(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/170431 A2 13 December 2012 (13.12.2012) P O P C T (51) International Patent Classification: Not classified HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US20 12/040932 OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, (22) International Filing Date: SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, 5 June 2012 (05.06.2012) TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 61/493,918 6 June 201 1 (06.06.201 1) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicant (for all designated States except US) : BLUE¬ MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, BIRD BIO, INC. [US/US]; 840 Memorial Drive, Cam TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, bridge, Massachusetts 02139 (US). ML, MR, NE, SN, TD, TG). (72) Inventor; and Declarations under Rule 4.17 : (75) Inventor/Applicant (for US only): KUTNER, Robert H. — as to applicant's entitlement to applyfor and be granted a [US/US]; 15 North Beacon Street #91 5, Allston, Mas patent (Rule 4.1 7(H)) sachusetts 02134 (US). — as to the applicant's entitlement to claim the priority of the (74) Agents: MCDONALD, Michael J. et al; Cooley LLP, earlier application (Rule 4.1 7(in)) 777 - 6th Street, NW, Suite 1100, Washington, District of Columbia 20001 (US). Published: (81) Designated States (unless otherwise indicated, for every — without international search report and to be republished kind of national protection available): AE, AG, AL, AM, upon receipt of that report (Rule 48.2(g)) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, — with sequence listing part of description (Rule 5.2(a)) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, < o o- (54) Title: IMPROVED GENESWITCH SYSTEMS (57) Abstract: The present invention provides improved molecular switch gene expression systems and improved retroviral pack- aging cells and viral particle production. In various embodiments, the present invention also provides retroviral vectors that have in - creased control over gene expression. Further, the present invention provides vector systems that are useful in methods of gene ther- apy. IMPROVED GENESWITCH SYSTEMS CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 61/493,918, filed June 6, 201 1, which is incorporated by reference herein in its entirety. STATEMENT REGARDING SEQUENCE LISTING The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is BLBD_002_01WO_ST25.txt. The text file is 17 KB, was created on June 5, 201 1, and is being submitted electronically via EFS-Web, concurrent with the filing of the specification. BACKGROUND Technical Field The present invention generally relates to improved molecular switch systems and improved retroviral packaging cells and viral particle production. In particular, the present invention comprises retroviral vectors that have increased control over gene expression. Description of the Related Art The Food and Drug Administration (FDA) has not yet approved any human gene therapy product for sale. Current gene therapy is experimental and has not proven very successful in clinical trials. Little progress has been made since the first gene therapy clinical trial began in 1990. In 1999, gene therapy suffered a major setback with the death of 18-year-old Jesse Gelsinger. Jesse was participating in a gene therapy trial for ornithine transcarboxylase deficiency (OTCD). He died from multiple organ failures 4 days after starting the treatment. His death is believed to have been triggered by a severe immune response to the adenovirus carrier. Another major blow came in January 2003, when the FDA placed a temporary halt on all gene therapy trials using retroviral vectors in blood stem cells. FDA took this action after it learned that a second child treated in a French gene therapy trial had developed a leukemia-like condition. Both this child and another who had developed a similar condition in August 2002 had been successfully treated by gene therapy for X-linked severe combined immunodeficiency disease (X-SCID), also known as "bubble baby syndrome." FDA's Biological Response Modifiers Advisory Committee (BRMAC) met at the end of February 2003 to discuss possible measures that could allow a number of retroviral gene therapy trials for treatment of life- threatening diseases to proceed with appropriate safeguards. In April of 2003, the FDA eased the ban on gene therapy trials using retroviral vectors in blood stem cells. Recently, however, several groups have led moderately successful gene therapy trials in combating several diseases. In, 2008, UK researchers from the UCL Institute of Ophthalmology and Moorfields Eye Hospital NIHR Biomedical Research Centre announced a successful gene therapy clinical trial for treatment of Leber's congenital amaurosis, a type of inherited blindness. The results showed that the experimental treatment is safe and can improve sight (Maguire et al., N EnglJ Med. 358(21):2240 (2008)). In 201 1, Neurologix, Inc. announced positive results in a Phase 2 trial of its investigational gene therapy for advanced Parkinson's disease (PD), NLX-P101. Study participants who received NLX-P101 experienced statistically significant and clinically meaningful improvements in off-medication motor scores compared to control subjects who received sham surgery. In the trial, this benefit was seen at one month and continued virtually unchanged throughout the six month blinded study period. The results also demonstrated a positive safety profile for NLX-P101, with no serious adverse events related to the gene therapy or surgical procedure reported. Patients enrolled in the trial had moderate to advanced PD and were not adequately responsive to current therapies. In 2009, a French groups of scientists reported using hematopoietic stem cell mediated gene therapy to successfully treat X-linked adrenoleukodystrophy (ALD). Autologous stem cells were removed from the patients, genetically corrected ex vivo and then re-infused into the patients after they had received myeloablative treatment. Over a span of 24 to 30 months of follow-up, polyclonal reconstitution, with 9 to 14% of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein was detected. These results strongly suggest that hematopoietic stem cells were transduced in the patients. Beginning 14 to 16 months after infusion of the genetically corrected cells, progressive cerebral demyelination in the two patients stopped. Although before gene therapy can become a permanent cure for any condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent gene therapy from many times achieving any long-term benefits. Patients will have to undergo multiple rounds of gene therapy. Anytime a foreign object is introduced into human tissues, the immune system is designed to attack the invader. The risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a potential risk. Furthermore, the immune system's enhanced response to invaders it has seen before makes it difficult for gene therapy to be repeated in patients. Thus, while viruses are the carrier of choice, most gene therapy studies present a variety of potential problems to the patient—toxicity, immune and inflammatory responses, and gene control and targeting issues. In addition, there is always the fear that the viral vector, once inside the patient, may recover its ability to cause disease. In addition, while production of retroviral particles has undergone iterative rounds of optimization in recent years, the packaging cell lines that presently exist in the art have essentially the same components as they did ten years ago. As a consequence, while marginal improvements in safety have been achieved, they have been achieved at the expense of efficient viral particle production of high titer viruses, thus making retroviral-based gene therapy cost prohibitive in many contexts, e.g., direct injection of viral particles to the brain. Accordingly, the complete promise of gene therapy has yet to be realized due to issues with inconsistent therapeutic efficacy and inefficient production of viral particles, and thus, there exists a significant need in the art for improved viral vectors that have higher therapeutic efficacy in gene therapy methods and that can be used to efficiently produce viral particles. The present invention addresses these needs. BRIEF SUMMARY Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.