechnol 34, 204-209 (2016). 20. Gonzalez, T.J. et al. Cross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing. Nat Commun 13, 5947 (2022). 21. Ravindra Kumar, S. et al. Multiplexed Cre-dependent selection yields systemic AAVs for targeting distinct brain cell types. Nat Methods 17, 541-550 (2020). 22. Kotchey, N.M. et al. A potential role of distinctively delayed blood clearance of recombinant adeno-associated virus serotype 9 in robust cardiac transduction. Mol Ther 19, 1079-1089 (2011). 23. Bergoug, M. et al. Neurofibromin Structure, Functions and Regulation. Cells 9 (2020). 24. Naschberger, A., Baradaran, R., Rupp, B. & Carroni, M. The structure of neurofibromin isoform 2 reveals different functional states. Nature 599, 315-319 (2021). 25. Lupton, C.J. et al. The cryo-EM structure of the human neurofibromin dimer reveals the molecular basis for neurofibromatosis type 1. Nat Struct Mol Biol 28, 982-988 (2021). 26. Chaker-Margot, M. et al. Structural basis of activation of the tumor suppressor protein neurofibromin. Mol Cell 82, 1288-1296 e1285 (2022). 27. Young, L.C. et al. Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization. Proc Natl Acad Sci U S A 120, e2208960120 (2023). 28. Huang, D.C., Marshall, C.J. & Hancock, J.F. Plasma membrane-targeted ras GTPase-activating protein is a potent suppressor of p21ras function. Mol Cell Biol 13, 2420-2431 (1993). 29. Prior, I.A., Hood, F.E. & Hartley, J.L. The Frequency of Ras Mutations in Cancer. Cancer Res 80, 2969-2974 (2020). 30. Hordeaux, J. et al. The Neurotropic Properties of AAV-PHP.B Are Limited to C57BL / 6J Mice. Mol Ther 26, 664-668 (2018). JHU-43764.601 Client Docket No: P18504-02 Hordeaux, J. et al. The GPI-Linked Protein LY6A Drives AAV-PHP.B Transport across the Blood-Brain Barrier. Mol Ther 27, 912-921 (2019). DeClue, J.E. et al. Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell 69, 265-273 (1992). Magallon-Lorenz, M. et al. Deep genomic analysis of malignant peripheral nerve sheath tumor cell lines challenges current malignant peripheral nerve sheath tumor diagnosis. iScience 26, 106096 (2023). Duan, D. Lethal immunotoxicity in high-dose systemic AAV therapy. Mol Ther 31, 3123-3126 (2023). Gampala, S. et al. Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours. Br J Cancer 124, 1566-1580 (2021). McGillicuddy, L.T. et al. Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis. Cancer Cell 16, 44-54 (2009). Mazuelas, H. et al. Modeling iPSC-derived human neurofibroma-like tumors in mice uncovers the heterogeneity of Schwann cells within plexiform neurofibromas. Cell Rep 38, 110385 (2022). Challis, R.C. et al. Systemic AAV vectors for widespread and targeted gene delivery in rodents. Nat Protoc 14, 379-414 (2019). Bai, R.Y., Staedtke, V., Aprhys, C.M., Gallia, G.L. & Riggins, G.J. Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme. Neuro Oncol 13, 974-982 (2011). Staedtke, V. et al. Neutrophil depletion enhanced the Clostridium novyi-NT therapy in mouse and rabbit tumor models. Neurooncol Adv 4, vdab184 (2022). Mendell, J.R. et al. Testing preexisting antibodies prior to AAV gene transfer therapy: rationale, lessons and future considerations. Mol Ther Methods Clin Dev 25, 74-83 (2022). Ito, T. et al. A convenient enzyme-linked immunosorbent assay for rapid screening of anti-adeno-associated virus neutralizing antibodies. Ann Clin Biochem 46, 508-510 (2009). JHU-43764.601 Client Docket No: P18504-02 43. Meliani, A. et al. Determination of anti-adeno-associated virus vector neutralizing antibody titer with an in vitro reporter system. Hum Gene Ther Methods 26, 45-53 (2015). All publications and patents mentioned in the above specification are herein incorporated by reference in their entirety for all purposes. Various modifications and variations of the described compositions, methods, and uses of the technology will be apparent to those skilled in the art without departing from the scope and spirit of the technology as described. Although the technology has been described in connection with specific exemplary embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the following claims.

Claims

JHU-43764.601 Client Docket No: P18504-02 CLAIMS WE CLAIM:

1. A recombinant adeno-associated virus (rAAV) comprising: a nucleic acid comprising a nucleotide sequence encoding a polypeptide comprising a neurofibromatosis type 1 GAP-related domain (NF1-GRD) fused to a Ras hypervariable region (HVR); and a capsid polypeptide comprising an amino acid sequence that is optimized for tropism to NF1-related tumors.

2. The rAAV of claim 1, wherein the NF1-GRD is optimized for expression and anti- tumor effectiveness.

3. The rAAV of claim 1, wherein the NF1-GRD comprises amino acids 1200–1532 of NF1 (SEQ ID NO: 18) (GRD333).

4. The rAAV of claim 1, wherein the NF1-GRD has an amino acid sequence provided by SEQ ID NO: 18 (GRD333).

5. The rAAV of claim 1, wherein the Ras HVR comprises a HVR amino acid sequence from a HRas HVR, NRas HVR, KRas4A HVR, or KRas4B HVR.

6. The rAAV of claim 1, wherein the Ras HVR comprises a HVR amino acid sequence from a KRas4B HVR.

7. The rAAV of claim 1, wherein the Ras HVR comprises a sequence provided by SEQ ID NO: 16 (C24).

8. The rAAV of claim 1, wherein the nucleic acid comprises a nucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 43 (GRD333- C24).JHU-43764.601 Client Docket No: P18504-02 9. The rAAV of claim 1, wherein the capsid polypeptide comprises an amino acid sequence provided by SEQ ID NO: 31 to 42.

10. The rAAV of claim 1, wherein the capsid polypeptide comprises an amino acid sequence provided by SEQ ID NO: 32 (K57) or SEQ ID NO: 36 (K55).

11. The rAAV of claim 1, wherein the capsid polypeptide comprises an amino acid sequence provided by SEQ ID NO: 36 (K55).

12. The rAAV of claim 1, wherein the NF1-GRD has an amino acid sequence that has at least 75% identity to SEQ ID NO: 18 (GRD333).

13. The rAAV of claim 1, wherein the capsid polypeptide comprises an amino acid sequence that has at least 75% identity to SEQ ID NO: 32 (K57) or SEQ ID NO: 36 (K55).

14. The rAAV of claim 1, wherein the capsid polypeptide comprises an amino acid sequence that has at least 75% identity to SEQ ID NO: 36 (K55).

15. A method of treating a patient having neurofibromatosis type 1 (NF1), said method comprising: administering a recombinant adeno-associated virus (rAAV) to the patient, wherein the rAAV comprises: a nucleic acid comprising a nucleotide sequence encoding a polypeptide comprising a neurofibromatosis type 1 GAP-related domain (NF1-GRD) fused to a Ras hypervariable region (HVR); and a capsid polypeptide comprising an amino acid sequence that is optimized for tropism to NF1-related tumors.

16. The method of claim 15, wherein the patient is a human.

17. The method of claim 15, wherein the patient has a mutation in a NF1 gene.JHU-43764.601 Client Docket No: P18504-02 18. The method of claim 15, wherein the patient has a tumor.

19. The method of claim 15, wherein a nucleotide sequence encoding a polypeptide comprising SEQ ID NO: 43 is integrated into a chromosome of the patient after said administration.

20. The method of claim 19, wherein said chromosome is chromosome 19.

21. A kit for producing a recombinant adeno-associated virus (rAAV), said kit comprising: a first AAV vector comprising a nucleic acid comprising a nucleotide sequence encoding a polypeptide comprising a neurofibromatosis type 1 GAP-related domain (NF1-GRD) fused to a Ras hypervariable region (HVR); and a second AAV vector comprising a nucleic acid comprising a cap gene sequence encoding a capsid polypeptide comprising an amino acid sequence that is optimized for tropism to NF1-related tumors.

22. The kit of claim 21, wherein the first AAV vector comprises a nucleotide sequence encoding a GRD333 polypeptide (SEQ ID NO: 18).

23. The kit of claim 21, wherein the first AAV vector comprises a nucleotide sequence encoding a GRD333-C24 polypeptide (SEQ ID NO: 43).

24. The kit of claim 21, wherein the second AAV vector comprises a nucleotide sequence encoding a K55 cap gene sequence (SEQ ID NO: 9) or a K57 cap gene sequence (SEQ ID NO: 11).

25. The kit of claim 21, wherein the second AAV vector comprises a nucleotide sequence encoding a capsid polypeptide comprising a K55 peptide (SEQ ID NO: 36) or a K57 peptide (SEQ ID NO: 32).JHU-43764.601 Client Docket No: P18504-02 26. The kit of claim 21, wherein the second AAV vector comprises a nucleotide sequence encoding a K55 capsid (SEQ ID NO: 10) or a K57 capsid (SEQ ID NO: 12).

27. The kit of claim 21, further comprising a helper plasmid.

28. Use of a rAAV for treating NF1, wherein said rAAV comprises a nucleic acid comprising a nucleotide sequence encoding a polypeptide comprising a neurofibromatosis type 1 GAP-related domain (NF1-GRD) fused to a Ras hypervariable region (HVR); and a capsid polypeptide comprising an amino acid sequence that is optimized for tropism to NF1-related tumors.

29. Use of a rAAV for the manufacture of a medicament for treating NF1, wherein said rAAV comprises a nucleic acid comprising a nucleotide sequence encoding a polypeptide comprising a neurofibromatosis type 1 GAP-related domain (NF1-GRD) fused to a Ras hypervariable region (HVR); and a capsid polypeptide comprising an amino acid sequence that is optimized for tropism to NF1-related tumors.

30. The use of claim 28 or claim 29, wherein the NF1-GRD is optimized for expression and anti-tumor effectiveness.

31. The use of claim 28 or claim 29, wherein the NF1-GRD comprises amino acids 1200– 1532 of NF1 (SEQ ID NO: 18) (GRD333).

32. The use of claim 28 or claim 29, wherein the NF1-GRD has an amino acid sequence provided by SEQ ID NO: 18 (GRD333).

33. The use of claim 28 or claim 29, wherein the Ras HVR comprises a HVR amino acid sequence from a HRas HVR, NRas HVR, KRas4A HVR, or KRas4B HVR.

34. The use of claim 28 or claim 29, wherein the Ras HVR comprises a HVR amino acid sequence from a KRas4B HVR.JHU-43764.601 Client Docket No: P18504-02 35. The use of claim 28 or claim 29, wherein the Ras HVR comprises a sequence provided by SEQ ID NO: 16 (C24).

36. The use of claim 28 or claim 29, wherein the nucleic acid comprises a nucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 43 (GRD333-C24).

37. The use of claim 28 or claim 29, wherein the capsid polypeptide comprises an amino acid sequence provided by SEQ ID NO: 31 to 42.

38. The use of claim 28 or claim 29, wherein the capsid polypeptide comprises an amino acid sequence provided by SEQ ID NO: 32 (K57) or SEQ ID NO: 36 (K55).

39. The use of claim 28 or claim 29, wherein the capsid polypeptide comprises an amino acid sequence provided by SEQ ID NO: 36 (K55).

40. The use of claim 28 or claim 29, wherein the NF1-GRD has an amino acid sequence that has at least 75% identity to SEQ ID NO: 18 (GRD333).

41. The use of claim 28 or claim 29, wherein the capsid polypeptide comprises an amino acid sequence that has at least 75% identity to SEQ ID NO: 32 (K57) or SEQ ID NO: 36 (K55).

44. The use of claim 28 or claim 29, wherein the capsid polypeptide comprises an amino acid sequence that has at least 75% identity to SEQ ID NO: 36 (K55).

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