Compositions for and methods of treating solute carrier (SLC) protein deficiencies

Abstract

Disclosed herein are compositions for and methods of treating and / or slowing and / or reversing disease progression for one or more solute carrier (SLC) protein diseases.

Description

COMPOSITIONS FOR AND METHODS OF TREATING SOLUTE CARRIER (SLC) PROTEIN DEFICIENCIESI. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claim priority to U.S. Provisional Application No. 63 / 708,350 filed 17 October 2024, which is incorporated herein in its entirety.II. REFERENCE TO THE SEQUENCE LISTING

[0002] The Sequence Listing submitted 17 October 2025 as a text file named “25-4045-WO_SL”, created on 17 October 2025 and having a size of 495,616 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5).III. BACKGROUND

[0003] Solute carrier family 25, member 4 (SLC25A4,' also known as adenine nucleotide translocase 1 (ANTI)) is a gated pore that exchanges cytosolic ADP for mitochondrial ATP across the inner mitochondrial membrane of heart and skeletal muscle tissues. This exchange is necessary to supply substrate to complex V of the respiratory chain; functional SLC25A4 is thus a critical member of mitochondrial oxidative phosphorylation. Biallelic loss-of-function variants in SLC25A4 result in skeletal myopathy, hypertrophic cardiomyopathy, exercise intolerance, and lactic acidosis marked by proliferation of hypofunctional mitochondria in myocytes. An ancestral frameshift variant of SLC25A4 (c.523delC; p.Q175RfxX38) is relatively common among North American Mennonites and individuals homozygous for this variant exhibit cardiac dysfunction and progressive myocardial thickening that can culminate in end-stage heart failure necessitating transplantation. There are no disease-modifying therapies available for SLC25A4 deficiency. There is no uniform treatment strategy as treatments are only directed at alleviating symptoms.

[0004] Thus, there remains an urgent need for a minimally invasive, definitive therapy to address the underlying cause of as well as the sequelae of symptoms associated with these various SLC diseases and disorders (including SLC25A4). Consequently, the present disclosure provides compositions for and methods of treating SLCs, which can be used alone or in combination with other treatments.IV. BRIEF DESCRIPTION OF THE FIGURES

[0005] FIG. 1A shows a schematic of rAAV-SLC25A4 while FIG. IB shows a plasmid map of rAAV-SLC25A4. For in vitro studies, this construct was packaged into AAV.cc47 while for in vivo studies, this construct was packaged into AAV.cc84.

[0006] FIG. 2A - FIG. 2B shows that rAAV-SLC25A4 resulted in appropriate localization and expression of transgene. rAAV-SLC25A4 (packaged in AAV.cc47 capsid) tagged with HA was delivered to wild-type induced pluripotent stem cell derived cardiomyocytes and mouse myoblast cells (C2C12). 48 hours after delivery, 1) a fluorescent dye (MitoTracker Red) was used to labelmitochondria and the cells were fixed for immunofluorescence and 2) cells were harvested for western blot analysis using an anti-HA primary antibody. FIG. 2A shows that when delivered to cells, SLC25 A4 localized to the mitochondria (co-localized with MitoTracker Red) in iPSC-CMs and C2C12 cells while FIG. 2B shows that the transgene is expressed. Here, iPSC-CM = induced pluripotent stem cell derived cardiomyocyte; C2C12 = mouse myoblast cell; HA = hemagglutinin; and cTNT = cardiac troponin T.

[0007] FIG. 3 shows that patient-specific iPSC cells were created by knocking-in the c.523delC mutation. These cells were differentiated into cardiomyocytes and subsequently treated with rAAV-SLC25A4 (packaged in AAV.cc47 capsid). Expression of SLC25A4 localized to the inner mitochondrial membrane as seen by co-localization of the transgene with MitoTracker Red.

[0008] FIG. 4A - FIG. 4D show that the construct using the MHCK7 promoter resulted in the best cardiac and skeletal muscle transduction, while being de-targeted from the liver in vivo. FIG. 4A show that wild-type mice (n = 6) were injected with buffer or rAAV-SLC25A4 via tail vein at a dose of lel2 vg / mouse. Organs were harvested 4 weeks post-injection. FIG. 4B shows the vector genome copy numbers per ug DNA input for quantitative polymerase chain reaction biodistribution analysis are represented as log vg / ug DNA. Biodistribution of rAAV constructs using either MHCK7, CK8, or CBh promoters are displayed. Displayed are the mean value and error bars representing the standard error mean. FIG. 4C shows western blot analysis was performed to evaluate SLC25A4 protein expression in target tissues (heart, skeletal muscle, and liver) following AAV delivery. SLC25A4 was probed via the HA tag. GAPDH was used as an internal loading control. The construct that resulted in the greatest SLC25A4 expression in heart and skeletal muscle, as well as the lowest transgene expression in the liver was the construct containing the MHCK7 promoter. FIG. 4D shows the immunohistochemistry of anti-HA primary antibody in harvested heart and skeletal muscle tissues. Statistical significance was determined by One-Way ANOVA with Tukey’s post-test for vector genome biodistribution. * p < 0.05; ns = not significant. TA = tibialis anterior; M = male; F = female; CBh, CK8, MHCK7 = promoters.

[0009] FIG. 5A - FIG. 5D shows the rAAV-SLC25A4 delivery to Slc25a4 knockout mouse model results in delivery of transgene to the heart and skeletal muscle. FIG. 5A shows wild-type (n = 6) and Slc25a4-I- (n = 12) mice were injected with buffer (n = 6 wild type; n = 6 Slc25a4-I-) or rAAV-SLC25A4 (n = 6) via tail vein at a dose of lel2 vg / mouse. Organs were harvested 4 weeks post-injection. FIG. 5B shows vector genome copy numbers per ug DNA input for quantitative polymerase chain reaction biodistribution analysis are represented as log vg / ug DNA. Displayed are the mean value and error bars representing the standard error mean. FIG. 5C shows gene expression of SLC25A4 mRNA in heart, skeletal muscle, and liver tissues. mRNA levels for SLC25A4 were normalized to the house keeping gene (beta-actin) and analyzed with quantitativepolymerase chain reaction. Displayed are the mean value and error bars representing standard error mean. FIG. 5D shows mitochondrial copy number for the 3 treatment groups. Mitochondrial copy number was quantified using quantitative polymerase chain reaction to compare the ratio of a mitochondrial gene (ND1) to a nuclear gene (NEB). Displayed are the mean value and error bars representing standard error mean. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p<0.0001; ns = not significant.

[0010] FIG. 6A - FIG. 6D shows the functional evaluation of Slc25a4-KO mice after neonatal treatment with rAAV-SLC25A4. FIG. 6A shows wild-type (n = 10) and Slc25a4-I- (n = 20) mice were injected at age P14 with buffer (n = 10 wild type; n = 10 Slc25a4-I~) or rAAV-SLC25A4 (n = 13) via retro-orbital injection at a dose of 2el4 vg / kg. FIG. 6B shows the Kaplan-Meier survival curve of the studied mice. Dotted lines represent 95% confidence intervals. FIG. 6C shows the evaluation of exercise tolerance, as measured by treadmill testing and evaluated at 1 month, 3 months, 6 months, and 9 months post-injection. The time that each group of mice lasted in the treadmill protocol is displayed as the mean value with error bars representing the standard error mean. FIG. 6D - FIG. 6E show echocardiographic parameters measured in the study cohorts. * = significant p-value between p < 0.001 and p < 0.05.

[0011] FIG. 7A - FIG. 7G show the functional evaluation of Slc25a4-KO mice after treatment with rAAV-SLC25A4 at 6 months of age. FIG. 7A shows that Slc25a4-I- (n = 6) mice were injected at age 6 months with rAAV-SLC25A4 intravenous route at a dose of 5el3 vg / kg. These mice are compared to age-matched wild-type mice (n = 10) and Slc25a4-I- control (n = 10) mice. FIG. 7B - FIG. 7G show the echocardiographic parameters measured in the study cohorts. Red arrow indicates time at which the SLC25A4-I- were treated (at 6 months). * = significant p-value between p < 0.0001 and p < 0.05.V. BRIEF SUMMARY

[0012] Disclosed herein is a nucleic acid molecule comprising a nucleic acid sequence encoding a solute carrier (SLC) protein or fragment thereof. Disclosed herein is a nucleic acid molecule comprising a nucleic acid sequence encoding a disclosed SLC protein operably linked to a promoter and / or enhancer.

[0013] Disclosed herein is an expression cassette comprising a disclosed nucleic acid operably linked to a disclosed promoter. Disclosed herein is an expression cassette comprising (i) a disclosed nucleic acid operably linked to a disclosed promoter and (ii) one or more disclosed regulatory elements. Disclosed herein is an expression cassette comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a solute carrier (SLC) protein or fragment thereof. Disclosed herein is an expression cassette comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1,SLC25A3, SLC25A4, or SLC25A20. Disclosed herein is an expression cassette comprising (i) a nucleic acid sequence encoding SLC25A4 and comprising the sequence set forth in SEQ ID NO:03, SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81; (ii) a nucleic acid sequence encoding SLC25A4 and comprising the sequence set forth in SEQ ID NO:05; (iii) a nucleic acid sequence encoding SLC2A4 and comprising the sequence set forth in SEQ ID NO:29; (iv) a nucleic acid sequence encoding SLC4A3 and comprising the sequence set forth in SEQ ID NO:30 or SEQ ID NO:31; (v) a nucleic acid sequence encoding SLC8A1 and comprising the sequence set forth in SEQ ID NO:32; (vi) a nucleic acid sequence encoding SLC16A1 and comprising the sequence set forth in SEQ ID NO:33; (vii) a nucleic acid sequence encoding SLC22A5 and and comprising the sequence set forth in SEQ ID NO:34; (viii) a nucleic acid sequence encoding SLC25A1 and comprising the sequence set forth in SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37; (ix) a nucleic acid sequence encoding SLC25A3 and comprising the sequence set forth in SEQ ID NO:38 or SEQ ID NO:39; or (x) a nucleic acid sequence encoding SLC25A20 and comprising the sequence set forth in SEQ ID NO:40; wherein the nucleic acid sequence is operably linked to a disclosed promoter.

[0014] Disclosed herein is an expression cassette comprising (i) a nucleic acid sequence encoding SLC25A4 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:03, SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81; (ii) a nucleic acid sequence encoding SLC25A4 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:05; (iii) a nucleic acid sequence encoding SLC2A4 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:29; (iv) a nucleic acid sequence encoding SLC4A3 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:30 or SEQ ID NO: 31; (v) a nucleic acid sequence encoding SLC8A1 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:32; (vi) a nucleic acid sequence encoding SLC16A1 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:33; (vii) a nucleic acid sequence encoding SLC22A5 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:34; (viii) a nucleic acid sequence encoding SLC25A1 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37; (ix) a nucleic acid sequence encoding SLC25A3 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:38 or SEQ ID NO:39; or (x) a nucleic acid sequence encoding SLC25A20 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:40; wherein the nucleic acid sequence is operably linked to a disclosed promoter.

[0015] Disclosed herein is a vector comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a solute carrier (SLC) protein. Disclosed herein is a vector comprising a nucleic acid molecule comprising a nucleic acid sequence encoding SLC2A4, SLC4A3, SLC8A1,SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, or SLC25A20. Disclosed herein is a vector comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a fragment or portion of a solute carrier (SLC) protein.

[0016] Disclosed herein an AAV vector comprising a nucleic acid sequence encoding SLC25A4 and a nucleic acid sequence encoding a MHCK7 promoter. Disclosed herein an AAV vector comprising the nucleic acid sequence set forth in SEQ ID NO:03, SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81, and the nucleic acid sequence set forth in SEQ ID NO: 10. Disclosed herein an AAV vector comprising the nucleic acid sequence set forth in SEQ ID NO:03, SEQ ID NO:79, SEQ ID NO: 80, or SEQ ID NO: 81 or a fragment or portion thereof and the nucleic acid sequence set forth in SEQ ID NO: 10 or a fragment or portion thereof. Disclosed herein an AAV vector comprising a nucleic acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:03, SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81 and a nucleic acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO: 10. In an aspect, the a capsid protein of a disclosed AAV vector can comprise AAV.cc47 (SEQ ID NO:60) or AAV.cc84 (SEQ ID NO:66). In an aspect, a disclosed capsid protein of a disclosed AAV vector can comprise the sequence set forth in SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84 or SEQ ID NO:85.

[0017] Disclosed herein is a pharmaceutical formulation comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a solute carrier (SLC) protein or fragment thereof. In an aspect, a disclosed solute carrier (SLC) protein can comprise SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, or SLC25A20. Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a solute carrier (SLC) protein. In an aspect, a disclosed solute carrier (SLC) protein can comprise SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, or SLC25A20.

[0018] Disclosed herein is a method of treating and / or slowing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed nucleic acid molecule comprising a disclosed nucleic acid sequence for a disclosed SLC protein, wherein, following expression of nucleic acid sequence in cardiac and skeletal muscle cells and / or cardiac and skeletal muscle tissues, the activity level of the SLC protein is increased.

[0019] Disclosed herein is a method of treating and / or slowing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount an AAV vector comprising a nucleic acid sequence encoding SLC25A4 and a nucleic acidsequence encoding a MHCK7 promoter, wherein, following expression of nucleic acid sequence in the cells and / or tissues, the expression and / or activity level of the SLC25A4 protein is increased. Disclosed herein is a method of treating and / or slowing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount of an AAV vector comprising the nucleic acid sequence set forth in SEQ ID NO:03, SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81 and the nucleic acid sequence set forth in SEQ ID NO: 10, wherein, following expression of nucleic acid sequence in the cells and / or tissues, the expression and / or activity level of the SLC25A4 protein is increased.

[0020] Disclosed herein is a method of treating and / or slowing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount of an AAV vector comprising the nucleic acid sequence set forth in SEQ ID NO:03, SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81 or a fragment or portion thereof and the nucleic acid sequence set forth in SEQ ID NO: 10 or a fragment or portion thereof, wherein, following expression of nucleic acid sequence in the cells and / or tissues, the expression and / or activity level of the SLC25A4 protein is increased.VI. DETAILED DESCRIPTION

[0021] The present disclosure describes formulations, compounded compositions, kits, capsules, containers, and / or methods thereof. It is to be understood that the inventive aspects of which are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0022] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.A. Definitions

[0023] Before the present compounds, compositions, articles, systems, devices, and / or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods andmaterials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0024] This disclosure describes inventive concepts with reference to specific examples. However, the intent is to cover all modifications, equivalents, and alternatives of the inventive concepts that are consistent with this disclosure.

[0025] As used in the specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.

[0026] The phrase “consisting essentially of’ limits the scope of a claim to the recited components in a composition or the recited steps in a method as well as those that do not materially affect the basic and novel characteristic or characteristics of the claimed composition or claimed method. The phrase “consisting of’ excludes any component, step, or element that is not recited in the claim. The phrase “comprising” is synonymous with “including”, “containing”, or “characterized by”, and is inclusive or open-ended. “Comprising” does not exclude additional, unrecited components or steps.

[0027] In an aspect, when referring to any numerical value, the term “about” means a value falling within a range that is ± 10% of the stated value.

[0028] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0029] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0030] In an aspect, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where saidevent or circumstance occurs and instances where it does not. In an aspect, a disclosed method can optionally comprise one or more additional steps, such as, for example, repeating an administering step or altering an administering step.

[0031] In an aspect, the term “subject” refers to the target of administration, e.g., a human being. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.). Thus, the subject of herein disclosed methods can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Alternatively, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex, and thus, adult and child subjects, as well as fetuses, whether male or female, are intended to be covered. In an aspect, a subject can be a human patient. In an aspect, a subject can have a SLC protein deficiency, be suspected of having a SLC protein deficiency, or be at risk of developing a SLC protein deficiency.

[0032] In an aspect, the term “diagnosed” means having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by one or more of the disclosed isolated nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof, or by one or more of the disclosed methods. For example, “diagnosed with a SLC protein deficiency” means having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition that can be treated by one or more of the disclosed isolated nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof, or by one or more of the disclosed methods. For example, “suspected of having a SLC protein deficiency” can mean having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition that can likely be treated by one or more of by one or more of the disclosed isolated nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof, or by one or more of the disclosed methods. In an aspect, an examination can be physical, can involve various tests (e.g., blood tests, genotyping, biopsies, etc.) and assays (e.g., enzymatic assay), or a combination thereof.

[0033] A “patient” refers to a subject afflicted with a disclosed SLC protein deficiency. In an aspect, a patient can refer to a subject that has been diagnosed with or is suspected of having a disclosed SLC protein deficiency. In an aspect, a patient can refer to a subject that has been diagnosed with or is suspected of having a disclosed SLC protein deficiency and is seeking treatment or receiving treatment for a SLC protein deficiency.

[0034] In an aspect, the phrase “identified to be in need of treatment for a disorder,” or the like, refers to selection of a subject based upon need for treatment of the disorder. For example, asubject can be identified as having a need for treatment of a disorder (e.g., such a SLC protein deficiency) based upon an earlier diagnosis by a person of skill and thereafter subjected to treatment for the disorder (e.g., such as a SLC protein deficiency). In an aspect, the identification can be performed by a person different from the person making the diagnosis. In an aspect, the administration can be performed by one who performed the diagnosis.

[0035] In an aspect, “inhibit,” “inhibiting”, and “inhibition” mean to diminish or decrease an activity, level, response, condition, severity, disease, or other biological parameter. This can include, but is not limited to, the complete ablation of the activity, level, response, condition, severity, disease, or other biological parameter. This can also include, for example, a 10% inhibition or reduction in the activity, level, response, condition, severity, disease, or other biological parameter as compared to the native or control level (e.g., a subject not having a SLC protein deficiency). Thus, in an aspect, the inhibition or reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of reduction in between as compared to native or control levels. In an aspect, the inhibition or reduction can be 10-20%, 20-30%, 30-40%, 40- 50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% as compared to native or control levels. In an aspect, the inhibition or reduction can be 0-25%, 25-50%, 50-75%, or 75-100% as compared to native or control levels.

[0036] The words “treat” or “treating” or “treatment” include palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In an aspect, the terms cover any treatment of a subject, including a mammal e.g., a human), and includes: (i) preventing the undesired physiological change, disease, pathological condition, or disorder from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the physiological change, disease, pathological condition, or disorder, i.e., arresting its development; or (iii) relieving the physiological change, disease, pathological condition, or disorder, i.e., causing regression of the disease. For example, in an aspect, treating a SLC protein deficiency (such as any in Table 1) can reduce the severity of an established SLC protein deficiency in a subject by 1%- 100% as compared to a control (such as, for example, an individual not having a SLC protein deficiency). In an aspect, treating can refer to a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of a SLC protein deficiency (such as any in Table 1). For example, treating a SLC protein deficiency can reduce one or more symptoms of a SLC proteindeficiency in a subject by 1 %- 100% as compared to a control (such as, for example, an individual not having a SLC protein deficiency). In an aspect, treating can refer to 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% reduction of one or more symptoms of an established SLC protein deficiency (such as any in Table 1). It is understood that treatment does not necessarily refer to a cure or complete ablation or eradication of a SLC protein deficiency. However, in an aspect, treatment can refer to a cure or complete ablation or eradication of a SLC protein deficiency.

[0037] In an aspect, the term “prevent” or “preventing” or “prevention” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit, or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed. In an aspect, preventing a SLC protein deficiency is intended. The words “prevent” and “preventing” and “prevention” also refer to prophylactic or preventative measures for protecting or precluding a subject (e.g., an individual) not having a given a SLC protein deficiency-related complication from progressing to that complication.

[0038] In an aspect, the terms “administering” and “administration” refer to any method of providing one or more of the disclosed isolated nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof to a subject.

[0039] In an aspect, a therapeutically effective amount of disclosed vector can be delivered intravenously and can comprise a range of about 1 x 1010vg / kg to about 2 x 1014vg / kg.

[0040] In an aspect, the skilled person can determine an efficacious dose, an efficacious schedule, and an efficacious route of administration for one or more of the disclosed isolated nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof so as to treat or prevent a SLC protein deficiency. In an aspect, the skilled person can also alter, change, or modify an aspect of an administering step to improve efficacy of one or more of the disclosed isolated nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof.

[0041] In an aspect, “modifying the method” can comprise modifying or changing one or more features or aspects of one or more steps of a disclosed method. For example, in an aspect, a method can be altered by changing the amount of one or more of the disclosed isolated nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof administered to a subject, or by changing the frequency of administration of one or more of the disclosed isolated nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof to a subject, or by changing the duration of time one ormore of the disclosed isolated nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination are administered to a subject.

[0042] In an aspect, “concurrently” means (1) simultaneously in time, or (2) at different times during the course of a common treatment schedule.

[0043] In an aspect, the term “contacting” refers to bringing one or more of the disclosed isolated nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof together with a target area or intended target area in such a manner that the one or more of the disclosed isolated nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof exert an effect on the intended target or targeted area either directly or indirectly. A target area or intended target area can be one or more of a subject’s organs (e.g., heart, muscle, etc.). In an aspect, a target area or intended target area can be any cell or any organ infected by a SLC protein deficiency. In an aspect, a target area or intended target area can be the liver.

[0044] In an aspect, “determining” can refer to measuring or ascertaining the presence and severity of a SLC protein deficiency. Methods and techniques used to determine the presence and / or severity of a SLC protein deficiency are typically known to the medical arts. For example, the art is familiar with the ways to identify and / or diagnose the presence, severity, or both of a SLC protein deficiency.

[0045] In an aspect, “effective amount” and “amount effective” can refer to an amount that is sufficient to achieve the desired result such as, for example, the treatment and / or prevention of a SLC protein deficiency or a suspected SLC protein deficiency. In an aspect, the terms “effective amount” and “amount effective” can refer to an amount that is sufficient to achieve the desired an effect on an undesired condition e.g., a SLC protein deficiency). For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms but is generally insufficient to cause adverse side effects. In an aspect, “therapeutically effective amount” means an amount of a disclosed isolated nucleic acid molecule, a disclosed vector, or a disclosed pharmaceutical formulation; that (i) treats the particular disease, condition (such as a SLC protein deficiency), (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein (e.g., a SLC protein deficiency). The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the disclosed isolated nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations employed; the disclosed methods employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations employed; the duration of the treatment; drugs used in combination or coincidental with the disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations employed, and other like factors well-known in the medical arts. For example, it is well within the skill of the art to start doses of the disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, then the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, a single dose of the disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition, such as, for example, a SLC protein deficiency.

[0046] In an aspect, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. In an aspect, a pharmaceutical carrier employed can be a solid, liquid, or gas. In an aspect, examples of solid carriers can include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. In an aspect, examples of liquid carriers can include sugar syrup, peanut oil, olive oil, and water. In an aspect, examples of gaseous carriers can include carbon dioxide and nitrogen. In preparing a disclosed composition for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated bystandard aqueous or nonaqueous techniques. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0047] In an aspect, the term “excipient” refers to an inert substance which is commonly used as a diluent, vehicle, preservative, binder, or stabilizing agent, and includes, but is not limited to, proteins (e.g., serum albumin, etc.), amino acids (e.g., aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc.), fatty acids and phospholipids (e.g., alkyl sulfonates, caprylate, etc.), surfactants (e.g., SDS, polysorbate, nonionic surfactant, etc.), saccharides (e.g., sucrose, maltose, trehalose, etc.) and polyols (e.g., mannitol, sorbitol, etc.). See, also, for reference, Remington’s Pharmaceutical Sciences, (1990) Mack Publishing Co., Easton, Pa., which is hereby incorporated by reference in its entirety.

[0048] In an aspect, “RNA therapeutics” can refer to the use of oligonucleotides to target RNA. RNA therapeutics can offer the promise of uniquely targeting the precise nucleic acids involved in a particular disease with greater specificity, improved potency, and decreased toxicity. This could be particularly powerful for genetic diseases where it is most advantageous to aim for the RNA as opposed to the protein. In an aspect, a therapeutic RNA can comprise one or more expression sequences. As known to the art, expression sequences can comprise an RNAi, shRNA, mRNA, non-coding RNA (ncRNA), an antisense such as an antisense RNA, miRNA, morpholino oligonucleotide, peptide-nucleic acid (PNA) or ssDNA (with natural, and modified nucleotides,including but not limited to, LNA, BNA, 2’-0-Me-RNA, 2’-ME0-RNA, 2’-F-RNA), or analog or conjugate thereof. In an aspect, a disclosed therapeutic RNA can comprise one or more long non-coding RNA (IncRNA), such as, for example, a long intergenic non-coding RNA (lincRNA), pre-transcript, pre-miRNA, pre-mRNA, competing endogenous RNA (ceRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), pseudo-gene, rRNA, or tRNA. In an aspect, ncRNA can be piwi-interacting RNA (piRNA), primary miRNA (pri-miRNA), or premature miRNA (pre-miRNA). In an aspect, a disclosed therapeutic RNA or a RNA therapeutic can comprise antisense oligonucleotides (ASOs) that inhibit mRNA translation, oligonucleotides that function via RNA interference (RNAi) pathway, RNA molecules that behave like enzymes (ribozymes), RNA oligonucleotides that bind to proteins and other cellular molecules, and ASOs that bind to mRNA and form a structure that is recognized by RNase H resulting in cleavage of the mRNA target. In an aspect, RNA therapeutics can comprise RNAi and ASOs that inhibit mRNA translation of one or more relevant enzymes in an affected pathway. Generally speaking, as known to the art, RNAi operates sequence specifically and post-transcriptionally by activating ribonucleases which, along with other enzymes and complexes, coordinately degrade the RNA after the original RNA target has been cut into smaller pieces while antisense oligonucleotides bind to their target nucleic acid via Watson-Crick base pairing, and inhibit or alter gene expression via steric hindrance, splicing alterations, initiation of target degradation, or other events.

[0049] In an aspect, “small molecule” can refer to any organic or inorganic material that is not a polymer. Small molecules exclude large macromolecules, such as large proteins (e.g., proteins with molecular weights over 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000), large nucleic acids (e.g., nucleic acids with molecular weights of over 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000), or large polysaccharides (e.g., polysaccharides with a molecular weight of over 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000). In an aspect, a “small molecule”, for example, can be a drug that can enter cells easily because it has a low molecular weight.

[0050] In an aspect, “CpG-free” can mean completely free of CpGs or partially free of CpGs. In an aspect, “CpG-free” can mean “CpG-depleted”. In an aspect, “CpG-depleted” can mean completely depleted of CpGs or partially depleted of CpGs. In an aspect, “CpG-free” can mean “CpG-optimized” for a desired and / or ideal expression level. CpG depletion and / or optimization is known to the skilled person in the art. In an aspect, “codon optimization” can refer to a process of modifying a nucleic acid sequence for enhanced expression in the host cells of interest by replacing one or more codons or more of the native sequence with codons that are more frequently or most frequently used in the genes of that host cell while maintaining the native amino acid sequence. Various species exhibit particular bias for certain codons of a particular amino acid.As contemplated herein, genes can be tailored for optimal gene expression in a given organism based on codon optimization. Codon usage tables are readily available, for example, at the “Codon Usage Database.” Many methods and software tools for codon optimization have been reported previously. (See, for example, genomes.urv.es / OPTIMIZER / ).

[0051] In an aspect, “operably linked” means that expression of a gene or a transgene is under the control of a promoter with which it is spatially connected. A promoter can be positioned 5’ (upstream) or 3’ (downstream) of a gene under its control. The distance between the promoter and a gene can be approximately the same as the distance between that promoter and the gene it controls in the gene from which the promoter is derived. As is known in the art, variation in this distance can be accommodated without loss of promoter function.

[0052] In an aspect, an “enhancer” such as a transcription or transcriptional enhancer refers to regulatory DNA segment that is typically found in multicellular eukaryotes. An enhancer can strongly stimulate (“enhance”) the transcription of a linked transcription unit, / .< ., it acts in cis. An enhancer can activate transcription over very long distances of many thousand base pairs, and from a position upstream or downstream of the site of transcription initiation. An enhancer can have a modular structure by being composed of multiple binding sites for transcriptional activator proteins. Many enhancers control gene expression in a cell type-specific fashion. Several remote enhancers can control the expression of a singular gene while a singular enhancer can stimulate the transcription of one or more genes.

[0053] In an aspect, “expression cassette” or “transgene cassette” can refer to a distinct component of vector DNA comprising a transgene and one or more regulatory sequences to be expressed by a transfected cell. Generally, an expression cassette or transgene cassette can comprise a promoter sequence, an open reading frame (i.e., the transgene), and a 3’ untranslated region (e.g., in eukaryotes a polyadenylation site).

[0054] In an aspect, “promoter” or “promoters” are known to the art. Depending on the level and tissue-specific expression desired, a variety of promoter elements can be used. A promoter can be tissue-specific or ubiquitous and can be constitutive or inducible, depending on the pattern of the gene expression desired. A promoter can be native (endogenous) or foreign (exogenous) and can be a natural or a synthetic sequence. By foreign or exogenous, it is intended that the transcriptional initiation region is not found in the wild-type host into which the transcriptional initiation region is introduced.

[0055] In an aspect, a disclosed promoter can be a promoter / enhancer. In an aspect, the term promoter / enhancer can refer to a segment of DNA that contains nucleotide sequences capable of providing both promoter and enhancer functions.

[0056] As discussed above, a disclosed promoter can be an endogenous promoter. Endogenous refers to a disclosed promoter or disclosed prom oter / enhancer that is naturally linked with its gene. In an aspect, a disclosed endogenous promoter can generally be obtained from a non-coding region upstream of a transcription initiation site of a gene (such as a disclosed SLC protein). In an aspect, a disclosed endogenous promoter can be used for constitutive and efficient expression of a disclosed transgene (e.g., a nucleic acid sequence encoding a disclosed SLC protein such as SLC25A4).

[0057] As discussed above, a disclosed promoter can be an exogenous promoter. Exogenous (or heterologous) refers to a disclosed promoter or a disclosed prom oter / enhancer that can be placed in juxtaposition to a gene by means of molecular biology techniques such that the transcription of that gene can be directed by the linked promoter or linked prom oter / enhancer. In an aspect, a disclosed endogenous promoter can be an endogenous prom oter / enhancer.

[0058] In an aspect, “de-targeted” refers to an engineered AAV designed to avoid the liver and target other tissues more specifically such as, for example, cardiac tissue and / or skeletal muscle.

[0059] In an aspect, an “inducible promoter” refers to a promoter that can be regulated by positive or negative control. Factors that can regulate an inducible promoter include, but are not limited to, chemical agents (e.g., the metallothionein promoter or a hormone inducible promoter), temperature, and light.

[0060] In an aspect, the term “serotype” is a distinction used to refer to an AAV having a capsid that is serologically distinct from other AAV serotypes. Serologic distinctiveness can be determined on the basis of the lack of cross-reactivity between antibodies to one AAV as compared to another AAV. Such cross-reactivity differences are usually due to differences in capsid protein sequences / antigenic determinants (e.g., due to VP1, VP2, and / or VP3 sequence differences of AAV serotypes).

[0061] In an aspect, “tropism” refers to the specificity of an AAV capsid protein present in an AAV viral particle, for infecting a particular type of cell or tissue. The tropism of an AAV capsid for a particular type of cell or tissue may be determined by measuring the ability of AAV vector particles comprising the hybrid AAV capsid protein to infect or to transduce a particular type of cell or tissue, using standard assays that are well- known in the art such as those disclosed in the examples of the present application. In an aspect, the term “liver tropism” or “hepatic tropism” refers to the tropism for liver or hepatic tissue and cells, including hepatocytes.

[0062] “Sequence identity” and “sequence similarity” can be determined by alignment of two peptide or two nucleotide sequences using global or local alignment algorithms. Sequences may then be referred to as “substantially identical” or “essentially similar” when they are optimally aligned. For example, sequence similarity or identity can be determined by searching againstdatabases such as FASTA, BLAST, etc., but hits should be retrieved and aligned pairwise to compare sequence identity. Two proteins or two protein domains, or two nucleic acid sequences can have “substantial sequence identity” if the percentage sequence identity is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more, preferably 90%, 95%, 98%, 99% or more. Such sequences are also referred to as “variants” herein, e.g., other variants of SLC proteins. It should be understood that sequence with substantial sequence identity do not necessarily have the same length and may differ in length. For example, sequences that have the same nucleotide sequence but of which one has additional nucleotides on the 3’- and / or 5’-side are 100% identical.

[0063] In an aspect, “immune tolerance,” “immunological tolerance,” and “immunotolerance” refers to a state of unresponsiveness or blunted response of the immune system to substances (e.g., a disclosed isolated nucleic acid molecule, a disclosed vector, a disclosed transgene product, a disclosed pharmaceutical formulation, a disclosed therapeutic agent, etc.) that have the capacity to elicit an immune response in a subject. Immune tolerance is induced by prior exposure to a specific antigen. Immune tolerance can be determined in a subject by measuring antibodies against a particular antigen or by liver-restricted transgene expression with an AAV vector. Low or absent antibody titers over time is an indicator of immune tolerance. For example, in some embodiments, immune tolerance can be established by having IgG antibody titers of less than or equal to about 12,000, 11,500, 11,000, 10,500, 10,000, 9,500, 9,000, 8,500, 8,000, 7,500, 7,000, 6,500, or 6,000 within following gene therapy (such as the administration of the transgene encoding, for example, a SLC protein.

[0064] As known to the art, antibodies (Abs) can mitigate AAV infection through multiple mechanisms by binding to AAV capsids and blocking critical steps in transduction such as cell surface attachment and uptake, endosomal escape, productive trafficking to the nucleus, or uncoating as well as promoting AAV opsonization by phagocytic cells, thereby mediating their rapid clearance from the circulation. For example, in humans, serological studies reveal a high prevalence of NAbs in the worldwide population, with about 67% of people having antibodies against AAV1, 72% against AAV2, and approximately 40% against AAV serotypes 5 through 9. Vector immunogenicity represents a major challenge in re-administration of AAV vectors.

[0065] In an aspect, also disclosed herein are partial self-complementary parvovirus (e.g., a disclosed AAV) genomes, plasmid vectors encoding the parvovirus genomes, and parvovirus (e.g., a disclosed AAV) particles including such genomes. In an aspect, provided herein is a plasmid vector comprising a nucleotide sequence encoding a disclosed parvovirus genome such as for example, a disclosed AAV. In an aspect, provided herein is a partial self-complementary parvovirus genome including a payload construct, parvovirus ITRs flanking the payload construct, and a self-complementary region flanking one of the ITRs. A self-complementary region cancomprise a nucleotide sequence that is complementary to the payload construct. A disclosed self- complementary region can have a length that is less the entire length of the payload construct.

[0066] In an aspect, a disclosed self-complementary region of a disclosed parvovirus genome can comprise a minimum length, while still having a length that is less the entire length of the payload construct. In an aspect, a disclosed self-complementary region can comprise at least 50 bases in length, at least 100 bases in length, at least 200 in length, at least 300 bases in length, at least 400 bases in length, at least 500 bases in length, at least 600 bases in length, at least 700 bases in length, at least 800 bases in length, at least 900 bases in length, or at least 1,000 bases in length.

[0067] In an aspect, a “self-complementary parvovirus genome” can be a single stranded polynucleotide having, in the 5' to 3' direction, a first parvovirus ITR sequence, a heterologous sequence (e.g., payload construct comprising, for example, a SLC protein), a second parvovirus ITR sequence, a second heterologous sequence, wherein the second heterologous sequence is complementary to the first heterologous sequence, and a third parvovirus ITR sequence. In contrast to a self-complementary genome, a “partial self-complementary genome” does not include three parvovirus ITRs and the second heterologous sequence that is complementary to the first heterologous sequence has a length that is less than the entire length of the first heterologous sequence (e.g., payload construct). Accordingly, a partial self-complementary genome is a single stranded polynucleotide having, in the 5' to 3' direction or the 3' to 5' direction, a first parvovirus ITR sequence, a heterologous sequence (e.g., payload construct), a second parvovirus ITR sequence, and a self-complementary region that is complementary to a portion of the heterologous sequence and has a length that is less than the entire length the heterologous sequence.

[0068] In an aspect, “immune-modulating” refers to the ability of a disclosed isolated nucleic acid molecule, a disclosed vector, a disclosed pharmaceutical formulation, or a disclosed agent to alter (modulate) one or more aspects of the immune system. The immune system functions to protect the organism from infection and from foreign antigens by cellular and humoral mechanisms involving lymphocytes, macrophages, and other antigen-presenting cells that regulate each other by means of multiple cell-cell interactions and by elaborating soluble factors, including lymphokines and antibodies, that have autocrine, paracrine, and endocrine effects on immune cells.

[0069] In an aspect, “immune modulator” refers to an agent that is capable of adjusting a given immune response to a desired level (e.g. as in immunopotentiation, immunosuppression, or induction of immunologic tolerance). Examples of immune modulators include but are not limited to, a disclosed immune modulator can comprise aspirin, azathioprine, belimumab, betamethasone dipropionate, betamethasone valerate, bortezomib, bredinin, cyazathioprine, cyclophosphamide, cyclosporine, deoxyspergualin, didemnin B, fluocinolone acetonide, folinic acid, ibuprofen, IL6inhibitors (such as sarilumab) indomethacin, inebilizumab, intravenous gamma globulin (IVIG), methotrexate, methylprednisolone, mycophenolate mofetil, naproxen, prednisolone, prednisone, prednisolone indomethacin, rapamycin, rituximab, sirolimus, sulindac, synthetic vaccine particles containing rapamycin (SVP -Rapamycin or ImmTOR), thalidomide, tocilizumab, tolmetin, triamcinolone acetonide, anti-CD3 antibodies, anti-CD4 antibodies, anti-CD19 antibodies, anti- CD20 antibodies, anti-CD22 antibodies, anti-CD40 antibodies, anti-FcRN antibodies, anti-IL6 antibodies, anti-IGFIR antibodies, an IL2 mutein, a BTK inhibitor, or a combination thereof. In an aspect, a disclosed immune modulator can comprise one or more Treg (regulatory T cells) infusions (e.g., antigen specific Treg cells to AAV). In an aspect, a disclosed immune modulator can be bortezomib or SVP -Rapamycin. In an aspect, a disclosed immune modulator can be Tacrolimus. In an aspect, an immune modulator can be administered by any suitable route of administration including, but not limited to, in utero, intra-CSF, intrathecally, intravenously, subcutaneously, transdermally, intradermally, intramuscularly, orally, transcutaneously, intraperitoneally (IP), or intravaginally. In an aspect, a disclosed immune modulator can be administered using a combination of routes. Administration can also include hepatic intra-arterial administration or administration through the hepatic portal vein (HPV). Administration of an immune modulator can be continuous or intermittent, and administration can comprise a combination of one or more routes.

[0070] In an aspect, the term “immunotolerant” refers to unresponsiveness to an antigen (e.g., a vector, a therapeutic protein, a transgene product, etc.). An immunotolerant promoter can reduce, ameliorate, or prevent transgene-induced immune responses that can be associated with gene therapy. Assays known in the art to measure immune responses, such as immunohistochemical detection of cytotoxic T cell responses, can be used to determine whether one or more promoters can confer immunotolerant properties.

[0071] In an aspect, the term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and / or warnings concerning the use of such therapeutic products.

[0072] In an aspect, the term “in combination” in the context of the administration of other therapies (e.g., other agents) includes the use of more than one therapy (e.g., drug therapy). Administration “in combination with” one or more further therapeutic agents includes simultaneous (e.g., concurrent) and consecutive administration in any order. The use of the term “in combination” does not restrict the order in which therapies are administered to a subject. By way of non-limiting example, a first therapy (e.g., a disclosed isolated nucleic acid molecule, a disclosed vector, a disclosed pharmaceutical formulation, or a combination thereof) may beadministered prior to (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks), concurrently, or after (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks or longer) the administration of a second therapy (e.g., agent) to a subject having or diagnosed with a SLC protein deficiency.

[0073] Disclosed are the components to be used to prepare the disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations as well as the disclosed isolated nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.B. Solute Carrier Proteins (SLC)

[0074] The SLC superfamily currently includes 458 transport proteins in 65 families that transport a wide variety of substances across cell membranes. These families are defined by the HUGO Gene Nomenclature Committee (HGNC) of the Human Genome Organization (HUGO) and organized such that member proteins within each family share at least 20-25% sequence similarity with at least one other member of the family. The average SLC family contains seven members,with eight families containing only one member (SLC32, SLC40, SLC48, SLC50, SLC53, SLC61, SLC62, and SLC64) and the largest, SLC25, containing 53 members. More recently, newer models of classification have emerged based on clustering and phylogenic analysis or a combination of functional and phylogenetic analysis. For example, Hbglund et al. analyzed the entire human genome (along with 16 other species) and identified 400 unique SLC genes. They further found that several of the HUGO-defined families could be organized into four large phylogenic clusters. The largest of these clusters was the a group, containing 13 SLC families.

[0075] Overall, SLC proteins transport a wide array of molecules, including sugars, amino acids, vitamins, nucleotides, metals, inorganic ions, organic anions, oligopeptides, and drugs. General substrate class specificity tends to be consistent within most families. SLC proteins also have a range of substrate specificity, with some proteins transporting a range of biomolecules, while others are currently known to transport only one biomolecule and still others are ‘orphan’ — with no known substrate. Recent reviews estimated that as many as 30% of SLC proteins remain such orphan transporters, even as recent technological developments have afforded novel methods to study these transport proteins. The SLC superfamily does not contain active transporters that directly use the energy released by ATP hydrolysis to drive the transport of substances against their concentration gradient. Rather, these proteins act as passive facilitative transporters or secondary active transporters. Facilitative transport is a system of transport in which the SLC acts as a simple gatekeeper for a compound to passively move down its gradient. Facilitative transport refers to systems in which only one molecule is transported in a thermodynamically favorable direction. In secondary active transport, transporters couple the passage of two or more substances. One substrate goes down its electrochemical gradient, which provides the free energy to drive the transport of the other substrate(s). Thus, the thermodynamically favorable transport of one substance provides the necessary free energy to transport the other in an unfavorable direction. In many of these cases, the rate of transport is proportional to the electrochemical gradient of the coupled ion. Such secondary active transporters can either be symporters, which transport their substrates in the same direction, or antiporters, in which the substrates cross the membrane in opposite directions. The substrate specificity of these transporters is determined not only by interactions between amino acid residues and the substrate, but also by intramolecular interactions that regulate gating and / or selectivity elements. Most secondary active transporters are thought to use the ‘alternating access’ transport mechanism, whereby protein domains are arranged to have a ligand binding site available on only one side of the membrane at a time, changing conformations to transport their substrates by shifting to the other side of the membrane.C. Compositions for Treating and / or Slowing and / or Reversing Disease Progression1. Nucleic Acid Sequences and Molecules

[0076] Disclosed herein is a nucleic acid molecule comprising a nucleic acid sequence encoding a solute carrier (SLC) protein or fragment thereof.

[0077] In an aspect, a disclosed solute carrier (SLC) protein can comprise SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, or SLC25A20. In an aspect, a disclosed solute carrier protein can comprise any SLC protein identified in Table 1. In an aspect, a disclosed solute carrier protein can comprise SLC25A4. In an aspect, a deficiency of a disclosed SLC protein can result in cardiac and / or skeleton-muscular dysfunction.Table 1 - Selected Solute Carrier Protein Genes and the Defective Enzymes

[0078] In an aspect, a disclosed encoded SLC25A4 can comprise the amino acid sequence set forth in SEQ ID NO:06. In an aspect, a disclosed encoded SLC2A4 can comprise the amino acid sequence set forth in SEQ ID NO:41. In an aspect, a disclosed encoded SLC4A3 can comprise the amino acid sequence set forth in SEQ ID NO:42 or SEQ ID NO:43. In an aspect, a disclosed encoded SLC8A1 can comprise the amino acid sequence set forth in SEQ ID NO:44. In an aspect, a disclosed encoded SLC16A1 can comprise the amino acid sequence set forth in SEQ ID NO:45.In an aspect, a disclosed encoded SLC22A5 can comprise the amino acid sequence set forth in SEQ ID NO:46. In an aspect, a disclosed encoded SLC25A1 can comprise the amino acid sequence set forth in SEQ ID NO:47, SEQ ID NO:48, or SEQ ID NO:49. In an aspect, a disclosed encoded SLC25A3 can comprise the amino acid sequence set forth in SEQ ID NO:50 or SEQ ID NO:51. In an aspect, a disclosed encoded SLC25A20 can comprise the amino acid sequence set forth in SEQ ID NO:52.

[0079] In an aspect, a disclosed encoded SLC25A4 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:06. In an aspect, a disclosed encoded SLC2A4 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:41. In an aspect, a disclosed encoded SLC4A3 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:42 or SEQ ID NO:43. In an aspect, a disclosed encoded SLC8A1 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:44. In an aspect, a disclosed encoded SLC16A1 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:45. In an aspect, a disclosed encoded SLC22A5 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:46. In an aspect, a disclosed encoded SLC25A1 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:47, SEQ ID NO:48, or SEQ ID NO:49. In an aspect, a disclosed encoded SLC25A3 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:50 or SEQ ID NO:51. In an aspect, a disclosed encoded SLC25A20 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:52.

[0080] In an aspect, a disclosed encoded SLC25A4 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the amino acid sequence set forth in SEQ ID NO:06. In an aspect, a disclosed encoded SLC2A4 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:41. In an aspect, a disclosed encoded SLC4A3 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:42 or SEQ ID NO:43. In an aspect, a disclosed encoded SLC8A1 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:44. In an aspect, a disclosed encoded SLC16A1 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:45. In an aspect, a disclosed encoded SLC22A5 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:46. In an aspect, a disclosed encoded SLC25A1can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:47, SEQ ID NO:48, or SEQ ID NO:49. In an aspect, a disclosed encoded SLC25A3 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:50 or SEQ ID NO:51. In an aspect, a disclosed encoded SLC25A20 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:52.

[0081] In an aspect, a disclosed nucleic acid sequence encoding SLC25A4 can comprise the sequence set forth in SEQ ID NO:03. In an aspect, a disclosed nucleic acid sequence encoding SLC25A4 can comprise the sequence set forth in SEQ ID NO:05.

[0082] In an aspect, a disclosed nucleic acid sequence encoding a SLC can be codon-optimized or CpG-depleted. In an aspect, a disclosed nucleic acid sequence encoding a SLC can be codon- optimized and CpG-depleted. In an aspect, a disclosed codon-optimized nucleic acid sequence encoding SLC25A4 can comprise the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81.

[0083] In an aspect, a disclosed nucleic acid sequence encoding SLC2A4 can comprise the sequence set forth in SEQ ID NO:29. In an aspect, a disclosed nucleic acid sequence encoding SLC4A3 can comprise the sequence set forth in SEQ ID NO:30 or SEQ ID NO:31. In an aspect, a disclosed nucleic acid sequence encoding SLC8A1 can comprise the sequence set forth in SEQ ID NO:32. In an aspect, a disclosed nucleic acid sequence encoding SLC16A1 can comprise the sequence set forth in SEQ ID NO:33. In an aspect, a disclosed nucleic acid sequence encoding SLC22A5 can comprise the sequence set forth in SEQ ID NO:34. In an aspect, a disclosed nucleic acid sequence encoding SLC25A1 can comprise the sequence set forth in SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37. In an aspect, a disclosed nucleic acid sequence encoding SLC25A3 can comprise the sequence set forth in SEQ ID NO:38 or SEQ ID NO:39. In an aspect, a disclosed nucleic acid sequence encoding SLC25A20 can comprise the sequence set forth in SEQ ID NO:40.

[0084] In an aspect, a disclosed nucleic acid sequence encoding SLC25A4 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:03. In an aspect, a disclosed nucleic acid sequence encoding SLC25A4 can comprise a fragment or a portion of the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81.

[0085] In an aspect, a disclosed nucleic acid sequence encoding SLC25A4 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:05. In an aspect, a disclosed nucleic acid sequence encoding SLC2A4 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:29. In an aspect, a disclosed nucleic acid sequence encoding SLC4A3 can comprisea fragment or portion of the sequence set forth in SEQ ID NO:30 or SEQ ID NO: 31. In an aspect, a disclosed nucleic acid sequence encoding SLC8A1 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:32. In an aspect, a disclosed nucleic acid sequence encoding SLC16A1 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:33. In an aspect, a disclosed nucleic acid sequence encoding SLC22A5 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:34. In an aspect, a disclosed nucleic acid sequence encoding SLC25A1 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37. In an aspect, a disclosed nucleic acid sequence encoding SLC25A3 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:38 or SEQ ID NO:39. In an aspect, a disclosed nucleic acid sequence encoding SLC25A20 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:40.

[0086] In an aspect, a disclosed nucleic acid sequence encoding SLC2A4 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:03. In an aspect, a disclosed nucleic acid sequence encoding SLC2A4 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81.

[0087] In an aspect, a disclosed nucleic acid sequence encoding SLC2A4 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO: 05. In an aspect, a disclosed nucleic acid sequence encoding SLC2A4 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:29. In an aspect, a disclosed nucleic acid sequence encoding SLC4A3 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:30 or SEQ ID NO:31. In an aspect, a disclosed nucleic acid sequence encoding SLC8A1 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:32. In an aspect, a disclosed nucleic acid sequence encoding SLC16A1 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:33. In an aspect, a disclosed nucleic acid sequence encoding SLC22A5 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:34. In an aspect, a disclosed nucleic acid sequence encoding SLC25A1 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or morethan 95% identity to the sequence set forth in SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37. In an aspect, a disclosed nucleic acid sequence encoding SLC25A3 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:38 or SEQ ID NO:39. In an aspect, a disclosed nucleic acid sequence encoding SLC25A20 can comprise the sequence set forth in SEQ ID NO:40.

[0088] Disclosed herein is a nucleic acid molecule comprising a nucleic acid sequence encoding a disclosed SLC protein operably linked to a promoter and / or enhancer. In an aspect, a disclosed nucleic acid molecule can comprise a promoter operably linked to a disclosed nucleic acid encoding a disclosed SLC protein. In an aspect, a disclosed nucleic acid sequence can be operably linked to a promoter. In an aspect, a disclosed promoter can comprise any promoter known to the art including, for example, a MHCK7 minimal promoter or alternate MHCK7 minimal promoter, a CK8 minimal promoter, a muscle creatine kinase (MCK) minimal promoter, a desmin (DES) minimal promoter, a cardiac Troponin T (cTnT) minimal promoter, a cardiac Troponin I (cTnl) minimal promoter, an alpha myosin heavy chain (aMHC) minimal promoter, or a SPc5-12 minimal promoter. Minimal promoters are known to the art.

[0089] In an aspect, a disclosed promoter can comprise a ubiquitous promoter, a constitutive promoter, or a tissue specific promoter. In an aspect, a disclosed promoter can be native or foreign and can be a natural or a synthetic sequence. By foreign, it is intended that the transcriptional initiation region is not found in the wild-type host into which the transcriptional initiation region is introduced. In an aspect, a disclosed promoter can be a promoter / enhancer. In an aspect, a disclosed promoter for one or more disclosed nucleic acid sequences can be an endogenous promoter. In an aspect, a disclosed endogenous promoter can be an endogenous promoter / enhancer. In an aspect, a disclosed endogenous promoter or a disclosed endogenous promoter / enhancer can generally be obtained from a non-coding region upstream of a transcription initiation site of a gene of interest. In an aspect, a disclosed endogenous promoter or a disclosed endogenous promoter / enhancer can be used for constitutive and efficient expression of a disclosed gene or a disclosed nucleic acid sequence.

[0090] In an aspect, a disclosed promoter can comprise a promoter that targets cardiac cells and / or cardiac tissue. In an aspect, a disclosed promoter can comprise a promoter that targets muscle cells and / or muscle tissue. In an aspect, a disclosed promoter can comprise a promoter that targets muscle cells and / or cardiac cells and / or muscle tissue and / or cardiac tissue. In an aspect, a disclosed tissue-specific promoter can be a promoter that demonstrates a preference or a tropism for cardiac tissue and / or cardiac cell types. In an aspect, a disclosed tissue-specific promoter can be a promoter that demonstrates a preference or a tropism for muscle and / or muscle cell types.

[0091] In an aspect, a disclosed promoter can comprise the sequence set forth in any one of SEQ ID NO: 10 - SEQ ID NO: 18. In an aspect, a disclosed promoter can comprise a fragment or a portion of the sequence set forth in any one of SEQ ID NO: 10 - SEQ ID NO: 18. In an aspect, a disclosed promoter can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO: 10 - SEQ ID NO: 18. In an aspect, a disclosed promoter can comprise the sequence set forth in SEQ ID NO: 10. In an aspect, a disclosed promoter can comprise a promoter listed in Table 2. In an aspect, a disclosed promoter can comprise a fragment or a portion of a promoter listed in Table 2. In an aspect, a disclosed promoter can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to a sequence listed in Table 2. In an aspect, a disclosed promoter can comprise a MHCK7 promoter.

[0092] In an aspect, a disclosed tissue-specific promoter can be a promoter that demonstrates a preference or a tropism for cardiac tissue and / or cardiac cell types and / or muscle tissue and / or muscle cell types. In an aspect, a disclosed promoter and / or a disclosed enhancer can drive supraphysiologic expression of a disclosed SLC protein in a subject’s heart and / or a subject’s skeletal muscle. In an aspect, a disclosed promoter and / or a disclosed enhancer can restore normal SLC protein content in a subject’s heart and / or skeletal muscle. In an aspect, restoration of SLC protein content can improve a subject’s muscle strength. In an aspect, the SLC protein can be SLC25A4.Table 2 - Cardiac and Cardiac / Musculoskeletal Tropic Promoters

[0093] In an aspect, a disclosed nucleic acid sequence can comprise the sequence for a disclosed solute carrier (SLC) protein and the sequence for a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, or SLC25A20 and the sequence for a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and the sequence for a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and the sequence for a MHCK7, wherein SLC25A4 comprises the sequence set forth in SEQ ID NO: 03 or SEQ ID NO: 05.

[0094] In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and the sequence for a MHCK7, wherein SLC25A4 comprises the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81.

[0095] In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and the sequence for a MHCK7 promoter or alternate MHCK7 promoter, a CK8 promoter, a muscle creatine kinase (MCK) promoter, a desmin (DES) promoter, a cardiac Troponin T (cTnT) promoter, a cardiac Troponin I (cTnl) promoter, an alpha myosin heavy chain (aMHC) promoter, or a SPc5-12 promoter. In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and the sequence for a MHCK7 minimal promoter or alternate MHCK7 minimal promoter, a CK8 minimal promoter, a muscle creatine kinase (MCK) minimal promoter, a desmin (DES) minimal promoter, a cardiac Troponin T (cTnT) minimal promoter, a cardiac Troponin I (cTnl) minimal promoter, an alpha myosin heavy chain (aMHC) minimal promoter, or a SPc5-12 minimal promoter. Minimal promoters are known to the art.

[0096] In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and a promoter comprising the sequence set forth in any one of SEQ ID NO: 10 - SEQ ID NO: 18. In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and a promoter comprising a portion or a fragment of the sequence set forth in any one of SEQ ID NO: 10 - SEQ ID NO: 18. In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and a promoter comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO: 10 - SEQ ID NO: 18.

[0097] In an aspect, a disclosed nucleic acid sequence can comprise the sequence for a disclosed solute carrier (SLC) protein and the sequence for a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, or SLC25A20 and the sequence for a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and the sequence for a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and the sequence for a MHCK7, wherein SLC25A4 comprises the sequence set forth in SEQ ID NO:03 or SEQ ID NO:05. In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and the sequence for a MHCK7, wherein SLC25A4 comprises the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81. In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and the sequence for a MHCK7 or alternate MHCK7 promoter, a CK8 promoter, a muscle creatine kinase (MCK) promoter, a desmin (DES) promoter, a cardiac Troponin T (cTnT) promoter, a cardiacTroponin I (cTnl) promoter, an alpha myosin heavy chain (aMHC) promoter, or a SPc5-12 promoter.

[0098] In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and a promoter comprising the sequence set forth in any one of SEQ ID NO: 10 - SEQ ID NO: 18. In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and a promoter comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO: 10 - SEQ ID NO: 18. In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and a promoter comprising a portion or a fragment of the sequence set forth in any one of SEQ ID NO: 10 - SEQ ID NO: 18.

[0099] In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and the sequence for a MHCK7. In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4, wherein SLC25A4 comprises the sequence set forth in SEQ ID NO:03 or SEQ ID NO:05, and the sequence for a MHCK7, wherein the MHCK7 comprises the sequence set forth in SEQ ID NO: 10 or SEQ ID NO: 11. In an aspect, a disclosed nucleic acid sequence can comprise (i) the sequence set forth in SEQ ID NO:03 or SEQ ID NO:05, and (ii) the sequence set forth in SEQ ID NO: 10 or SEQ ID NO: 11. In an aspect, a disclosed nucleic acid sequence can comprise (i) the sequence set forth in SEQ ID NO: 03, and (ii) the sequence set forth in SEQ ID NO: 10.

[0100] In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4 and the sequence for a MHCK7. In an aspect, a disclosed nucleic acid sequence can comprise the sequence for SLC25A4, wherein SLC25A4 comprises the sequence set forth in SEQ ID NO:79, SEQ ID NO: 80, or SEQ ID NO:81, and the sequence for a MHCK7, wherein the MHCK7 comprises the sequence set forth in SEQ ID NO: 10 or SEQ ID NO: 11. In an aspect, a disclosed nucleic acid sequence can comprise (i) the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81, and (ii) the sequence set forth in SEQ ID NO: 10 or SEQ ID NO: 11. In an aspect, a disclosed nucleic acid sequence can comprise (i) the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81, and (ii) the sequence set forth in SEQ ID NO: 10.

[0101] In an aspect, a disclosed nucleic acid sequence can comprise (i) the sequence for a disclosed solute carrier (SLC) protein, and (ii) the sequence for a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise (i) a disclosed solute carrier (SLC) protein comprising the sequence set forth in SEQ ID NO:03 or SEQ ID NO:05, and (ii) the sequence for a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise (i) a disclosed solute carrier (SLC) protein comprising a portion or a fragment of the sequence set forth in SEQ ID NO:03 or SEQ ID NO:05, and (ii) the sequence for a disclosed promoter. In an aspect, adisclosed nucleic acid sequence can comprise (i) a disclosed solute carrier (SLC) protein comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO: 03 or SEQ ID NO:05, and (ii) a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise (i) a disclosed solute carrier (SLC) protein comprising the sequence set forth in SEQ ID NO:03 or SEQ ID NO:05, and (ii) the sequence for a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise (i) a disclosed solute carrier (SLC) protein comprising a portion or a fragment of the sequence set forth in SEQ ID NO:03 or SEQ ID NO:05, and (ii) the sequence for a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise (i) a disclosed solute carrier (SLC) protein comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:03 or SEQ ID NO:05, and (ii) a disclosed promoter.

[0102] In an aspect, a disclosed nucleic acid sequence can comprise (i) the sequence for a disclosed solute carrier (SLC) protein, and (ii) the sequence for a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise (i) a disclosed solute carrier (SLC) protein comprising the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81, and (ii) the sequence for a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise (i) a disclosed solute carrier (SLC) protein comprising a portion or a fragment of the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81, and (ii) the sequence for a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise (i) a disclosed solute carrier (SLC) protein comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81, and (ii) a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise (i) a disclosed solute carrier (SLC) protein comprising the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81, and (ii) the sequence for a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise (i) a disclosed solute carrier (SLC) protein comprising a portion or a fragment of the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81, and (ii) the sequence for a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise (i) a disclosed solute carrier (SLC) protein comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81, and (ii) a disclosed promoter.

[0103] In an aspect, a disclosed nucleic acid sequence can comprise (i) a disclosed solute carrier (SLC) protein comprising the sequence set forth in any one of SEQ ID NO:29 - SEQ ID NO:40, and (ii) a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise (i) adisclosed solute carrier (SLC) protein comprising a portion or a fragment of the sequence set forth in any one of SEQ ID NO:29 - SEQ ID NO:40, and (ii) a disclosed promoter. In an aspect, a disclosed nucleic acid sequence can comprise (i) a disclosed solute carrier (SLC) protein comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:29 - SEQ ID NO:40, and (ii) a disclosed promoter.

[0104] In an aspect, a disclosed nucleic acid sequence can comprise (i) a solute carrier (SLC) protein comprising the sequence set forth in SEQ ID NO:03, and (ii) a promoter comprising the sequence set forth in SEQ ID NO: 10. In an aspect, a disclosed nucleic acid sequence can comprise (i) a solute carrier (SLC) protein comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:03, and (ii) a promoter comprising the sequence set forth in SEQ ID NO: 10. In an aspect, a disclosed nucleic acid sequence can comprise (i) a solute carrier (SLC) protein comprising a fragment or a portion of the sequence set forth in SEQ ID NO:03, and (ii) a promoter comprising the sequence set forth in SEQ ID NO: 10. In an aspect, a disclosed nucleic acid sequence can comprise (i) a solute carrier (SLC) protein comprising the sequence set forth in any one of SEQ ID NO:29 - SEQ ID NO:40, and (ii) a promoter comprising the sequence set forth in SEQ ID NO: 10. In an aspect, a disclosed nucleic acid sequence can comprise (i) a solute carrier (SLC) protein comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:29 - SEQ ID NO:40, and (ii) a promoter comprising the sequence set forth in SEQ ID NO: 10. In an aspect, a disclosed nucleic acid sequence can comprise (i) a disclosed solute carrier (SLC) protein comprising a portion or a fragment of the sequence set forth in any one of SEQ ID NO:29 - SEQ ID NO:40, and (ii) a promoter comprising the sequence set forth in SEQ ID NO: 10.

[0105] In an aspect, a disclosed nucleic acid sequence can comprise (i) a solute carrier (SLC) protein comprising the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81, and (ii) a promoter comprising the sequence set forth in SEQ ID NO: 10. In an aspect, a disclosed nucleic acid sequence can comprise (i) a solute carrier (SLC) protein comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81, and (ii) a promoter comprising the sequence set forth in SEQ ID NO: 10. In an aspect, a disclosed nucleic acid sequence can comprise (i) a solute carrier (SLC) protein comprising a fragment or a portion of the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81, and (ii) a promoter comprising the sequence set forth in SEQ ID NO: 10. In an aspect, a disclosed nucleic acid sequence can comprise (i) a solute carrier (SLC) protein comprising the sequence set forth inany one of SEQ ID NO:29 - SEQ ID NO:40, and (ii) a promoter comprising the sequence set forth in SEQ ID NO: 10. .

[0106] In an aspect, a disclosed nucleic acid sequence can comprise (i) a solute carrier (SLC) protein comprising the sequence set forth in SEQ ID NO:05, and (ii) a promoter comprising the sequence set forth in SEQ ID NO: 10. In an aspect, a disclosed nucleic acid sequence can comprise (i) a solute carrier (SLC) protein comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:05, and (ii) a promoter comprising the sequence set forth in SEQ ID NO: 10. In an aspect, a disclosed nucleic acid sequence can comprise (i) a solute carrier (SLC) protein comprising a fragment or a portion of the sequence set forth in SEQ ID NO:05, and (ii) a promoter comprising the sequence set forth in SEQ ID NO: 10.

[0107] In an aspect, a disclosed nucleic acid sequence can comprise (i) a solute carrier (SLC) protein comprising the sequence set forth in any one of SEQ ID NO:29 - SEQ ID NO:40, and (ii) a promoter comprising the sequence set forth in any one of SEQ ID NO: 10 - SEQ ID NO: 18.

[0108] In an aspect, a disclosed nucleic acid sequence can comprise (i) a solute carrier (SLC) protein comprising a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO:29 - SEQ ID NO:40, and (ii) a promoter comprising the sequence set forth in any one of SEQ ID NO: 10 - SEQ ID NO: 18. In an aspect, a disclosed nucleic acid sequence can comprise (i) a disclosed solute carrier (SLC) protein comprising a portion or a fragment of the sequence set forth in any one of SEQ ID NO:29 - SEQ ID NO:40, and (ii) a promoter comprising the sequence set forth any one of SEQ ID NO: 10 - SEQ ID NO: 18.

[0109] In an aspect, a disclosed nucleic acid molecule can comprise a human skeletal musclespecific transcriptional cis-regulatory module. In an aspect, a disclosed hybrid promoter can comprise a human skeletal muscle-specific enhancer. In an aspect, a disclosed human skeletal muscle-specific transcriptional cis-regulatory module or enhancer can comprise Sk-CRM4. In an aspect, a disclosed Sk-CRM4 can comprise the sequence set forth in SEQ ID NO: 19 or SEQ ID NO:2. In an aspect, a disclosed Sk-CRM4 can comprise a fragment of the sequence set forth in SEQ ID NO: 19 or SEQ ID NO:20. In an aspect, a disclosed Sk-CRM4 can comprise a sequence having at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or more than at least 95% identity to the sequence set forth in SEQ ID NO: 19 or SEQ ID NO:20.

[0110] In an aspect, a disclosed nucleic acid sequence can comprise one or more invented terminal repeats (ITRs). ITRs are known to the skilled person. In an aspect, a disclosed ITR can comprise the sequence of SEQ ID NO:08 or SEQ ID NO:09. In an aspect, a disclosed nucleic acid sequencecan comprise an ITR comprising the sequence of SEQ ID NO:08 and an ITR comprising the sequence of SEQ ID NO:09. In an aspect, a disclosed nucleic acid sequence can comprise a HA tag. HA tags are known to the skilled person in the art. In an aspect, a disclosed HA tag can comprise the sequence set forth in SEQ ID NO:07.

[0111] In an aspect, a disclosed nucleic acid molecule can comprise a nucleotide sequence encoding a signal peptide that is cleaved during post-translation processing. In an aspect, a disclosed nucleic acid molecule can comprise a nucleotide sequence encoding a signal peptide that is not cleaved during post-translation processing. In an aspect, a disclosed encoded signal peptide can comprise the sequence set forth in any one of SEQ ID NO:74 - SEQ ID NO:78. In an aspect, a disclosed nucleotide sequence encoding a signal peptide can comprise the sequence set forth in SEQ ID NO: 72 or SEQ ID NO: 73.

[0112] In an aspect, a disclosed encoded signal / leader peptide can be the signal / leader peptide of Human Oncostatin (OSM), Human IgKV III, Human Chymotrypsinogen, Human Trypsinogen- 2, Human Insulin, Human IL-2, Human BM40 (osteonectin SPARC), Human Serum Albumin, Human Tissue Plasminogen Activator, Secrecon, CD33, Vesicular stomatitis virus G protein (VSV-G), Gaussia luc, Influenza Haemagglutinin, Silkworm Fibroin LC, Mouse Ig Kappa, or Mouse Ig Heavy.Table 3 - Loss-of-Function Mutations in SLC25A4 Resulting in Disease Phenotype

[0113] In an aspect, a disclosed nucleic acid molecule can comprise a CpG-free sequence. In an aspect, “CpG-free” can mean completely free of CpGs or partially free of CpGs. In an aspect, “CpG-free” can mean “CpG-depleted”. In an aspect, “CpG-depleted” can mean “CpG-free”. In an aspect, “CpG-depleted” can mean completely depleted of CpGs or partially depleted of CpGs.In an aspect, “CpG-free” can mean “CpG-optimized” for a desired and / or ideal expression level. CpG depletion and / or optimization is known to the skilled person in the art.

[0114] In an aspect, a disclosed nucleic acid molecule can comprise the sequence for one or more regulatory elements. In an aspect, a disclosed regulatory element can comprise promoters, enhancers, internal ribosomal entry sites (IRES), and other expression control elements (e.g., transcription termination signals, such as polyadenylation signals and poly-U sequences). Regulatory elements can include those that direct constitutive expression of a nucleotide sequence in many types of host cells and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). In an aspect, a disclosed regulatory element can comprise Woodchuck Hepatitis Virus (WHV) Posttranscriptional Regulator Element (WPRE), triplex from MALAT1, the PRE of Hepatitis B virus (HPRE), an iron response element, or any combination thereof. For example, a disclosed regulatory element can comprise a promoter operably linked to a disclosed nucleic acid molecule, wherein the promoter drives the expression of a disclosed encoded SLC protein (e.g., SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, or SLC25A20).

[0115] In an aspect, a disclosed nucleic acid molecule can be encapsulated in lipid nanoparticles. In an aspect, lipid nanoparticles or LNPs can deliver nucleic acid (e.g., DNA or RNA), protein (e.g., RNA-guided DNA binding agent), or nucleic acid together with protein. LNPs can comprise biodegradable, ionizable lipids. For example, LNPs can comprise (9Z,12Z)-3-((4,4- bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl octadeca-9,12-di enoate, also called 3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl (9Z, 12Z)-octadeca-9, 12-di enoate) or another ionizable lipid. In an aspect, the term cationic and ionizable in the context of LNP lipids can be used interchangeably, e.g., wherein ionizable lipids are cationic depending on the pH.

[0116] Disclosed herein is an expression cassette comprising a disclosed nucleic acid operably linked to a disclosed promoter. Disclosed herein is an expression cassette comprising (i) a disclosed nucleic acid operably linked to a disclosed promoter and (ii) one or more disclosed regulatory elements. Disclosed herein is an expression cassette comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a solute carrier (SLC) protein or fragment thereof. In an aspect, a disclosed solute carrier (SLC) protein can comprise SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, or SLC25A20. In an aspect, a disclosed solute carrier protein can comprise any SLC protein identified in Table 1. In an aspect, a disclosed solute carrier protein can comprise SLC25A4. In an aspect, a deficiency of a disclosed SLC protein can result in cardiac and / or skeleton-muscular dysfunction.

[0117] Disclosed herein is an expression cassette comprising (i) a nucleic acid sequence encoding SLC25A4 and comprising the sequence set forth in SEQ ID NO:03; (ii) a nucleic acid sequence encoding SLC25A4 and comprising the sequence set forth in SEQ ID NO:05; (iii) a nucleic acid sequence encoding SLC2A4 and comprising the sequence set forth in SEQ ID NO:29; (iv) a nucleic acid sequence encoding SLC4A3 and comprising the sequence set forth in SEQ ID NO:30 or SEQ ID NO:31; (v) a nucleic acid sequence encoding SLC8A1 and comprising the sequence set forth in SEQ ID NO:32; (vi) a nucleic acid sequence encoding SLC16A1 and comprising the sequence set forth in SEQ ID NO:33; (vii) a nucleic acid sequence encoding SLC22A5 and and comprising the sequence set forth in SEQ ID NO:34; (viii) a nucleic acid sequence encoding SLC25A1 and comprising the sequence set forth in SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37; (ix) a nucleic acid sequence encoding SLC25A3 and comprising the sequence set forth in SEQ ID NO:38 or SEQ ID NO: 39; or (x) a nucleic acid sequence encoding SLC25A20 and comprising the sequence set forth in SEQ ID NO:40; wherein the nucleic acid sequence is operably linked to a disclosed promoter.

[0118] Disclosed herein is an expression cassette comprising a nucleic acid sequence encoding SLC25A4 and comprising the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81, wherein the nucleic acid sequence is operably linked to a disclosed promoter.

[0119] Disclosed herein is an expression cassette comprising (i) a nucleic acid sequence encoding SLC25A4 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:03; (ii) a nucleic acid sequence encoding SLC25A4 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:05; (iii) a nucleic acid sequence encoding SLC2A4 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:29; (iv) a nucleic acid sequence encoding SLC4A3 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:30 or SEQ ID NO:31; (v) a nucleic acid sequence encoding SLC8A1 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:32; (vi) a nucleic acid sequence encoding SLC16A1 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:33; (vii) a nucleic acid sequence encoding SLC22A5 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:34; (viii) a nucleic acid sequence encoding SLC25A1 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37; (ix) a nucleic acid sequence encoding SLC25A3 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:38 or SEQ ID NO:39; or (x) a nucleic acid sequence encoding SLC25A20 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:40; wherein the nucleic acid sequence is operably linked to a disclosed promoter.

[0120] Disclosed herein is an expression cassette comprising a nucleic acid sequence encoding SLC25A4 and comprising a fragment or portion of the sequence set forth in SEQ ID NO:79, SEQID NO:80, or SEQ ID NO:81; wherein the nucleic acid sequence is operably linked to a disclosed promoter.

[0121] Disclosed herein is an expression cassette comprising (i) a nucleic acid sequence encoding SLC2A4 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO: 03; (ii) a nucleic acid sequence encoding SLC2A4 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:05; (iii) a nucleic acid sequence encoding SLC2A4 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:29; (iv) a nucleic acid sequence encoding SLC4A3 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:30 or SEQ ID NO:31; (v) a nucleic acid sequence encoding SLC8A1 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:32; (vi) a nucleic acid sequence encoding SLC16A1 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:33; (vii) a nucleic acid sequence encoding SLC22A5 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:34; (viii) a nucleic acid sequence encoding SLC25A1 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37; (ix) a nucleic acid sequence encoding SLC25A3 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:38 or SEQ ID NO:39; or (x) a nucleic acid sequence encoding SLC25A20 can comprise the sequence set forth in SEQ ID NO:40; wherein the nucleic acid sequence is operably linked to a disclosed promoter.

[0122] Disclosed herein is an expression cassette comprising (i) a nucleic acid sequence encoding SLC2A4 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81; wherein the nucleic acid sequence is operably linked to a disclosed promoter.

[0123] In an aspect of a disclosed expression cassette, a disclosed nucleic acid sequence can be operably linked to a promoter. In an aspect, a disclosed promoter can comprise any promoter known to the art including, for example, a MHCK7 minimal promoter or alternate MHCK7minimal promoter, a CK8 minimal promoter, a muscle creatine kinase (MCK) minimal promoter, a desmin (DES) minimal promoter, a cardiac Troponin T (cTnT) minimal promoter, a cardiac Troponin I (cTnl) minimal promoter, an alpha myosin heavy chain (aMHC) minimal promoter, or a SPc5-12 minimal promoter. Minimal promoters are known to the art.

[0124] In an aspect, a disclosed expression cassette can comprise a human skeletal musclespecific transcriptional cis-regulatory module. In an aspect, a disclosed hybrid promoter can comprise a human skeletal muscle-specific enhancer. In an aspect, a disclosed human skeletal muscle-specific transcriptional cis-regulatory module or enhancer can comprise Sk-CRM4. In an aspect, a disclosed Sk-CRM4 can comprise the sequence set forth in SEQ ID NO: 19 or SEQ ID NO:2. In an aspect, a disclosed Sk-CRM4 can comprise a fragment of the sequence set forth in SEQ ID NO: 19 or SEQ ID NO:20. In an aspect, a disclosed Sk-CRM4 can comprise a sequence having at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or more than at least 95% identity to the sequence set forth in SEQ ID NO: 19 or SEQ ID NO:20.

[0125] In an aspect, a disclosed regulatory element can comprise promoters, enhancers, internal ribosomal entry sites (IRES), and other expression control elements (e.g., transcription termination signals, such as polyadenylation signals and poly-U sequences). Regulatory elements can include those that direct constitutive expression of a nucleotide sequence in many types of host cells and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). In an aspect, a disclosed regulatory element can comprise Woodchuck Hepatitis Virus (WHV) Posttranscriptional Regulator Element (WPRE), triplex from MALAT1, the PRE of Hepatitis B virus (HPRE), an iron response element, or any combination thereof. For example, a disclosed regulatory element can comprise a promoter operably linked to a disclosed nucleic acid molecule, wherein the promoter drives the expression of a disclosed encoded SLC protein (e.g., SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, or SLC25A20).

[0126] In an aspect, a disclosed nucleic acid sequence can generate expression of a SLC protein in one or more tissues including, for example, cardiac tissue and / or skeletal muscle tissue. In an aspect, the SLC protein can be SLC25A4. In an aspect, a disclosed nucleic acid sequence can generate a cellular depot or reservoir of a disclosed SLC protein in one or more tissues including, for example, cardiac tissue and / or skeletal muscle tissue. In an aspect, the SLC protein can be SLC25A4.

[0127] In an aspect, a disclosed SLC protein can restore one or more aspects of cellular homeostasis and / or cellular functionality. In an aspect, when expressed in a cell, a disclosed nucleic acid sequence can generate a SLC protein that can restore one or more aspects of cellularhomeostasis and / or cellular functionality. In an aspect, a disclosed restoration of one or more aspects of cellular homeostasis and / or cellular functionality can comprise (i) restoring myocyte bioenergetics in the subject; (ii) normalizing tissue biomarkers in the subject; (iii) normalizing mitochondrial copy number in the subject’s heart and / or skeletal muscle; (iv) improving and / or restoring of mitochondrial functionality and / or structural integrity; (v) improving and / or restoring of organelle functionality and / or structural integrity; (vi) improving mitochondrial ADT-ATP exchange; (vii) increasing ADP-stimulated tissue respirations rates, (viii) decreasing production of mitochondrial reactive oxygen species; or (ix) any combination thereof. In an aspect, the SLC protein can be SLC25A4.

[0128] In an aspect, a disclosed restoration of one or more aspects of cellular homeostasis and / or cellular functionality can comprise correction and / or mitigation of one or more presenting symptoms associated with one or more symptoms of a SLC deficiency. In an aspect, the SLC protein can be SLC25A4.

[0129] In an aspect, the expression of a disclosed SLC protein that can restore one or more aspects of the subject’s cardiac function and / or cardiac health. In an aspect, a disclosed SLC protein can (i) reverse cardiac remodeling in the subject; (ii) prevent cardiac remodeling in the subject; (iii) restore the cardiac dimensions to normal levels (i.e., the levels of a subject not having a disclosed SLC deficiency); (iv) improve the exercise capacity of the subject; (v) improve contractile mechanics; or (vi) any combination thereof. In an aspect, expression of a disclosed SLC protein can (i) reverse cardiac remodeling in the subject; (ii) prevent cardiac remodeling in the subject; (iii) restore the cardiac dimensions of the subject to a normal level; (iv) improve the exercise capacity of the subject; (v) improve cardiac contractile mechanics of the subject; (vi) restore myocyte bioenergetics in the subject; (vii) decrease production of mitochondrial reactive oxygen species in the heart or skeletal muscle of the subject; (viii) restore myocyte bioenergetics in the subject; (ix) improve mitochondrial ADT-ATP exchange in the subject; (x) increase ADP- stimulated tissue respirations rates; (xi) correct and / or reversing hyperlactinemia and hyperalanemia; (xii) correct and / or normalize plasma biomarkers lactate and alanine; or (xiii) any combination thereof. In an aspect, the SLC protein can be SLC25A4. In an aspect, the SLC protein can be SLC25A4. In an aspect, the expression of a disclosed SLC protein can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, the SLC protein can be SLC25A4.

[0130] In an aspect, the expression of a disclosed SLC protein can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, can diminish and / or ameliorate one or more symptoms of a disease or conditioncaused by one or more loss of functions in a SLC gene (i.e., SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, SLC25A20, or any combination thereof). In an aspect, the SLC protein can be SLC25A4.

[0131] In an aspect, the expression of a disclosed SLC protein can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, can diminish and / or ameliorate one or more symptoms of a disease or condition caused by one or more loss of functions in a SLC25A4 gene (e.g., c.523delC, c. H6_137del, c.707G>C, c.46_47del, c.111+1G>A, or c.423G>C, or any combination thereof). Representative mutations in SLC25A4 are listed in Table 3. In an aspect, the SLC protein can be SLC25A4.

[0132] In an aspect, the expression of a disclosed SLC protein can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, can diminish and / or ameliorate one or more symptoms of a disease or condition caused by one or more loss of functions in a SLC25A4 gene (e.g., c.523delC, c. H6_137del, c.707G>C, c.46_47del, c. l l l+lG>A, or c.423G>C, or any combination thereof). In an aspect, the SLC protein can be SLC25A4.

[0133] In an aspect, when expressed in a cell, a disclosed nucleic acid sequence can generate a SLC protein that can restore one or more aspects of cellular homeostasis and / or cellular functionality. In an aspect, a disclosed restoration of one or more aspects of cellular homeostasis and / or cellular functionality can comprise (i) restoring myocyte bioenergetics in the subject; (ii) normalizing tissue biomarkers in the subject; (iii) normalizing mitochondrial copy number in the subject’s heart and / or skeletal muscle; (iv) improving and / or restoring of mitochondrial functionality and / or structural integrity; (v) improving and / or restoring of organelle functionality and / or structural integrity; (vi) improving mitochondrial ADT-ATP exchange; (vii) increasing ADP-stimulated tissue respirations rates, (viii) decreasing production of mitochondrial reactive oxygen species; or (ix) any combination thereof. In an aspect, the SLC protein can be SLC25A4.

[0134] In an aspect, a disclosed restoration of one or more aspects of cellular homeostasis and / or cellular functionality can comprise correction and / or mitigation of one or more presenting symptoms associated with one or more symptoms of a SLC deficiency. In an aspect, the SLC protein can be SLC25A4.

[0135] In an aspect, the expression of a disclosed SLC protein that can restore one or more aspects of the subject’s cardiac function and / or cardiac health. In an aspect, a disclosed SLC protein can (i) reverse cardiac remodeling in the subject; (ii) prevent cardiac remodeling in the subject; (iii) restore the cardiac dimensions to normal levels (i.e., the levels of a subject not having a disclosed SLC deficiency); (iv) improve the exercise capacity of the subject; (v) improve contractile mechanics; or (vi) any combination thereof. In an aspect, the expression of a disclosed SLCprotein can (i) reverse cardiac remodeling in the subject; (ii) prevent cardiac remodeling in the subject; (iii) restore the cardiac dimensions of the subject to a normal level; (iv) improve the exercise capacity of the subject; (v) improve cardiac contractile mechanics of the subject; (vi) restore myocyte bioenergetics in the subject; (vii) decrease production of mitochondrial reactive oxygen species in the heart or skeletal muscle of the subject; (viii) restore myocyte bioenergetics in the subject; (ix) improve mitochondrial ADT-ATP exchange in the subject; (x) increase ADP- stimulated tissue respirations rates; (xi) correct and / or reversing hyperlactinemia and hyperalanemia; (xii) correct and / or normalize plasma biomarkers lactate and alanine; or (xiii) any combination thereof. In an aspect, the SLC protein can be SLC25A4. In an aspect, an improvement in one or more symptoms of a SLC protein deficiency can be subjective and / or objective. In an aspect, an improvement in one or more symptoms of an a SLC protein deficiency can improve a subject’s motor skills. In an aspect, an improvement in one or more symptoms of a SLC protein deficiency can improve a subject’s quality of life.

[0136] In an aspect, a disclosed expression can be incorporated into a disclosed viral vector or disclosed non-viral vector.2. Vectors and Plasmids

[0137] Disclosed herein is a vector comprising a disclosed nucleic acid molecule. Disclosed herein is a plasmid comprising a disclosed nucleic acid molecule. Disclosed herein is a vector comprising one or more disclosed nucleic acid molecules. Disclosed herein is a plasmid comprising one or more disclosed nucleic acid molecules.

[0138] Disclosed herein is a vector comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a solute carrier (SLC) protein. In an aspect, a disclosed solute carrier (SLC) protein can comprise SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, or SLC25A20. In an aspect, a disclosed solute carrier protein can comprise any SLC protein identified in Table 1. In an aspect of a disclosed vector, a disclosed solute carrier protein can comprise SLC25A4. In an aspect of a disclosed vector, a deficiency of a disclosed SLC protein can result in cardiac and / or skeleton-muscular dysfunction.

[0139] Disclosed herein is an AAV vector comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a solute carrier (SLC) protein, wherein the AAV vector comprises a capsid protein designed to diminish an immune response, wherein the capsid protein comprises the sequence set forth in SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84 or SEQ ID NO:85. In an aspect, a disclosed solute carrier (SLC) protein can comprise SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, or SLC25A20. In an aspect, a disclosed solute carrier protein can comprise any SLC protein identified in Table 1. In an aspect of a disclosed vector, a disclosed solute carrier protein can comprise SLC25A4. In an aspect of adisclosed vector, a deficiency of a disclosed SLC protein can result in cardiac and / or skeleton- muscular dysfunction.

[0140] In an aspect of a disclosed vector, a disclosed encoded SLC25A4 can comprise the amino acid sequence set forth in SEQ ID NO:06. In an aspect of a disclosed vector, a disclosed encoded SLC2A4 can comprise the amino acid sequence set forth in SEQ ID NO:41. In an aspect of a disclosed vector, a disclosed encoded SLC4A3 can comprise the amino acid sequence set forth in SEQ ID NO:42 or SEQ ID NO:43. In an aspect of a disclosed vector, a disclosed encoded SLC8A1 can comprise the amino acid sequence set forth in SEQ ID NO:44. In an aspect of a disclosed vector, a disclosed encoded SLC16A1 can comprise the amino acid sequence set forth in SEQ ID NO:45. In an aspect of a disclosed vector, a disclosed encoded SLC22A5 can comprise the amino acid sequence set forth in SEQ ID NO:46. In an aspect of a disclosed vector, a disclosed encoded SLC25A1 can comprise the amino acid sequence set forth in SEQ ID NO:47, SEQ ID NO:48, or SEQ ID NO:49. In an aspect of a disclosed vector, a disclosed encoded SLC25A3 can comprise the amino acid sequence set forth in SEQ ID NO:50 or SEQ ID N0:51. In an aspect of a disclosed vector, a disclosed encoded SLC25A20 can comprise the amino acid sequence set forth in SEQ ID NO:52.

[0141] Disclosed herein is a vector comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a fragment or portion of a solute carrier (SLC) protein. Disclosed herein is an AAV vector comprising a nucleic acid molecule encoding a fragment or portion of a solute carrier (SLC) protein, wherein the AAV vector comprises a capsid protein designed to diminish an immune response, wherein the capsid protein comprises the sequence set forth in SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84 or SEQ ID NO:85. In an aspect of a disclosed vector, a disclosed encoded SLC25A4 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:06. In an aspect of a disclosed vector t, a disclosed encoded SLC2A4 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:41. In an aspect of a disclosed vector, a disclosed encoded SLC4A3 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:42 or SEQ ID NO:43. In an aspect of a disclosed vector, a disclosed encoded SLC8A1 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:44. In an aspect of a disclosed vector, a disclosed encoded SLC16A1 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:45. In an aspect of a disclosed vector, a disclosed encoded SLC22A5 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:46. In an aspect of a disclosed vector, a disclosed encoded SLC25A1 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:47, SEQ ID NO:48, or SEQ ID NO:49. In an aspect of a disclosed vector, a disclosed encoded SLC25A3 can comprise a fragment or portion of the amino acid sequence set forth inSEQ ID NO:50 or SEQ ID NO:51. In an aspect of a disclosed vector, a disclosed encoded SLC25A20 can comprise a fragment or portion of the amino acid sequence set forth in SEQ ID NO:52.

[0142] Disclosed herein is a vector comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a solute carrier (SLC) protein or fragment thereof. In an aspect of a disclosed vector, a disclosed encoded SLC25A4 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the amino acid sequence set forth in SEQ ID NO:06. In an aspect of a disclosed vector, a disclosed encoded SLC2A4 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:41. In an aspect of a disclosed vector, a disclosed encoded SLC4A3 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:42 or SEQ ID NO:43. In an aspect of a disclosed vector, a disclosed encoded SLC8A1 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:44. In an aspect of a disclosed vector, a disclosed encoded SLC16A1 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:45. In an aspect of a disclosed vector, a disclosed encoded SLC22A5 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:46. In an aspect of a disclosed vector, a disclosed encoded SLC25A1 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:47, SEQ ID NO:48, or SEQ ID NO:49. In an aspect of a disclosed vector, a disclosed encoded SLC25A3 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:50 or SEQ ID NO:51. In an aspect of a disclosed vector, a disclosed encoded SLC25A20 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:52.

[0142] Disclosed herein is a vector comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a solute carrier (SLC) protein or fragment thereof. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC25A4 can comprise the sequence set forth in SEQ ID NO:03. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC25A4 can comprise the sequence set forth in SEQ ID NO:05. In an aspect of a disclosedvector, a disclosed nucleic acid sequence encoding SLC25A4 can comprise the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81.

[0143] In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC2A4 can comprise the sequence set forth in SEQ ID NO:29. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC4A3 can comprise the sequence set forth in SEQ ID NO:30 or SEQ ID NO:31. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC8A1 can comprise the sequence set forth in SEQ ID NO:32. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC16A1 can comprise the sequence set forth in SEQ ID NO:33. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC22A5 can comprise the sequence set forth in SEQ ID NO:34. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC25A1 can comprise the sequence set forth in SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC25A3 can comprise the sequence set forth in SEQ ID NO:38 or SEQ ID NO:39. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC25A20 can comprise the sequence set forth in SEQ ID NO:40.

[0144] Disclosed herein is a vector comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a solute carrier (SLC) protein or fragment thereof. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC25A4 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:03. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC25A4 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC25A4 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:05. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC2A4 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:29. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC4A3 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:30 or SEQ ID NO:31. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC8A1 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:32. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC16A1 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:33. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC22A5 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:34. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC25A1 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC25A3 can comprise a fragment or portion of the sequence set forth in SEQ ID NO: 38or SEQ ID NO:39. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC25A20 can comprise a fragment or portion of the sequence set forth in SEQ ID NO:40.

[0142] Disclosed herein is a vector comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a solute carrier (SLC) protein or fragment thereof. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC2A4 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:03. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC2A4 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC2A4 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:05. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC2A4 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:29. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC4A3 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:30 or SEQ ID NO:31. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC8A1 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:32. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC16A1 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:33. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC22A5 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:34. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC25A1 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:35, SEQ ID NO:36, or SEQ ID NO:37. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC25A3 can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:38 or SEQ ID NO:39. In an aspect of a disclosed vector, a disclosed nucleic acid sequence encoding SLC25A20 can comprise the sequence set forth in SEQ ID NO:40.

[0145] In an aspect of a disclosed vector, a disclosed nucleic acid sequence can be operably linked to a promoter. In an aspect, a disclosed promoter can comprise any promoter known to the art including, for example, a MHCK7 minimal promoter or alternate MHCK7 minimal promoter, a CK8 minimal promoter, a muscle creatine kinase (MCK) minimal promoter, a desmin (DES) minimal promoter, a cardiac Troponin T (cTnT) minimal promoter, a cardiac Troponin I (cTnl) minimal promoter, an alpha myosin heavy chain (aMHC) minimal promoter, or a SPc5-12 minimal promoter. Minimal promoters are known to the art.

[0146] In an aspect of a disclosed vector, a disclosed promoter can comprise a promoter that targets cardiac cells and / or cardiac tissue. In an aspect, a disclosed promoter can comprise a promoter that targets muscle cells and / or muscle tissue. In an aspect, a disclosed promoter can comprise a promoter that targets muscle cells and / or cardiac cells and / or muscle tissue and / or cardiac tissue. In an aspect, a disclosed tissue-specific promoter can be a promoter that demonstrates a preference or a tropism for cardiac tissue and / or cardiac cell types. In an aspect, a disclosed tissue-specific promoter can be a promoter that demonstrates a preference or a tropism for muscle and / or muscle cell types.

[0147] In an aspect of a disclosed vector, a disclosed promoter can comprise the sequence set forth in any one of SEQ ID NO: 10 - SEQ ID NO: 18. In an aspect, a disclosed promoter can comprise a fragment or a portion of the sequence set forth in any one of SEQ ID NO: 10 - SEQ ID NO: 18. In an aspect, a disclosed promoter can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in any one of SEQ ID NO: 10 - SEQ ID NO: 18. In an aspect, a disclosed promoter can comprise the sequence set forth in SEQ ID NO: 10.

[0148] In an aspect of a disclosed vector, a disclosed promoter can comprise a promoter listed in Table 2. In an aspect, a disclosed promoter can comprise a fragment or a portion of a promoter listed in Table 2. In an aspect, a disclosed promoter can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to a sequence listed in Table 2. In an aspect, a disclosed promoter can comprise a MHCK7 promoter.

[0149] In an aspect of a disclosed vector, a disclosed nucleic acid molecule can comprise a human skeletal muscle-specific transcriptional cis-regulatory module. In an aspect, a disclosed hybrid promoter can comprise a human skeletal muscle-specific enhancer. In an aspect, a disclosed human skeletal muscle-specific transcriptional cis-regulatory module or enhancer can comprise Sk-CRM4. In an aspect, a disclosed Sk-CRM4 can comprise the sequence set forth in SEQ ID NO: 19 or SEQ ID NO:2. In an aspect, a disclosed Sk-CRM4 can comprise a fragment of the sequence set forth in SEQ ID NO: 19 or SEQ ID NO:20. In an aspect, a disclosed Sk-CRM4 can comprise a sequence having at least about 75%, at least about 80%, at least about 85%, at leastabout 90%, at least about 95%, or more than at least 95% identity to the sequence set forth in SEQ ID NO: 19 or SEQ ID NO:20.

[0150] In an aspect of a disclosed vector, a disclosed nucleic acid molecule can comprise the sequence for one or more regulatory elements. In an aspect, a disclosed regulatory element can comprise promoters, enhancers, internal ribosomal entry sites (IRES), and other expression control elements (e.g., transcription termination signals, such as polyadenylation signals and poly- U sequences). Regulatory elements can include those that direct constitutive expression of a nucleotide sequence in many types of host cells and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). In an aspect, a disclosed regulatory element can comprise Woodchuck Hepatitis Virus (WHV) Posttranscriptional Regulator Element (WPRE), triplex from MALAT1, the PRE of Hepatitis B virus (HPRE), an iron response element, or any combination thereof. For example, a disclosed regulatory element can comprise a promoter operably linked to a disclosed nucleic acid molecule, wherein the promoter drives the expression of a disclosed encoded SLC protein (e.g., SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, or SLC25A20).

[0151] In an aspect, a disclosed vector can be a viral vector or a non-viral vector. In an aspect, a disclosed non-viral vector can be a polymer-based vector, a peptide-based vector, a lipid nanoparticle, a solid lipid nanoparticle, or a cationic lipid-based vector. In an aspect, a disclosed viral vector can be an adenovirus vector, an AAV vector, a herpes simplex virus vector, a retrovirus vector, a lentivirus vector, and alphavirus vector, a flavivirus vector, a rhabdovirus vector, a measles virus vector, a Newcastle disease viral vector, a poxvirus vector, or a picomavirus vector.

[0152] In an aspect, a disclosed viral vector can be an adeno-associated virus (AAV) vector In an aspect, a disclosed AAV vector can include naturally isolated serotypes including, but not limited to, AAV1, AAV2, AAV3 (including 3a and 3b), AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh8, AAV9, AAV10, AAVrhlO, AAV11, AAV12, AAV13, AAVrh39, AAVrh43, AAVcy.7 as well as bovine AAV, caprine AAV, canine AAV, equine AAV, ovine AAV, avian AAV, primate AAV, non-primate AAV, and any other virus classified by the International Committee on Taxonomy of Viruses (ICTV) as an AAV. In an aspect, an AAV capsid can be a chimera either created by capsid evolution or by rational capsid engineering from a naturally isolated AAV variants to capture desirable serotype features such as enhanced or specific tissue tropism and / or a host immune response escape. Naturally isolated AAV variants include, but not limited to, AAV- DJ, AAV-HAE1, AAV-HAE2, AAVM41, AAV-1829, AAV2 Y / F, AAV2 T / V, AAV2i8, AAV2.5, AAV9.45, AAV9.61, AAV-B1, AAV-AS, AAV9.45A-String (e.g., AAV9.45-AS), AAV9.45Angiopep, AAV9.47-Angiopep, and AAV9.47-AS, AAV-PHP.B, AAV-PHP.eB,AAV-PHP.S, AAV-F, MyoAAV4A, MyoAAV4E, AAV.cc47, and AAV.cc84. In an aspect, a disclosed AAV vector can be AAV-Rh74 or a related variant (e.g., capsid variants like RHM4-1). In an aspect, a disclosed AAV can comprise a wild-type capsid protein or a recombinant capsid protein. In an aspect, recombinant AAV capsid proteins can comprise the sequence set forth in any one of SEQ ID NO:54 - SEQ ID NO:71. In an aspect, recombinant AAV capsid proteins can comprise the sequence set forth in SEQ ID NO:60 or SEQ ID NO:66. In an aspect, a disclosed capsid protein of a disclosed AAV vector can comprise AAV.cc47 (SEQ ID NO:60) or AAV.cc84 (SEQ ID NO:66).

[0153] In an aspect, a disclosed capsid protein of a disclosed AAV vector can diminish and / or escape and / or evade an immune response that comprises neutralizing antibodies to the vector and / or the disclosed SLC protein and / or a fragment or a portion thereof. In an aspect, a disclosed capsid protein of a disclosed AAV vector can comprise a capsid protein having one or more substitutions or one or more mutations in the VR8 region. In an aspect, the VR8 region of a disclosed capsid protein can comprise the sequence set forth in SEQ ID NOVO, SEQ ID NO:91, SEQ ID NO:92, or SEQ ID NO:93. In an aspect, the VR8 region of a disclosed capsid protein can be encoded by the sequence set forth in SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, or SEQ ID NO:97. In an aspect, a disclosed VR8 region comprising the sequence set forth in SEQ ID NOVO can be encoded by a sequence set forth in SEQ ID NO:94. In an aspect, a disclosed VR8 region comprising the sequence set forth in SEQ ID NOVI can be encoded by a sequence set forth in SEQ ID NO:95. In an aspect, a disclosed VR8 region comprising the sequence set forth in SEQ ID NO:92 can be encoded by a sequence set forth in SEQ ID NO:96. In an aspect, a disclosed VR8 region comprising the sequence set forth in SEQ ID NO:93 can be encoded by a sequence set forth in SEQ ID NO:97. In an aspect, a disclosed capsid protein of a disclosed AAV vector can comprise the sequence set forth in SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84 or SEQ ID NO:85. In an aspect, a disclosed capsid protein can be encoding by the sequence set forth in SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88 or SEQ ID NO:89. In an aspect, a disclosed capsid protein having the sequence set forth in SEQ ID NO: 82 can be encoded by the sequence set forth in SEQ ID NO:86. In an aspect, a disclosed capsid protein having the sequence set forth in SEQ ID NO:83 can be encoded by the sequence set forth in SEQ ID NO:87. In an aspect, a disclosed capsid protein having the sequence set forth in SEQ ID NO:84 can be encoded by the sequence set forth in SEQ ID NO:88. In an aspect, a disclosed capsid protein having the sequence set forth in SEQ ID NO:86 can be encoded by the sequence set forth in SEQ ID NO:89.

[0154] In an aspect, a disclosed AAV vector can be a self-complementary AAV as disclosed herein. In an aspect, a disclosed nucleic acid sequence can have a coding sequence that is less than about 4.0 kilobases.

[0155] Disclosed herein an AAV vector comprising a nucleic acid sequence encoding SLC25A4 and a nucleic acid sequence encoding a MHCK7 promoter, wherein the disclosed AAV vector comprises a capsid protein designed to diminish an immune response, wherein the capsid protein comprises the sequence set forth in SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84 or SEQ ID NO:85.

[0156] Disclosed herein an AAV vector comprising a nucleic acid sequence encoding SLC25A4 and a nucleic acid sequence encoding a MHCK7 promoter. Disclosed herein an AAV vector comprising the nucleic acid sequence set forth in SEQ ID NO:03 and the nucleic acid sequence set forth in SEQ ID NO: 10. Disclosed herein an AAV vector comprising the nucleic acid sequence set forth in SEQ ID NO: 03 or a fragment or portion thereof and the nucleic acid sequence set forth in SEQ ID NO: 10 or a fragment or portion thereof. Disclosed herein an AAV vector comprising a nucleic acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:03 and a nucleic acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO: 10.

[0157] Disclosed herein an AAV vector comprising a nucleic acid sequence encoding SLC25A4 and a nucleic acid sequence encoding a MHCK7 promoter wherein the disclosed AAV vector comprises a capsid protein designed to diminish an immune response, wherein the capsid protein comprises the sequence set forth in SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84 or SEQ ID NO:85. Disclosed herein an AAV vector comprising the nucleic acid sequence set forth in SEQ ID NO:03 and the nucleic acid sequence set forth in SEQ ID NO: 10, wherein the disclosed AAV vector comprises a capsid protein designed to diminish an immune response, wherein the capsid protein comprises the sequence set forth in SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84 or SEQ ID NO:85.

[0158] Disclosed herein an AAV vector comprising the nucleic acid sequence set forth in SEQ ID NO:03 and the nucleic acid sequence set forth in SEQ ID NO: 10. Disclosed herein an AAV vector comprising the nucleic acid sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO: 81 or a fragment or portion thereof and the nucleic acid sequence set forth in SEQ ID NO: 10 or a fragment or portion thereof. Disclosed herein an AAV vector comprising a nucleic acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81 and a nucleic acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO: 10. In an aspect, a disclosed capsid protein of a disclosed AAV vector can comprise AAV.cc47 (SEQ ID NO:60) or AAV.cc84 (SEQ ID NO:66). In an aspect, a disclosed capsidprotein of a disclosed AAV vector can comprise the sequence set forth in SEQ ID NO: 82, SEQ ID NO:83, SEQ ID NO:84 or SEQ ID NO:85.

[0159] In an aspect, a disclosed vector can comprise the sequence set forth in SEQ ID NO:01 or SEQ ID NO:02. In an aspect, a disclosed vector can comprise a fragment or a portion of the sequence set forth in SEQ ID NO:01 or SEQ ID NO:02. In an aspect, a disclosed vector can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to a sequence set forth in SEQ ID NO:01 or SEQ ID NO:02.

[0160] In an aspect, a disclosed vector can be used to generate expression of a SLC protein in one or more tissues including, for example, cardiac tissue and / or skeletal muscle tissue. In an aspect, the SLC protein can be SLC25A4. In an aspect, a disclosed vector can be used to generate a cellular depot or reservoir of a disclosed SLC protein in one or more tissues including, for example, cardiac tissue and / or skeletal muscle tissue. In an aspect, the SLC protein can be SLC25A4.

[0161] In an aspect, a disclosed vector can be used to express a SLC protein that can restore one or more aspects of cellular homeostasis and / or cellular functionality. In an aspect, when expressed in a cell, a disclosed nucleic acid sequence can generate a SLC protein that can restore one or more aspects of cellular homeostasis and / or cellular functionality. In an aspect, a disclosed restoration of one or more aspects of cellular homeostasis and / or cellular functionality can comprise (i) restoring myocyte bioenergetics in the subject; (ii) normalizing tissue biomarkers in the subject; (iii) normalizing mitochondrial copy number in the subject’s heart and / or skeletal muscle; (iv) improving and / or restoring of mitochondrial functionality and / or structural integrity; (v) improving and / or restoring of organelle functionality and / or structural integrity; (vi) improving mitochondrial ADT-ATP exchange; (vii) increasing ADP-stimulated tissue respirations rates, (viii) decreasing production of mitochondrial reactive oxygen species; or (ix) any combination thereof. In an aspect, the SLC protein can be SLC25A4.

[0162] In an aspect, a disclosed vector can be used to restore one or more aspects of cellular homeostasis and / or cellular functionality can comprise correction and / or mitigation of one or more presenting symptoms associated with one or more symptoms of a SLC deficiency. In an aspect, the SLC protein can be SLC25A4. In an aspect, a disclosed vector can be used to express a disclosed SLC protein that can restore one or more aspects of the subject’s cardiac function and / or cardiac health. In an aspect, a disclosed SLC protein can (i) reverse cardiac remodeling in the subject; (ii) prevent cardiac remodeling in the subject; (iii) restore the cardiac dimensions to normal levels (i.e., the levels of a subject not having a disclosed SLC deficiency); (iv) improve the exercise capacity of the subject; (v) improve contractile mechanics; or (vi) any combinationthereof. In an aspect, a disclosed SLC protein can (i) reverse cardiac remodeling in the subject; (ii) prevent cardiac remodeling in the subject; (iii) restore the cardiac dimensions of the subject to a normal level; (iv) improve the exercise capacity of the subject; (v) improve cardiac contractile mechanics of the subject; (vi) restore myocyte bioenergetics in the subject; (vii) decrease production of mitochondrial reactive oxygen species in the heart or skeletal muscle of the subject; (viii) restore myocyte bioenergetics in the subject; (ix) improve mitochondrial ADT-ATP exchange in the subject; (x) increase ADP-stimulated tissue respirations rates; (xi) correct and / or reversing hyperlactinemia and hyperalanemia; (xii) correct and / or normalize plasma biomarkers lactate and alanine; or (xiii) any combination thereof. In an aspect, the SLC protein can be SLC25A4.

[0163] In an aspect, a disclosed vector can be used to express a disclosed SLC protein that can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, the SLC protein can be SLC25A4.

[0164] In an aspect, a disclosed vector can be used to express a disclosed SLC protein that can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, can diminish and / or ameliorate one or more symptoms of a disease or condition caused by one or more loss of functions in a SLC gene (i.e., SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, SLC25A20, or any combination thereof). In an aspect, the SLC protein can be SLC25A4.

[0165] In an aspect, a disclosed vector can be used to express a disclosed SLC protein that can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, that can increase and / or prolong a subject’s life span, that can diminish and / or ameliorate one or more symptoms of a disease or condition caused by one or more loss of functions in a SLC25A4 gene (e.g., c.523delC, c. H6_137del, c.707G>C, c.46_47del, c.l l l+lG>A, or c.423G>C, or any combination thereof). Representative mutations in SLC25A4 are listed in Table 3. In an aspect, the SLC protein can be SLC25A4.

[0166] In an aspect, a disclosed vector can be used to express a disclosed SLC protein that can improve and / or extend the survivability of the subject, that can improve a subject’s quality of life, that can increase and / or prolong a subject’s life span, that can diminish and / or ameliorate one or more symptoms of a disease or condition caused by one or more loss of functions in a SLC25A4 gene (e.g., c.523delC, c. H6_137del, c.707G>C, c.46_47del, c.l l l+lG>A, or c.423G>C, or any combination thereof). In an aspect, the SLC protein can be SLC25A4.

[0167] In an aspect, a disclosed vector can be used to express a disclosed nucleic acid sequence can generate a SLC protein that can restore one or more aspects of cellular homeostasis and / orcellular functionality in one or more cells. In an aspect, a disclosed restoration of one or more aspects of cellular homeostasis and / or cellular functionality can comprise (i) restoring myocyte bioenergetics in the subject; (ii) normalizing tissue biomarkers in the subject; (iii) normalizing mitochondrial copy number in the subject’s heart and / or skeletal muscle; (iv) improving and / or restoring of mitochondrial functionality and / or structural integrity; (v) improving and / or restoring of organelle functionality and / or structural integrity; (vi) improving mitochondrial ADT-ATP exchange; (vii) increasing ADP-stimulated tissue respirations rates, (viii) decreasing production of mitochondrial reactive oxygen species; or (ix) any combination thereof. In an aspect, the SLC protein can be SLC25A4.

[0168] In an aspect, a disclosed vector can be used to restore one or more aspects of cellular homeostasis and / or cellular functionality can comprise correction and / or mitigation of one or more presenting symptoms associated with one or more symptoms of a SLC deficiency. In an aspect, the SLC protein can be SLC25A4. In an aspect, a disclosed vector can be used to express a disclosed SLC protein that can restore one or more aspects of the subject’s cardiac function and / or cardiac health. In an aspect, a disclosed SLC protein can (i) reverse cardiac remodeling in the subject; (ii) prevent cardiac remodeling in the subject; (iii) restore the cardiac dimensions to normal levels (i.e., the levels of a subject not having a disclosed SLC deficiency); (iv) improve the exercise capacity of the subject; (v) improve contractile mechanics; or (vi) any combination thereof. In an aspect, a disclosed SLC protein can (i) reverse cardiac remodeling in the subject; (ii) prevent cardiac remodeling in the subject; (iii) restore the cardiac dimensions of the subject to a normal level; (iv) improve the exercise capacity of the subject; (v) improve cardiac contractile mechanics of the subject; (vi) restore myocyte bioenergetics in the subject; (vii) decrease production of mitochondrial reactive oxygen species in the heart or skeletal muscle of the subject; (viii) restore myocyte bioenergetics in the subject; (ix) improve mitochondrial ADT-ATP exchange in the subject; (x) increase ADP-stimulated tissue respirations rates; (xi) correct and / or reversing hyperlactinemia and hyperalanemia; (xii) correct and / or normalize plasma biomarkers lactate and alanine; or (xiii) any combination thereof. In an aspect, the SLC protein can be SLC25A4. In an aspect, the SLC protein can be SLC25A4. In an aspect, a disclosed vector can be used to improve one or more symptoms of a SLC protein deficiency can be subjective and / or objective. In an aspect, an improvement in one or more symptoms of an a SLC protein deficiency can improve a subject’s motor skills. In an aspect, an improvement in one or more symptoms of a SLC protein deficiency can improve a subject’s quality of life. In an aspect, a disclosed vector can be incorporated into a disclosed pharmaceutical formulation.3. Pharmaceutical Formulations

[0169] Disclosed herein is a pharmaceutical formulation comprising a disclosed nucleic acid molecule. Disclosed herein is a pharmaceutical formulation comprising a disclosed vector. Disclosed herein is a pharmaceutical formulation comprising a disclosed nucleic acid molecule and one or more pharmaceutically acceptable carriers, excipients, and / or ingredients. Disclosed herein is a pharmaceutical formulation comprising a disclosed vector and one or more pharmaceutically acceptable carriers, excipients, and / or ingredients. Nucleic acid molecules are discussed supra. Vectors are discussed supra.

[0170] Disclosed herein is a pharmaceutical formulation comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a solute carrier (SLC) protein or fragment thereof. In an aspect, a disclosed solute carrier (SLC) protein can comprise SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, or SLC25A20. In an aspect, a disclosed solute carrier protein can comprise any SLC protein identified in Table 1. In an aspect, a disclosed solute carrier protein can comprise SLC25A4.

[0171] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a solute carrier (SLC) protein. In an aspect, a disclosed solute carrier (SLC) protein can comprise SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, or SLC25A20. In an aspect, a disclosed solute carrier protein can comprise any SLC protein identified in Table 1. In an aspect of a disclosed vector, a disclosed solute carrier protein can comprise SLC25A4.

[0172] In an aspect, a disclosed pharmaceutical formulation can comprise (i) one or more active agents, (ii) biologically active agents, (iii) one or more pharmaceutically active agents, (iv) one or more immune-based therapeutic agents, (v) one or more clinically approved agents, or (vi) a combination thereof. In an aspect, a disclosed composition can comprise one or more proteasome inhibitors. In an aspect, a disclosed composition can comprise one or more immunosuppressives or immunosuppressive agents. In an aspect, an immunosuppressive agent can be anti-thymocyte globulin (ATG), cyclosporine (CSP), my cophenolate mofetil (MMF), or a combination thereof. In an aspect, a disclosed formulation can comprise an anaplerotic agent (such as, for example, C7 compounds like triheptanoin or MCT). In an aspect, a disclosed formulation can comprise an RNA therapeutic. A RNA therapeutic can comprise RNA-mediated interference (RNAi) and / or antisense oligonucleotides (ASO). In an aspect, a disclosed pharmaceutical formulation can comprise an enzyme or enzyme precursor for enzyme replacement therapy (ERT).

[0173] In an aspect, a disclosed pharmaceutical formulation can be used to generate expression of a SLC protein in one or more tissues including, for example, cardiac tissue and / or skeletal muscle tissue. In an aspect, the SLC protein can be SLC25A4. In an aspect, a disclosed vector canbe used to generate a cellular depot or reservoir of a disclosed SLC protein in one or more tissues including, for example, cardiac tissue and / or skeletal muscle tissue. In an aspect, the SLC protein can be SLC25A4.

[0174] In an aspect, a disclosed pharmaceutical formulation can be used to express a SLC protein that can restore one or more aspects of cellular homeostasis and / or cellular functionality. In an aspect, when expressed in a cell, a disclosed nucleic acid sequence can generate a SLC protein that can restore one or more aspects of cellular homeostasis and / or cellular functionality. In an aspect, a disclosed restoration of one or more aspects of cellular homeostasis and / or cellular functionality can comprise (i) restoring myocyte bioenergetics in the subject; (ii) normalizing tissue biomarkers in the subject; (iii) normalizing mitochondrial copy number in the subject’s heart and / or skeletal muscle; (iv) improving and / or restoring of mitochondrial functionality and / or structural integrity; (v) improving and / or restoring of organelle functionality and / or structural integrity; (vi) improving mitochondrial ADT-ATP exchange; (vii) increasing ADP-stimulated tissue respirations rates, (viii) decreasing production of mitochondrial reactive oxygen species; or (ix) any combination thereof. In an aspect, the SLC protein can be SLC25A4.

[0175] In an aspect, a disclosed pharmaceutical formulation can be used to restore one or more aspects of cellular homeostasis and / or cellular functionality can comprise correction and / or mitigation of one or more presenting symptoms associated with one or more symptoms of a SLC deficiency. In an aspect, the SLC protein can be SLC25A4.

[0176] In an aspect, a disclosed pharmaceutical formulation can be used to express a disclosed SLC protein that can restore one or more aspects of the subject’s cardiac function and / or cardiac health. In an aspect, a disclosed SLC protein can (i) reverse cardiac remodeling in the subject; (ii) prevent cardiac remodeling in the subject; (iii) restore the cardiac dimensions to normal levels (i.e., the levels of a subject not having a disclosed SLC deficiency); (iv) improve the exercise capacity of the subject; (v) improve contractile mechanics; or (vi) any combination thereof. In an aspect, a disclosed SLC protein can (i) reverse cardiac remodeling in the subject; (ii) prevent cardiac remodeling in the subject; (iii) restore the cardiac dimensions of the subject to a normal level; (iv) improve the exercise capacity of the subject; (v) improve cardiac contractile mechanics of the subject; (vi) restore myocyte bioenergetics in the subject; (vii) decrease production of mitochondrial reactive oxygen species in the heart or skeletal muscle of the subject; (viii) restore myocyte bioenergetics in the subject; (ix) improve mitochondrial ADT-ATP exchange in the subject; (x) increase ADP-stimulated tissue respirations rates; (xi) correct and / or reversing hyperlactinemia and hyperalanemia; (xii) correct and / or normalize plasma biomarkers lactate and alanine; or (xiii) any combination thereof. In an aspect, the SLC protein can be SLC25A4. In an aspect, the SLC protein can be SLC25A4.

[0177] In an aspect, a disclosed pharmaceutical formulation can be used to express a disclosed SLC protein that can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, the SLC protein can be SLC25A4.

[0178] In an aspect, a disclosed pharmaceutical formulation can be used to express a disclosed SLC protein that can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, can diminish and / or ameliorate one or more symptoms of a disease or condition caused by one or more loss of functions in a SLC gene (i.e., SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, SLC25A20, or any combination thereof). In an aspect, the SLC protein can be SLC25A4.

[0179] In an aspect, a disclosed pharmaceutical formulation can be used to express a disclosed SLC protein that can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, that can increase and / or prolong a subject’s life span, that can diminish and / or ameliorate one or more symptoms of a disease or condition caused by one or more loss of functions in a SLC25A4 gene (e.g., c.523delC, c.H6_137del, c.707G>C, c.46_47del, c.111+1G>A, or c.423G>C, or any combination thereof). Representative mutations in SLC25A4 are listed in Table 3. In an aspect, the SLC protein can be SLC25A4. In an aspect, a disclosed pharmaceutical formulation can be used to express a disclosed SLC protein that can improve and / or extend the survivability of the subject, that can improve a subject’s quality of life, that can increase and / or prolong a subject’s life span, that can diminish and / or ameliorate one or more symptoms of a disease or condition caused by one or more loss of functions in a SLC25A4 gene (e.g., c.523delC, c. H6_137del, c.707G>C, c.46_47del, c. l l l+lG>A, or c.423G>C, or any combination thereof). In an aspect, the SLC protein can be SLC25A4.

[0180] In an aspect, a disclosed pharmaceutical formulation can be used to express a disclosed nucleic acid sequence can generate a SLC protein that can restore one or more aspects of cellular homeostasis and / or cellular functionality in one or more cells. In an aspect, a disclosed restoration of one or more aspects of cellular homeostasis and / or cellular functionality can comprise (i) restoring myocyte bioenergetics in the subject; (ii) normalizing tissue biomarkers in the subject; (iii) normalizing mitochondrial copy number in the subject’s heart and / or skeletal muscle; (iv) improving and / or restoring of mitochondrial functionality and / or structural integrity; (v) improving and / or restoring of organelle functionality and / or structural integrity; (vi) improving mitochondrial ADT-ATP exchange; (vii) increasing ADP-stimulated tissue respirations rates, (viii) decreasing production of mitochondrial reactive oxygen species; or (ix) any combination thereof. In an aspect, the SLC protein can be SLC25A4.

[0181] In an aspect, a disclosed pharmaceutical formulation can be used to restore one or more aspects of cellular homeostasis and / or cellular functionality can comprise correction and / or mitigation of one or more presenting symptoms associated with one or more symptoms of a SLC deficiency. In an aspect, the SLC protein can be SLC25A4. In an aspect, a disclosed pharmaceutical formulation can be used to express a disclosed SLC protein that can restore one or more aspects of the subject’s cardiac function and / or cardiac health. In an aspect, a disclosed SLC protein can (i) reverse cardiac remodeling in the subject; (ii) prevent cardiac remodeling in the subject; (iii) restore the cardiac dimensions to normal levels (i.e., the levels of a subject not having a disclosed SLC deficiency); (iv) improve the exercise capacity of the subject; (v) improve contractile mechanics; or (vi) any combination thereof. In an aspect, a disclosed SLC protein can (i) reverse cardiac remodeling in the subject; (ii) prevent cardiac remodeling in the subject; (iii) restore the cardiac dimensions of the subject to a normal level; (iv) improve the exercise capacity of the subject; (v) improve cardiac contractile mechanics of the subject; (vi) restore myocyte bioenergetics in the subject; (vii) decrease production of mitochondrial reactive oxygen species in the heart or skeletal muscle of the subject; (viii) restore myocyte bioenergetics in the subject; (ix) improve mitochondrial ADT-ATP exchange in the subject; (x) increase ADP-stimulated tissue respirations rates; (xi) correct and / or reversing hyperlactinemia and hyp eral anemia; (xii) correct and / or normalize plasma biomarkers lactate and alanine; or (xiii) any combination thereof. In an aspect, the SLC protein can be SLC25A4. In an aspect, the SLC protein can be SLC25A4.

[0182] In an aspect, a disclosed pharmaceutical formulation can be used to improve one or more symptoms of a SLC protein deficiency can be subjective and / or objective. In an aspect, an improvement in one or more symptoms of an a SLC protein deficiency can improve a subject’s motor skills. In an aspect, an improvement in one or more symptoms of a SLC protein deficiency can improve a subject’s quality of life. In an aspect, a disclosed pharmaceutical formulation can be incorporated into a disclosed kit. In an aspect, a disclosed pharmaceutical formulation can be used in a disclosed method.

[0183] In an aspect, a disclosed pharmaceutical formulation can further comprise one or more enzymes that can degrade and / or cleave one or more neutralizing antibodies. In an aspect, a disclosed pharmaceutical formulation can further comprise one or more enzymes that can degrade and / or cleave one or more neutralizing antibodies against an administered nucleic acid molecule and / or an administered vector. In an aspect, a disclosed pharmaceutical formulation can further comprise one or more enzymes that can degrade and / or cleave one or more neutralizing antibodies against the SLC protein encoded therein. In an aspect, a disclosed pharmaceutical formulation can further comprise one or more enzymes that can degrade and / or cleave one or more neutralizing antibodies against the SLC protein encoded therein. In an aspect, a disclosed pharmaceuticalformulation can further comprise one or more enzymes that can degrade and / or cleave one or more neutralizing antibodies against an encoded SLC protein. Enzymes that can degrade and / or cleave one or more neutralizing antibodies against a disclosed nucleic acid molecule, a disclosed vector, a disclosed encoded SLC protein, or any combination thereof are disclosed in WO 2024 / 112492 and / or in PCT / US2025 / 030844, each of which are incorporated herein its entirety for teaching the enzymes (and their sequences) and methods of using these enzymes to decrease antibody titers.4. Cells and Animals

[0184] Disclosed herein are cells comprising a disclosed nucleic acid molecule, a disclosed vector, and / or a disclosed plasmid. Disclosed herein are cells contacted with one or more disclosed nucleic acid molecule, one or more disclosed vectors, and / or one or more disclosed plasmids. Cells are known to the art. Methods of transfecting and / or transducing cells with one or more disclosed nucleic acid molecules, one or more disclosed vectors, and / or one or more disclosed plasmids. Disclosed herein are animals treated with a disclosed nucleic acid molecule, a disclosed vector, and / or a disclosed plasmid. Disclosed herein are animals contacted with one or more disclosed nucleic acid molecule, one or more disclosed vectors, and / or one or more disclosed plasmids.5. Kits

[0185] Disclosed herein is a kit comprising a disclosed nucleic acid molecule, a disclosed vector, a disclosed pharmaceutical formulation, or a combination thereof. Disclosed herein is a kit comprising one or more disclosed nucleic acid molecules, one or more disclosed vectors, one or more disclosed pharmaceutical formulations, or a combination thereof. In an aspect, a kit can comprise a disclosed isolated nucleic acid molecule, a disclosed vector, a disclosed pharmaceutical formulation, or a combination thereof, and one or more agents. “Agents” and “Therapeutic Agents” are known to the art and are described supra. In an aspect, the one or more agents can treat, prevent, inhibit, and / or ameliorate one or more comorbidities in a subject. In an aspect, one or more active agents can treat, inhibit, prevent, and / or ameliorate a disclosed SLC protein deficiency or a SLC protein deficiency-related complication.

[0186] In an aspect, a disclosed kit can comprise at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose (such as, for example, treating a subject diagnosed with or suspected of having a SLC protein deficiency).

[0187] Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be suppliedon computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0188] In an aspect, a kit for use in a disclosed method can comprise one or more containers holding one or more disclosed nucleic acid molecules, one or more disclosed vectors, one or more disclosed pharmaceutical formulations, or a combination thereof, and a label or package insert with instructions for use. In an aspect, suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The containers can be formed from a variety of materials such as glass or plastic. The container can hold one or more disclosed isolated nucleic acid molecules, one or more disclosed vectors, one or more disclosed pharmaceutical formulations, or a combination thereof, and can have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).

[0189] The label or package insert can indicate that one or more disclosed isolated nucleic acid molecules, one or more disclosed vectors, one or more disclosed pharmaceutical formulations, or a combination thereof can be used for treating, preventing, inhibiting, and / or ameliorating a disclosed SLC protein deficiency or complications and / or symptoms associated with a disclosed SLC protein deficiency. A kit can comprise additional components necessary for administration such as, for example, other buffers, diluents, filters, needles, and syringes.D. Methods of Treating and / or Slowing and / or Reversing Disease Progression

[0190] Disclosed herein is a method of treating and / or slowing and / or reversing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed nucleic acid molecule, a disclosed vector, or a disclosed pharmaceutical formulation.

[0191] Disclosed herein is a method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed nucleic acid molecule, a disclosed vector, or a disclosed pharmaceutical formulation, and modulating the expression level and / or activity level of one or more enzymes associated with and / or related to the SLC protein deficiency.

[0192] Disclosed herein is a method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed nucleic acid molecule, a disclosed vector, or a disclosed pharmaceutical formulation, and increasing the expression level and / or activity level of one or more enzymes associated with and / or related to the SLC protein deficiency.

[0193] Disclosed herein is a method of treating and / or slowing and / or reversing disease progression, the method comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed nucleic acid molecule, a disclosed vector, or a disclosedpharmaceutical formulation, wherein the expression level and / or activity level of the SLC protein is increased.

[0194] Disclosed herein is a method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed nucleic acid molecule, a disclosed vector, or a disclosed pharmaceutical formulation, wherein, following expression of nucleic acid sequence in the cells and / or tissues, the activity level of the SLC protein is increased.

[0195] Disclosed herein is a method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed nucleic acid molecule comprising a disclosed nucleic acid sequence for a disclosed SLC protein, wherein, following expression of nucleic acid sequence in the cells and / or tissues, the activity level of the SLC protein is increased.

[0196] Disclosed herein is a method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed nucleic acid molecule comprising a disclosed nucleic acid sequence for a disclosed SLC protein, wherein, following expression of nucleic acid sequence in cardiac cells and / or cardiac tissues, the activity level of the SLC protein is increased.

[0197] Disclosed herein is a method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed nucleic acid molecule comprising a disclosed nucleic acid sequence for a disclosed SLC protein, wherein, following expression of nucleic acid sequence in skeletal muscle cells and / or skeletal muscle tissues, the activity level of the SLC protein is increased.

[0198] Disclosed herein is a method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount of a disclosed nucleic acid molecule comprising a disclosed nucleic acid sequence for a disclosed SLC protein, wherein, following expression of nucleic acid sequence in cardiac and skeletal muscle cells and / or cardiac and skeletal muscle tissues, the activity level of the SLC protein is increased.

[0199] Disclosed herein is a method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount an AAV vector comprising a nucleic acid sequence encoding SLC25A4 and a nucleic acid sequence encoding a MHCK7 promoter, wherein, following expression of nucleic acid sequence in the cells and / or tissues, the expression and / or activity level of the SLC25A4 protein is increased.

[0200] Disclosed herein is a method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount of an AAV vector comprising the nucleic acid sequence set forth in SEQ ID NO:03 and the nucleic acid sequence set forth in SEQ ID NO: 10, wherein, following expression of nucleic acid sequence in the cells and / or tissues, the expression and / or activity level of the SLC25A4 protein is increased.

[0201] Disclosed herein is a method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount of an AAV vector comprising the nucleic acid sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81 and the nucleic acid sequence set forth in SEQ ID NO: 10, wherein, following expression of nucleic acid sequence in the cells and / or tissues, the expression and / or activity level of the SLC25A4 protein is increased.

[0202] Disclosed herein is a method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount of an AAV vector comprising the nucleic acid sequence set forth in SEQ ID NO:03 or a fragment or portion thereof and the nucleic acid sequence set forth in SEQ ID NO: 10 or a fragment or portion thereof, wherein, following expression of nucleic acid sequence in the cells and / or tissues, the expression and / or activity level of the SLC25A4 protein is increased.

[0203] Disclosed herein is a method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount of an AAV vector comprising the nucleic acid sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81 or a fragment or portion thereof and the nucleic acid sequence set forth in SEQ ID NO: 10 or a fragment or portion thereof, wherein, following expression of nucleic acid sequence in the cells and / or tissues, the expression and / or activity level of the SLC25A4 protein is increased.

[0204] Disclosed herein is a method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount of an AAV vector comprising a nucleic acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO: 03 and a nucleic acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO: 10, wherein, following expression of nucleic acid sequence in the cells and / or tissues, the expression and / or activity level of the SLC25A4 protein is increased.

[0205] Disclosed herein is a method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency comprising administering to a subject in need thereof a therapeutically effective amount of an AAV vector comprising a nucleic acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:81 and a nucleic acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO: 10, wherein, following expression of nucleic acid sequence in the cells and / or tissues, the expression and / or activity level of the SLC25A4 protein is increased. .

[0206] In an aspect of a disclosed method, a disclosed recombinant AAV capsid protein can comprise the sequence set forth in SEQ ID NO:60 or SEQ ID NO:66. In an aspect of a disclosed method, a disclosed capsid protein of a disclosed AAV vector can comprise AAV.cc47 (SEQ ID NO:60) or AAV.cc84 (SEQ ID NO:66). In an aspect of a disclosed method, a disclosed capsid protein of a disclosed AAV vector can diminish and / or escape and / or evade an immune response that comprises neutralizing antibodies to the vector and / or the disclosed SLC protein and / or a fragment or a portion thereof. In an aspect of a disclosed method, a disclosed capsid protein of a disclosed AAV vector can comprise a capsid protein having one or more substitutions or one or more mutations in the VR8 region. In an aspect, the VR8 region of a disclosed capsid protein can comprise the sequence set forth in SEQ ID NOVO, SEQ ID NO:91, SEQ ID NO:92, or SEQ ID NO:93. In an aspect, the VR8 region of a disclosed capsid protein can be encoded by the sequence set forth in SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, or SEQ ID NO:97. In an aspect, a disclosed VR8 region comprising the sequence set forth in SEQ ID NOVO can be encoded by a sequence set forth in SEQ ID NO:94. In an aspect, a disclosed VR8 region comprising the sequence set forth in SEQ ID NOVI can be encoded by a sequence set forth in SEQ ID NO:95. In an aspect, a disclosed VR8 region comprising the sequence set forth in SEQ ID NO:92 can be encoded by a sequence set forth in SEQ ID NO:96. In an aspect, a disclosed VR8 region comprising the sequence set forth in SEQ ID NO:93 can be encoded by a sequence set forth in SEQ ID NO:97. In an aspect, a disclosed capsid protein of a disclosed AAV vector can comprise the sequence set forth in SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84 or SEQ ID NO:85. In an aspect, a disclosed capsid protein can be encoding by the sequence set forth in SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88 or SEQ ID NO:89. In an aspect, a disclosed capsid protein having the sequence set forth in SEQ ID NO: 82 can be encoded by the sequence set forth in SEQ ID NO:86. In an aspect, a disclosed capsid protein having the sequence set forth in SEQ ID NO:83 can be encoded by the sequence set forth in SEQ ID NO:87. In an aspect, a disclosed capsid protein having the sequence set forth in SEQ ID NO: 84 can be encoded by the sequence set forthin SEQ ID NO:88. In an aspect, a disclosed capsid protein having the sequence set forth in SEQ ID NO:86 can be encoded by the sequence set forth in SEQ ID NO:89.

[0207] In an aspect of a disclosed method, using one or more of the disclosed AAV vectors comprising one or more disclosed AAV capsid proteins (e.g., SEQ ID NO:60, SEQ ID NO:66, SEQ ID NOVO, SEQ ID NOV 1, SEQ ID NO: 92, or SEQ ID NO:93) allow for repeated administration of the transgene sequence for a disclosed SLC protein (such as, for example, SLC25A4). Using a disclosed capsid sequence designed to evade an immune response can ensure that the subject can receive more than one administration of a disclosed vector, thereby ensuring long-term treatment.

[0208] In an aspect, a subject can have a disclosed SLC deficiency including those, for example, Table 1 or Table 3. In an aspect, a subject can be an adult, a child, or an infant. In an aspect, a subject can be treatment-naive.

[0209] In an aspect, restoring the activity and / or expression and / or functionality of a disclosed SLC protein can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of restoration when compared to a pre-existing level such as, for example, a pre-treatment level. In an aspect, the amount of restoration can be 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60- 70%, 70-80%, 80-90%, or 90-100% more than a pre-existing level such as, for example, a pretreatment level. In an aspect, restoration can be measured against a control level (e.g., a level in a subject not having a SLC protein deficiency). In an aspect, restoration can be a partial or incomplete restoration. In an aspect, restoration can be complete or near complete restoration such that the level of expression, activity and / or functionality is similar to that of a wild-type or control level.

[0210] Thus, in an aspect, the increase or decrease in expression and / or activity level postadministration can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of reduction in between as compared to native or control levels (e.g., pre-administration level). In an aspect, the increase or decrease in expression and / or activity level post-administration can be 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% as compared to a native or control level (e.g., pre-administration level). In an aspect, the inhibition or reduction can be 0-25%, 25-50%, 50-75%, or 75-100% as compared to native or control levels (e.g., pre- administration level). In an aspect, a native or control level can be a pre-disease or pre-disorder level or pre-treatment level).

[0211] In an aspect, treating and / or slowing and / or reversing disease progression can comprise a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of a slowing and / or reversing disease progression when compared to a pre-existing level such as, for example, a pretreatment level. In an aspect, the amount of slowing and / or reversing disease progression can be10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% more than a pre-existing level such as, for example, a pre-treatment level. In an aspect, slowing and / or reversing disease progression can be measured against a control level (e.g., a level in a subject not having a SLC protein deficiency). In an aspect, slowing and / or reversing disease progression can be a partial or incomplete restoration. In an aspect, slowing and / or reversing disease progression can be complete or near complete restoration such that the level of expression, activity and / or functionality is similar to that of a wild-type or control level.

[0212] In an aspect of a disclosed method, techniques to monitor, measure, and / or assess the restoring one or more aspects of cellular homeostasis and / or cellular functionality can comprise qualitative (or subjective) means as well as quantitative (or objective) means. These means are known to the skilled person. In an aspect, a disclosed method can comprise measuring the level or amount of one or more biomarkers (e.g., cardiac enzymes, muscle enzymes, etc.), one or more indicators of the subject’s metabolomic health, or any combination thereof.

[0213] In an aspect, a disclosed method can comprise administering to the subject one or more additional therapeutic agents. In an aspect, a disclosed therapeutic agent can comprise enzyme replacement therapy, gene therapy, mRNA therapy, small molecule therapy, substrate reduction therapy, or any combination thereof.

[0214] In an aspect, a disclosed method can comprise validating the efficacy of the administered nucleic acid molecule or vector. In an aspect, validating the efficacy of the administered nucleic acid molecule or vector can comprise administering to the subject a disclosed nucleic acid molecule or a disclosed vector, measuring the activity or expression of one or more biomarkers related to cellular function; and comparing the resulting activity or expression level of the one or more biomarkers to a control level, wherein the administered nucleic acid molecule or vector is effective when the activity or expression level of the one or more biomarkers following treatment is modulated compared to the control level. In an aspect, modulated can comprise increasing the activity or expression level of the one or more biomarkers. In an aspect, modulated can comprise increasing the activity or expression level of the one or more biomarkers. In an aspect, modulated can comprise decreasing the activity or expression level of the one or more biomarkers. In an aspect, based on the pathology of a disclosed SLC protein deficiency, whether the modulated activity or expression level of the one or more biomarkers can be determined. In an aspect, a disclosed method can comprise measuring one or more biomarkers prior to the administering of one or more disclosed nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations. In an aspect, a disclosed method can comprise measuring one or more biomarkers during the administering of one or more disclosed nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations. In an aspect, a disclosed method can comprise measuringone or more biomarkers after the administering of a disclosed nucleic acid molecule or a disclosed vector. In an aspect of a disclosed method, the expression and / or activity level of a disclosed SLC protein deficiency can be modulated.

[0215] In an aspect, measuring the expression of one or more disclosed biomarkers can comprise measuring the protein concentration of the encoded SLC protein and / or the reporter gene or measuring the mRNA level of encoded SLC protein and / or the reporter gene. For example, in an aspect, measuring the protein concentration of encoded SLC protein and / or the reporter gene comprises a protein chip analysis, an immunoassay, a ligand binding assay, a MALDI-TOF (Matrix Assisted Laser Desorption / Ionization Time of Flight Mass Spectrometry) analysis, a SELDI-TOF (Sulface Enhanced Laser Desorption / Ionization Time of Flight Mass Spectrometry) analysis, a radioimmunoassay, a radioimmunodiffusion assay, an octeroni immunodiffusion method, rocket immunoelectrophoresis, tissue immunostaining, a complement fixation assay, 2D by electrophoretic analysis, liquid chromatography-Mass Spectrometry (LC-MS), liquid chromatography-Mass Spectrometry / Mass Spectrometry (LC-MS / MS), Western blotting, ELISA (enzyme linked immunosorbent assay), or any combination thereof. Similarly, in an aspect, measuring the mRNA level of a disclosed encoded SLC protein and / or the reporter gene comprises a reverse transcription polymerase reaction (RT-PCR), a competitive reverse transcription polymerase reaction (Competitive RT-PCR), a real-time reverse transcription polymerization, an enzyme reaction (Real-time RT-PCR), an RNase protection assay (RPA), Northern blotting, a DNA chip, or any combination thereof.

[0216] In an aspect, a disclosed method can further comprise monitoring the subject for adverse effects. In an aspect, in the absence of adverse effects, the method can further comprise continuing to treat the subject. In an aspect, in the presence of adverse effects, the method can further comprise modifying the treating step. Methods of monitoring a subject’s well-being can include both subjective and objective criteria. Such methods are known to the skilled person. In an aspect, a disclosed method can further comprise repeating a monitoring step.

[0217] In an aspect, a disclosed method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency can further comprise administering one or more immune modulators. In an aspect, a disclosed immune modulator can help to minimize the immune response to a disclosed nucleic acid molecule, a disclosed vector, a disclosed pharmaceutical formulation, or the recombinant SLC protein encoded therein. In an aspect, a disclosed immune modulator can be methotrexate, rituximab, intravenous gamma globulin, or bortezomib, or a combination thereof. In an aspect, a disclosed immune modulator can be bortezomib or SVP- Rapamycin. In an aspect, a disclosed immune modulator can be Tacrolimus. In an aspect, a disclosed immune modulator such as methotrexate can be administered at a transient low to highdose. In an aspect, a disclosed immune modulator can be administered at a dose of about 0.1 mg / kg body weight to about 0.6 mg / kg body weight. In an aspect, a disclosed immune modulator can be administered at a dose of about 0.4 mg / kg body weight. In an aspect, a disclosed immune modulator can be administered at about a daily dose of 0.4 mg / kg body weight for 3 to 5 or greater cycles, with up to three days per cycle. In an aspect, a disclosed immune modulator can be administered at about a daily dose of 0.4 mg / kg body weight for a minimum of 3 cycles, with 3 days per cycle. In an aspect, a person skilled in the art can determine the appropriate number of cycles. In an aspect, a disclosed immune modulator can be administered as many times as necessary to achieve a desired clinical effect.

[0218] In an aspect, a disclosed immune modulator can be administered orally about one hour before a disclosed therapeutic agent. In an aspect, a disclosed immune modulator can be administered subcutaneously about 15 minutes before a disclosed therapeutic agent. In an aspect, a disclosed immune modulator can be administered concurrently with a disclosed therapeutic agent. In an aspect, a disclosed immune modulator can be administered orally about one hour or a few days before a disclosed isolated nucleic acid molecule, a disclosed vector, a disclosed pharmaceutical formulation, or a combination thereof. In an aspect, a disclosed immune modulator can be administered subcutaneously about 15 minutes before or a few days before a disclosed isolated nucleic acid molecule, a disclosed vector, a disclosed pharmaceutical formulation, or a combination thereof. In an aspect, a disclosed immune modulator can be administered concurrently with a disclosed isolated nucleic acid molecule, a disclosed vector, a disclosed pharmaceutical formulation, or a combination thereof.

[0219] In an aspect, a disclosed method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency can further comprise administering one or more proteasome inhibitors (e.g., bortezomib, carfilzomib, marizomib, ixazomib, and oprozomib). In an aspect, a proteasome inhibitor can be an agent that acts on plasma cells (e.g., daratumumab). In an aspect, an agent that acts on a plasma cell can be melphalan hydrochloride, melphalan, pamidronate disodium, carmustine, carfilzomib, carmustine, cyclophosphamide, daratumumab, doxorubicin hydrochloride liposome, doxorubicin hydrochloride liposome, elotuzumab, melphalan hydrochloride, panobinostat, ixazomib citrate, carfilzomib, lenalidomide, melphalan, melphalan hydrochloride, plerixafor, ixazomib citrate, pamidronate disodium, panobinostat, plerixafor, pomalidomide, pomalidomide, lenalidomide, selinexor, thalidomide, thalidomide, bortezomib, selinexor, zoledronic acid, or zoledronic acid.

[0220] In an aspect, a disclosed method can further comprise administering one or more proteasome inhibitors or agents that act on plasma cells prior to administering a disclosed isolated nucleic acid molecule, a disclosed vector, or a disclosed pharmaceutical formulation. In an aspect,a disclosed method can comprise administering one or more proteasome inhibitors or one or more agents that act on plasma cells concurrently with administering a disclosed isolated nucleic acid molecule, a disclosed vector, or a disclosed pharmaceutical formulation. In an aspect, a disclosed method can comprise administering one or more proteasome inhibitors or one or more agents that act on plasma cells subsequent to administering a disclosed isolated nucleic acid molecule, a disclosed vector, or a disclosed pharmaceutical formulation. In an aspect, a disclosed method can further comprise administering one or more proteasome inhibitors more than 1 time. In an aspect, a disclosed method can comprise administering one or more proteasome inhibitors repeatedly over time.

[0221] In an aspect, a disclosed method of treating and / or slowing and / or reversing disease progression of a SLC deficiency can further comprise administering one or more immunosuppressive agents. In an aspect, an immunosuppressive agent can be, but is not limited to, azathioprine, methotrexate, sirolimus, anti-thymocyte globulin (ATG), cyclosporine (CSP), mycophenolate mofetil (MMF), steroids, or a combination thereof. In an aspect, a disclosed method can comprise administering one or more immunosuppressive agents more than 1 time. In an aspect, a disclosed method can comprise administering one or more one or more immunosuppressive agents repeatedly over time. In an aspect, a disclosed method can comprise administering a compound that targets or alters antigen presentation or humoral or cell mediated or innate immune responses.

[0222] In an aspect, a disclosed method of repairing a defective gene can further comprise administering a compound that exerts a therapeutic effect against B cells and / or a compound that targets or alters antigen presentation or humoral or cell mediated immune response. In an aspect, a disclosed compound can be rituximab, methotrexate, intravenous gamma globulin, anti CD4 antibody, anti CD2, an anti-FcRN antibody, a BTK inhibitor, an anti-IGFIR antibody, a CD19 antibody (e.g., inebilizumab), an anti-IL6 antibody (e.g., tocilizumab), an antibody to CD40, an IL2 mutein, or a combination thereof. Also disclosed herein are Treg infusions that can be administered as a way to help with immune tolerance (e.g., antigen specific Treg cells to AAV).

[0223] In an aspect, a disclosed method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency can further comprise repeating a disclosed administering step such as, for example, repeating the administering of a disclosed isolated nucleic acid molecule, a disclosed vector, a disclosed pharmaceutical formulation, a disclosed therapeutic agent, a disclosed immune modulator, a disclosed proteasome inhibitor, a disclosed immunosuppressive agent, a disclosed compound that exerts a therapeutic effect against B cells and / or a disclosed compound that targets or alters antigen presentation or humoral or cell mediated immune response.

[0224] In an aspect, a disclosed method can comprise re-administering a disclosed vector or a disclosed pharmaceutical formulation can comprise using the same recombinant AAV vector as the first dose. In an aspect, a disclosed method can comprise re-administering a disclosed vector or a disclosed pharmaceutical formulation can comprise using a different recombinant AAV vector as the first dose. In an aspect, a disclosed method can comprise re-administering a disclosed vector or a disclosed pharmaceutical formulation can comprise using a recombinant AAV vector having the same serotype of the first AAV vector. In an aspect, a disclosed method can comprise re-administering a disclosed vector or a disclosed pharmaceutical formulation can comprise using a recombinant AAV vector having a different serotype of the first AAV vector. In an aspect, a disclosed AAV vector can be administered one or more times. In an aspect, a disclosed method can comprise administering the same AAV vector one or more times. In an aspect, a disclosed method can comprise administering different AAV vectors one or more times.

[0225] In an aspect, a disclosed method can comprise re-administering a disclosed vector or a disclosed pharmaceutical formulation can comprise using an AAV vector designed to diminish and / or escape and / or evade an immune response that comprises neutralizing antibodies to the vector and / or the disclosed SLC protein and / or a fragment or a portion thereof.

[0226] In an aspect, a disclosed method can comprise re-administering a disclosed isolated nucleic acid molecule, a disclosed vector, a disclosed pharmaceutical formulation using a recombinant AAV vector having a capsid protein designed to escape and / or evade an immune response that comprises neutralizing antibodies to the vector and / or the disclosed SLC protein and / or a fragment or a portion thereof. In an aspect, a disclosed method can comprise re-administering a disclosed isolated nucleic acid molecule, a disclosed vector, a disclosed pharmaceutical formulation can comprise using a recombinant AAV vector having a capsid protein designed to diminish an immune response that comprises neutralizing antibodies to the vector and / or the disclosed SLC protein and / or a fragment or a portion thereof. In an aspect, a disclosed AAV vector having a capsid protein designed to diminish and / or escape and / or evade an immune response can comprise the sequence set forth in SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84 or SEQ ID NO:85. In an aspect, a disclosed AAV vector having a capsid protein designed to diminish and / or escape and / or evade an immune response can comprise a sequence having at least 70%, at least 75%, at least 80%, at least 85% at least 90%, at least 95%, or more than 95% identity to the sequence set forth in SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84 or SEQ ID NO:85. In an aspect, a disclosed AAV vector having a capsid protein designed to diminish and / or escape and / or evade an immune response can comprise a portion or a fragment of the sequence set forth in SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84 or SEQ ID NO:85.

[0227] In an aspect, a disclosed method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency can further comprise administering a [32 agonist. In an aspect, P2 agonists include but are not limited to albuterol, clenbuterol, formoterol, indacaterol, olodaterol, salmeterol, vilanterol, and any combination thereof, growth hormones (e.g., human growth hormone), autocrine glycoprotein (e.g., Follistatin), or any combination thereof.

[0228] In an aspect, a disclosed method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency can further comprise administering to a subject or patient one or more fibrates. In an aspect, a disclosed fibrate can comprise bezafibrate, fenofibrate, ciprofibrate, gemfibrozil, clofibrate, an analog thereof, or a combination thereof. In an aspect, a disclosed method can comprise repeating the administering of one or more fibrates one or more times. In an aspect, a therapeutically effective amount of one or more fibrates can comprise at least about 20 mg / day to at least 500 mg / day. In an aspect, a therapeutically effective amount of one or more fibrates can comprise at least about 20 mg / day, at least about 20 mg / day, about 30 mg / day, about 40 mg / day, at least about 50 mg / day, at least about 60 mg / day, at least about 70 mg / day, at least about 80 mg / day, at least about 90 mg / day, at least about 100 mg / day, at least about 120 mg / day, atleast about 140 mg / day, at least about 160 mg / day, atleast about 180 mg / day, at least about 200 mg / day, at least about 220 mg / day, at least about 240 mg / day, at least about 260 mg / day, at least about 280 mg / day, at least about 300 mg / day, at least about 320 mg / day, at least about 340 mg / day, at least about 360 mg / day, at least about 380 mg / day, at least about 400 mg / day, at least about 420 mg / day, at least about 440 mg / day, at least about 460 mg / day, at least about 480 mg / day, or at least about 500 mg / day.

[0229] In an aspect, a disclosed method can further comprise administering to the subject an enzyme that can degrade and / or cleave one or more neutralizing antibodies. In an aspect, a disclosed method can further comprise administering to the subject an enzyme that can degrade and / or cleave one or more neutralizing antibodies against an administered nucleic acid molecule and / or an administered vector. In an aspect, a disclosed method can further comprise administering to the subject an enzyme that can degrade and / or cleave one or more neutralizing antibodies against the SLC protein encoded therein. In an aspect, a disclosed method can further comprise administering to the subject an enzyme that can degrade and / or cleave one or more neutralizing antibodies against the SLC protein encoded therein. In an aspect, a disclosed method can further comprise administering to the subject an enzyme that can degrade and / or cleave one or more neutralizing antibodies against an encoded SLC protein. Enzymes that can degrade and / or cleave one or more neutralizing antibodies against a disclosed nucleic acid molecule, a disclosed vector, a disclosed encoded SLC protein, or any combination thereof are disclosed in WO 2024 / 112492 and / or in PCT / US2025 / 030844, each of which are incorporated herein its entiretyfor teaching the enzymes (and their sequences) and methods of using these enzymes to decrease antibody titers. In an aspect, a disclosed method can reduce an antibody titers.

[0230] In an aspect, a disclosed method can further comprise administering to the subject (i) one or more beta blockers (e.g., nadolol, atenolol, metoprolol, or carvedilol); (ii) angiotensin II receptor antagonists; (iii) calcium channel blockers; (iv) vitamin-anti oxidant therapy (e.g. vitamin E, vitamin C, B-complex, coenzyme Q10, and L-camitine); or (v) any combination thereof. In an aspect, a disclosed method can further comprise repeating the administration of one or more of these agents.

[0231] In an aspect of a disclosed method, patients with SLC protein deficiency can be treated with one or more renin-angiotensin-aldosterone system inhibitors (angiotensin-converting enzyme inhibitors, one or more angiotensin receptor blockers, one or more angiotensin receptor- neprilysin inhibitors, one or more beta-blockers, one or more mineralocorticoid receptor antagonists, one or more sodium-glucose cotransporter-2 inhibitors, and any combination thereof.

[0232] In an aspect, a disclosed method of treating and / or slowing and / or reversing disease progression of a SLC protein deficiency can further comprise modifying one or more of the disclosed steps. For example, modifying one or more of steps of a disclosed method can comprise modifying or changing one or more features or aspects of one or more steps of a disclosed method. For example, in an aspect, a method can be altered by changing the amount of a disclosed nucleic acid molecule, a disclosed vector, or a disclosed pharmaceutical formulation administered to a subject, or by changing the frequency of administration of a disclosed nucleic acid molecule, a disclosed vector, or a disclosed pharmaceutical formulation to a subject, or by changing the duration of time a disclosed nucleic acid molecule, a disclosed vector, or a disclosed pharmaceutical formulation is administered to a subject.

[0233] In an aspect, one or more disclosed nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations can be administered concurrently or sequentially.

[0234] In an aspect, a disclosed method can further comprise diagnosing a subject with a genetic defect using one or more known methods to the skilled person, such as, for example, genotyping.

[0235] In an aspect, one or more disclosed nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations do not elicit an immune response.

[0236] In an aspect, a disclosed vector can be delivered to the subject’s heart and / or skeletal muscle. In an aspect, a disclosed vector can be administered via intravenous, intraarterial, intramuscular, intraperitoneal, subcutaneous, intra-CSF, intrathecal, intraventricular, intrahepatic, hepatic intra-arterial, hepatic portal vein (HPV), intra-cardiac, or in utero administration. In an aspect, a disclosed vector can be administered via intra-CSF administration in combination with a disclosed nucleic acid molecule, a disclosed vector, and / or a disclosed pharmaceuticalformulation. In an aspect, a disclosed vector can be administered via intra-CSF administration in combination with RNAi, antisense oligonucleotides, miRNA, one or more small molecules, one or more therapeutic agents, one or more proteasome inhibitors, one or more immune modulators, and / or a gene editing system. In an aspect, a disclosed vector can be administered via LNP administration. In an aspect, a disclosed vector can be delivered to the subject’s liver, heart, skeletal muscle, smooth muscle, CNS, PNS, or a combination thereof. In an aspect, a disclosed vector can be concurrently and / or serially administered to a subject via multiple routes of administration.

[0237] In an aspect, a therapeutically effective amount of disclosed vector can be delivered via intravenous (IV) administration and can comprise a range of about 1 x IO10vg / kg to about 2 x 1014vg / kg. In an aspect, for example, a disclosed vector can be administered at a dose of about 1 x 1011to about 8 x 1013vg / kg or about 1 x 1012to about 8 x 1013vg / kg. In an aspect, a disclosed vector can be administered at a dose of about 1 x 1013to about 6 x 1013vg / kg. In an aspect, a disclosed vector can be administered at a dose of at least about 1 x IO10, at least about 5 x IO10, at least about 1 x 1011, at least about 5 x 1011, at least about 1 x 1012, at least about 5 x 1012, at least about 1 x 1013, at least about 5 x 1013, or at least about 1 x 1014vg / kg. In an aspect, a disclosed vector can be administered at a dose of no more than about 1 x IO10, no more than about 5 x IO10, no more than about 1 x 1011, no more than about 5 x 1011, no more than about 1 x 1012, no more than about 5 x 1012, no more than about 1 x 1013, no more than about 5 x 1013, or no more than about 1 x 1014vg / kg. In an aspect, a disclosed vector can be administered at a dose of about 1 x 1012vg / kg. In an aspect, a disclosed vector can be administered at a dose of about 1 x 1011vg / kg. In an aspect, a disclosed vector can be administered in a single dose, or in multiple doses (such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 doses) as needed for the desired therapeutic results.

[0238] In an aspect of a disclosed method, a disclosed nucleic acid molecule, a disclosed vector, or a disclosed pharmaceutical formulation can be encapsulated in lipid nanoparticles. In an aspect, lipid nanoparticles or LNPs can deliver nucleic acid (e.g., DNA or RNA), protein (e.g., RNA- guided DNA binding agent), or nucleic acid together with protein. LNPs can comprise biodegradable, ionizable lipids. For example, LNPs can comprise (9Z,12Z)-3-((4,4- bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl octadeca-9,12-di enoate, also called 3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3- (diethylamino)propoxy)carbonyl)oxy)methyl)propyl (9Z, 12Z)-octadeca-9, 12-di enoate) or another ionizable lipid. In an aspect, the term cationic and ionizable in the context of LNP lipids can be used interchangeably, e.g., wherein ionizable lipids are cationic depending on the pH.

[0239] In an aspect, a disclosed method can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, or anycombination thereof. In an aspect, a disclosed method can ensure persistent expression of a disclosed SLC in a cardiac cells and / or muscle cells and / or cardiac tissue and / or muscle tissues. In an aspect, a disclosed method can ensure persistent expression of a disclosed SLC protein. In an aspect, a disclosed method can ameliorate and / or mitigate the negative and / or deleterious effect that a SLC protein deficiency has on one or more organs in a subject including, for example, the heart and / or the muscle.

[0240] In an aspect, a disclosed method can be used to express a SLC protein that can restore one or more aspects of cellular homeostasis and / or cellular functionality. In an aspect, when expressed in a cell, a disclosed nucleic acid sequence can generate a SLC protein that can restore one or more aspects of cellular homeostasis and / or cellular functionality. In an aspect of a disclosed method, a disclosed restoration of one or more aspects of cellular homeostasis and / or cellular functionality can comprise (i) restoring myocyte bioenergetics in the subject; (ii) normalizing tissue biomarkers in the subject; (iii) normalizing mitochondrial copy number in the subject’s heart and / or skeletal muscle; (iv) improving and / or restoring of mitochondrial functionality and / or structural integrity; (v) improving and / or restoring of organelle functionality and / or structural integrity; (vi) improving mitochondrial ADT-ATP exchange; (vii) increasing ADP-stimulated tissue respirations rates, (viii) decreasing production of mitochondrial reactive oxygen species; or (ix) any combination thereof. In an aspect, the SLC protein can be SLC25A4. In an aspect, a disclosed method can be used to restore one or more aspects of cellular homeostasis and / or cellular functionality can comprise correction and / or mitigation of one or more presenting symptoms associated with one or more symptoms of a SLC deficiency. In an aspect of a disclosed method, the SLC protein can be SLC25A4.

[0241] In an aspect, a disclosed method can restore one or more aspects of the subject’s cardiac function and / or cardiac health. In an aspect, a disclosed method can (i) reverse cardiac remodeling in the subject; (ii) prevent cardiac remodeling in the subject; (iii) restore the cardiac dimensions to normal levels (i.e., the levels of a subject not having a disclosed SLC deficiency); (iv) improve the exercise capacity of the subject; (v) improve contractile mechanics; or (vi) any combination thereof. In an aspect, a disclosed SLC protein can (i) reverse cardiac remodeling in the subject; (ii) prevent cardiac remodeling in the subject; (iii) restore the cardiac dimensions of the subject to a normal level; (iv) improve the exercise capacity of the subject; (v) improve cardiac contractile mechanics of the subject; (vi) restore myocyte bioenergetics in the subject; (vii) decrease production of mitochondrial reactive oxygen species in the heart or skeletal muscle of the subject; (viii) restore myocyte bioenergetics in the subject; (ix) improve mitochondrial ADT-ATP exchange in the subject; (x) increase ADP-stimulated tissue respirations rates; (xi) correct and / or reversing hyperlactinemia and hyperalanemia; (xii) correct and / or normalize plasma biomarkerslactate and alanine; or (xiii) any combination thereof. In an aspect, the SLC protein can be SLC25A4. In an aspect, the SLC protein can be SLC25A4.

[0242] In an aspect, a disclosed method can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, the SLC protein can be SLC25A4. In an aspect, a disclosed method can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, can diminish and / or ameliorate one or more symptoms of a disease or condition caused by one or more loss of functions in a SLC gene (i.e., SLC2A4, SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, SLC25A20, or any combination thereof). In an aspect, the SLC protein can be SLC25A4.

[0243] In an aspect, a disclosed vector can be used to express a disclosed SLC protein that can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, that can increase and / or prolong a subject’s life span, that can diminish and / or ameliorate one or more symptoms of a disease or condition caused by one or more loss of functions in a SLC25A4 gene (e.g., c.523delC, c. H6_137del, c.707G>C, c.46_47del, c.l l l+lG>A, or c.423G>C, or any combination thereof). Representative mutations in SLC25A4 are listed in Table 3. In an aspect, the SLC protein can be SLC25A4.

[0244] In an aspect, a disclosed vector can be used to express a disclosed SLC protein that can improve and / or extend the survivability of the subject, that can improve a subject’s quality of life, that can increase and / or prolong a subject’s life span, that can diminish and / or ameliorate one or more symptoms of a disease or condition caused by one or more loss of functions in a SLC25A4 gene (e.g., c.523delC, c. H6_137del, c.707G>C, c.46_47del, c.l l l+lG>A, or c.423G>C, or any combination thereof). In an aspect, the SLC protein can be SLC25A4.

[0245] In an aspect of a disclosed method, a disclosed vector can be used to express a disclosed nucleic acid sequence can generate a SLC protein that can restore one or more aspects of cellular homeostasis and / or cellular functionality in one or more cells. In an aspect, a disclosed restoration of one or more aspects of cellular homeostasis and / or cellular functionality can comprise (i) restoring myocyte bioenergetics in the subject; (ii) normalizing tissue biomarkers in the subject; (iii) normalizing mitochondrial copy number in the subject’s heart and / or skeletal muscle; (iv) improving and / or restoring of mitochondrial functionality and / or structural integrity; (v) improving and / or restoring of organelle functionality and / or structural integrity; (vi) improving mitochondrial ADT-ATP exchange; (vii) increasing ADP-stimulated tissue respirations rates, (viii) decreasing production of mitochondrial reactive oxygen species; or (ix) any combination thereof. In an aspect, the SLC protein can be SLC25A4.

[0246] In an aspect, a disclosed method can be used to restore one or more aspects of cellular homeostasis and / or cellular functionality can comprise correction and / or mitigation of one or more presenting symptoms associated with one or more symptoms of a SLC deficiency. In an aspect, the SLC protein can be SLC25A4. In an aspect, a disclosed method can restore one or more aspects of the subject’s cardiac function and / or cardiac health. In an aspect, a disclosed SLC protein can (i) reverse cardiac remodeling in the subject; (ii) prevent cardiac remodeling in the subject; (iii) restore the cardiac dimensions to normal levels (i.e., the levels of a subject not having a disclosed SLC deficiency); (iv) improve the exercise capacity of the subject; (v) improve contractile mechanics; or (vi) any combination thereof. In an aspect, a disclosed SLC protein can (i) reverse cardiac remodeling in the subject; (ii) prevent cardiac remodeling in the subject; (iii) restore the cardiac dimensions of the subject to a normal level; (iv) improve the exercise capacity of the subject; (v) improve cardiac contractile mechanics of the subject; (vi) restore myocyte bioenergetics in the subject; (vii) decrease production of mitochondrial reactive oxygen species in the heart or skeletal muscle of the subject; (viii) restore myocyte bioenergetics in the subject; (ix) improve mitochondrial ADT-ATP exchange in the subject; (x) increase ADP-stimulated tissue respirations rates; (xi) correct and / or reversing hyperlactinemia and hyp eral anemia; (xii) correct and / or normalize plasma biomarkers lactate and alanine; or (xiii) any combination thereof. In an aspect, the SLC protein can be SLC25A4. In an aspect, the SLC protein can be SLC25A4.

[0247] In an aspect, a disclosed method can be used to improve one or more symptoms of a SLC protein deficiency can be subjective and / or objective. In an aspect, an improvement in one or more symptoms of an a SLC protein deficiency can improve a subject’s motor skills. In an aspect, an improvement in one or more symptoms of a SLC protein deficiency can improve a subject’s quality of life.Table 4 - Table of SequencesVII. EXAMPLES

[0248] Myocardial and skeletal muscle cells have a high energy demand and are thus dependent on oxidative energy generated through the mitochondrial oxidative phosphorylation (OXPHOS) system. In these bioenergetic cells, mitochondria have a critical role in cellular metabolism and can occupy up to 30% of the total volume of the cell. (Ramaccini D, et al. (2021) Front Cell DevBiol. 8:624216). With only thirteen of the approximately ninety OXPHOS subunits being encoded by mitochondrial DNA, mitochondria are dependent on additional nuclear-encoded proteins and assembly factors for OXPHOS function. (Chinnery PF, et al. (2013) Br Med Bull. 106(1): 135-159). Hence, nuclear DNA-encoded mitochondrial proteins that harbor mutations can impair OXPHOS and are thus linked to the development of skeletal myopathy, cardiomyopathy, and cardiac failure. (Strauss KA, et al. (2013) Proc Natl Acad Sci USA. 110(9):3453-3458; Ranjbarvaziri S, et al. (2021) Circulation. 144(21): 1714-1731; Olimpio C, et al. (2021) Neuromuscul Disord. 31(10):978-987; Guenthard J, et al. (1995) Arch Dis Child. 72(3):223-226; Nishizawa M, et al. (1987) J Neurolog Sci. 78(2): 189-201). Disorders associated with disruption of OXPHOS are typically devastating.

[0249] Solute carrier family 25, member 4 (SLC25A4,' also known as adenine nucleotide translocase 1 (ANTI)) is a gated pore that exchanges cytosolic ADP for mitochondrial ATP across the inner mitochondrial membrane of heart and skeletal muscle tissues. This exchange is necessary to supply substrate to complex V of the respiratory chain; functional SLC25A4 is thus a critical member of mitochondrial oxidative phosphorylation. Biallelic loss-of-function variants in SLC25A4 result in skeletal myopathy, hypertrophic cardiomyopathy, exercise intolerance, and lactic acidosis marked by proliferation of hypofunctional mitochondria in myocytes. An ancestral frameshift variant of SLC25A4 (c.523delC; p.Q175RfxX38) is relatively common among North American Mennonites and individuals homozygous for this variant exhibit cardiac dysfunction and progressive myocardial thickening that can culminate in end-stage heart failure necessitating transplantation.

[0250] SLC25A4 encodes the heart-muscle isoform of the adenine nucleotide translocator- 1 (historic nomenclature ANTI), which is an important member of mitochondrial metabolism. In the wild-type state, SLC25A4 acts as a solute carrier to exchange matrix ATP for cytosolic ADP, thus providing mitochondrial energy to the cytosol. The single base pair deletion in SLC25A4 prematurely terminates translation of the SLC25A4 protein, removing over a third of the polypeptide’s C-terminus that contains highly conserved amino acids critical to the formation of the solute channel. The absence of the functional solute channel thus results in dysfunctional OXPHOS and reduction of electron transport.

[0251] The Examples that follow are illustrative of specific embodiments of the invention, and various uses thereof. They set forth for explanatory purposes only and are not to be taken as limiting the invention.Example 1 Experimental Rationale

[0252] The Clinic for Special Children (CSC) was founded in 1989 to treat metabolic disorders among the Amish and Mennonite populations of Lancaster County, PA. Over the past thirty years, the CSC has evolved into a pediatric medical genetic clinic that treats and diagnoses genetic disorders of all types. The CSC characterized the pathophysiology and natural history of an inherited cardiomyopathy and generalized skeletal myopathy secondary to mitochondrial dysfunction. A 13 -generation Mennonite pedigree with autosomal recessive myopathy and hypertrophic cardiomyopathy due to a frameshift mutation in solute carrier family 25, member 4 (SLC25A4,- c.523delC, p.Q175RfsX38) was studied. (Strauss KA, et al. (2013) Proc Natl Acad Sci USA. 110(9):3453-3458).

[0253] Following identification of SLC25A4 deficiency among the CSC’s Mennonite patient cohort, we studied the clinical characteristics and natural history of the disorder over a period of eleven years. Affected individuals display exertional intolerance secondary to both a progressive cardiomyopathy as well as general skeletal myopathy. Among adults, even modest exertion (i.e., sweeping the floor) provokes weakness, dyspnea, and palpitations. Illnesses are often followed by protracted fatigue lasting several days. Due to the OXPHOS dysfunction, biochemical alterations including hyperalaninemia, lactic acidosis, and persistent adrenergic activation are also present. Insomnia and inattention are common among the patient cohort, and 75% of adult patients suffer from depression and anxiety. Electrocardiography and echocardiography reveal abnormal contractile mechanics, myocardial relaxation abnormalities, and impaired left ventricular relaxation. On exertion, cardiac systolic contraction time cannot be augmented, and cardiac output is not maintained. End-stage heart disease is characterized by massive, symmetric, concentric cardiac hypertrophy; widespread cardiomyocyte degeneration; overabundant and structurally abnormal mitochondria; extensive subendocardial interstitial fibrosis; and marked hypertrophy of arteriolar smooth muscle. (Strauss KA, et al. (2013) Proc Natl Acad Sci USA. 110(9):3453-3458). 20% of affected patients required heart transplantation for end-stage heart failure. While heart transplantation addresses the critical cardiac functional abnormalities of the end-stage heart disease, it does not provide a cure for the disorder, as the patients continue to suffer from exertional intolerance secondary to generalized skeletal myopathy; the systemic biochemical abnormalities persist as well.

[0254] In a Slc25a4 null murine model, Slc25a4 deficiency results in impaired mitochondrial ADP-ATP exchange as expected, markedly reduced ADP-stimulated tissue respiration rates, and increased production of mitochondrial reactive oxygen species (ROS). This reduction of mitochondrial ATP flux limits skeletal muscle sarcomere contraction and results in compensatoryproliferation of mitochondria. However, despite the increased number of mitochondria within cardiomyocytes, the myocardium continues to contract inefficiently. (Graham BH, et al. (1997) Nat Genet. 16(3):226-234; Esposito LA, et al. (1996). Proc Natl Acad Sci USA. 96(9):4820-4825). Longitudinal study of Slc25a4' / ' mice demonstrated progression of the hypertrophic cardiomyopathy to dilation and heart failure. (NarulaN, et al. (2011) JACC Cardiovasc Imaging. 4(1): 1-10). These data indicate that both reduced mitochondrial energy and increased mitochondrial oxidative stress are important factors in the pathophysiology of this mitochondrial disease.

[0255] AAV-mediated gene replacement therapy has emerged as a powerful strategy for the treatment of monogenic disease. Gene therapy is appealing as it targets the direct molecular cause of the disorder it’s aimed to treat. This therapeutic option relies on the delivery of nucleotide sequences directly to the target cells. The most direct type of gene therapy is gene replacement therapy, in which a wild-type gene is expressed by a promoter within a viral vector to replace gene function in the setting of a loss-of-function genetic variant. Four decades of research have shown that AAVs appear to be safe and effective delivery vectors to deliver genes of interest into a broad range of cell types. (Au HKE, et al. (2022). Front Med. 8:809118). Recombinant AAV (rAAV) lacks viral DNA and is a non-pathogenic protein-based nanoparticle engineered to traverse the cell membrane, where it can ultimately traffic and deliver its DNA cargo into the nucleus of the cell. Importantly, recombinant episomal DNA does not integrate into host genomes. The rAAV system can be engineered to have a relatively high affinity for muscle cells. There is also longterm expression of transgenes in post-mitotic cells, thus enhancing its attractiveness for treating myopathies. (Watchko J, et al. (2002) Hum Gene Ther. 13(12): 1451-1460; Pruchnic R, et al. (2000) Hum Gene Ther. 11 (4): 521 -536; Hamilton H, et al. (2004) J Virol. 78(15):7874-7882). In addition, rAAV has been a vector of choice for stable gene delivery to cardiomyocytes as they are relatively small in size, are non-pathogenic, and depending on design, can be effectively delivered to cardiomyocytes. (Vekstein AM, et al. (2022) Front Cardiovasc Med. 9:833335; Asokan A, et al. (2013) Hum Gene Ther. 24(11):906-913). As SLC25A4 deficiency is a progressive disorder, a disease-modifying treatment (such as the AAV therapy described herein) when delivered at any age of the patient is expected to delay disease progression and maintain quality of life.Example 2 Adeno-Associated Viral (AAV) Mediated Gene Replacement Therapy for SLC25A4 Deficiency

[0256] A Slc25a4 knockout mouse model (Slc25a4 nomenclature also includes “null mice” or “ANTI-KO” mice) was generated and characterized. By 14 weeks of age, Slc25a4mice have plasma alanine concentrations nearly two-fold higher than those of age-matched control mice (p = 0.022). Slc25a4 - / - mice develop a concentric dilated cardiomyopathy characterized byincreased cardiac mass, ventricular dilation, reduced contractile performance (p = 0.018), and fibrosis. Exercise tolerance is also significantly reduced by 4 months of age (p < 0.0001). Therefore, whether the replacement of SLC25 A4 activity through recombinant adeno-associated viral (rAAV) delivery could restore myocyte bioenergetics, prevent cardiac remodeling, and improve exercise capacity while normalizing tissue biomarkers and mitochondrial copy number was interrogated.

[0257] Here, a therapeutic vector (rAAV-SLC25A4) was synthesized to treat SLC25A4 deficiency. (FIG. 1A - FIG. IB). Specifically, Gonzalez et al. evolved two capsids with superior gene transfer efficiency in muscle and cardiomyocytes as compared to AAV9. (Gonzalez TJ, et al. (2022) Nat Comm. 13(1):5947). A cross-species evolved, liver de-targeted AAV capsid (AAV.cc84) was used for in vivo studies, while a cross-species evolved, cardiotropic AAV capsid (AAV.cc47) was used for in vitro studies. Several promoters were evaluated to determine which promoter resulted in robust expression of the SLC25A4 transgene; the cardiac / musculoskeletal promoter MHCK7 was determined to be the lead promoter based on in vivo expression of SLC25A4 in the heart and skeletal muscle (FIG. 4A - FIG. 4D) The final constructs employed were thus AAV.cc84 and AAV.cc47 packaging the SLC25A4 transgene under the control of a cardiac / musculoskeletal promoter (MHCK7). When delivered to human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and mouse myoblasts in vitro, rAAV-SLC25A4 vectors enabled robust expression of SLC25A4 protein, which localized appropriately to the inner mitochondrial membrane. (FIG. 2A - FIG. 2B). Additionally, a knock-in iPSC cell line carrying the c.523delC mutation was generated. In these patient-specific iPSC-CMs, transduction of rAAV-SLC25A4 also resulted in robust transgene expression and appropriate localization (FIG. 3).

[0258] Moreover, treatment of Slc25a4mice with a single systemic dose (5el3vg / kg) of rAAV-SLC25A4 (“null treated” or “ANT1-KO + rAAV-ANTl”) resulted in robust SLC25A4 protein expression in cardiac and skeletal muscle target tissues, and reduced biodistribution and expression in off-target organs, including the liver (FIG. 4A, FIG. 4C - FIG. 4D, FIG. 5A, FIG. 5C). To assess whether delivery of rAAV-SLC25A4 could treat SLC25A4 deficiency, Slc25a4 - / - mice were systemically treated at neonatal (preventative) and middle-age (rescue) timepoints. Efficacy of gene replacement was evaluated over a 6 to 12-month post-treatment period with serial echocardiography and exercise tolerance testing via a validated treadmill protocol. Neonatal rAAV-SLC25A4 treatment (with a dose of 2el4 vg / kg) improved survival (log-rank p = 0.024), preserved exercise capacity (p = 0.0020), and prevented cardiac remodeling in Slc25a4- / - mice (0.0032). (FIG. 6A - FIG. 6D). Treatment of mice at age 6 months (with a dose of 5el3 vg / kg)reversed cardiac remodeling and restored cardiac dimensions to wild-type levels (p < 0.0001).(FIG. 7 A - FIG. 7G)

[0259] In summary, described herein is the first example of a systemically injected liver- detargeted cardiomyotropic AAV construct that simultaneously treated both the cardiac and musculoskeletal phenotype of SLC25A4 deficiency. The AAV-mediated gene replacement strategy detailed herein with the specific optimized promoter and cassette combination represents a new, inventive, and effective therapeutic strategy to treat cardiac disease due to SLC25A4 deficiency.

Claims

VIII. CLAIMSWhat is claimed is:

1. A nucleic acid molecule, comprising: a nucleic acid sequence encoding a solute carrier (SLC) protein operably linked to a promoter.

2. The nucleic acid molecule of Claim 1, wherein the solute carrier (SLC) protein is SLC2A4,SLC4A3, SLC8A1, SLC16A1, SLC22A5, SLC25A1, SLC25A3, SLC25A4, or SLC25A20.

3. The nucleic acid molecule of Claim 1, wherein the SLC protein comprises the sequence of any one of SEQ ID NO:05 or SEQ ID NO:29 - SEQ ID NO:40 or a fragment or a portion thereof.

4. The nucleic acid molecule of Claim 1, wherein the SLC protein is SLC25A4.

5. The nucleic acid molecule of Claim 4, wherein the SLC25A4 comprises the sequence set forth in SEQ ID NO:03, SEQ ID NO:79, SEQ ID NO:80, or SEQ ID NO:

816. The nucleic acid molecule of any one of Claims 1 - 5 , wherein the promoter comprises aMHCK7 promoter, alternate MHCK7 promoter, a CK8 promoter, a muscle creatine kinase (MCK) promoter, a desmin (DES) promoter, a cardiac Troponin T (cTnT) promoter, a cardiac Troponin I (cTnl) promoter, an alpha myosin heavy chain (aMHC) promoter, or a SPc5-12 promoter.

7. The nucleic acid molecule of Claim 6, wherein the MHCK7 promoter comprises the sequence set forth in SEQ ID NO: 10.

8. A vector, comprising: the isolated nucleic acid molecule of any one of Claims 1 - 7.

9. The vector of Claim 8, wherein the vector is an adeno-associated virus (AAV) vector.

10. The vector of Claim 9, wherein the AAV vector comprises a capsid protein of SEQ ID NO:60 or SEQ ID NO:66.

11. The vector of any one of Claims 8 - 10, further comprising one or more regulatory elements.

12. The vector of Claim 11, wherein the one or more regulatory elements comprise a pair of inverted terminal repeats (ITRs).

13. A pharmaceutical formulation, comprising: the vector of any one of Claims 8 - 12 and one or more pharmaceutically acceptable carriers.

14. A method of treating and / or slowing and / or reversing disease progression, the method comprising: administering to a subject having a solute carrier (SLC) deficiency a therapeutically effective amount of the pharmaceutical formulation of Claim 13, wherein, following expression of nucleic acid sequence in the targeted cells or targeted tissues, the expression and / or activity level of the encoded SLC protein is increased.

15. The method of Claim 14, wherein the increased expression and / or activity level of the encodedSLC protein (i) reverses cardiac remodeling in the subject; (ii) prevents cardiac remodelingin the subject; (iii) restores the cardiac dimensions of the subject to a normal level; (iv) improves the exercise capacity of the subject; (v) improves cardiac contractile mechanics of the subject; (vi) restores myocyte bioenergetics in the subject; (vii) decreases production of mitochondrial reactive oxygen species in the heart or skeletal muscle of the subject; (viii) restores myocyte bioenergetics in the subject; (ix) improves mitochondrial ADT- ATP exchange in the subject; (x) increases ADP-stimulated tissue respirations rates; (xi) correcting and / or reversing hyperlactinemia and hyperalanemia; (xii) correcting and / or normalizing plasma biomarkers lactate and alanine; or (xiii) any combination thereof.

16. The method of Claim 14 or Claim 15, further comprising administering to the subject one or more additional therapeutic agents.

17. The method of Claim 16, wherein the additional therapeutic agents comprise (i) one or more beta blockers; (ii) one or more angiotensin II receptor antagonists; (iii) one or more calcium channel blockers; (iv) one or more vitamin-antioxidant therapy; or (v) any combination thereof.

18. The method of any one of Claims 14 - 17, further comprising repeating the administering of the pharmaceutical formulation.

19. The method of any one of Claims 14 - 18, further comprising administering to the subject one or more enzymes that degrade one or more neutralizing antibodies.

20. The method of Claim 18, wherein the one or more neutralizing antibodies are against the vector or the encoded SLC protein.

Images